bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from MYC Hyperactivates Wnt Signaling in APC/CTNNB1-Mutated Colorectal Cancer Cells through miR-92a–Dependent Repression of DKK3
Authors: Sehgal Priyanka , Lanauze Claudia , Wang Xin , Hayer Katharina E. , Torres-Diz Manuel , Leu N. Adrian , Sela Yogev , Stanger Ben Z. , Lengner Christopher J. , Thomas-Tikhonenko Andrei
Published: April 2023

Abstract
Activation of Wnt signaling is among the earliest events in colon cancer development. It is achieved either via activating mutations in the CTNNB1 gene encoding β-catenin, the key transcription factor in the Wnt pathway, or most commonly by inactivating mutations affecting APC, a major β-catenin binding partner and negative regulator. However, our analysis of recent Pan Cancer Atlas data revealed that CTNNB1 mutations significantly co-occur with those affecting Wnt receptor complex components (e.g., Frizzled and LRP6), underscoring the importance of additional regulatory events even in the presence of common APC/CTNNB1 mutations. In our effort to identify non-mutational hyperactivating events, we determined that KRAS-transformed murine colonocytes overexpressing direct β-catenin target MYC show significant upregulation of the Wnt signaling pathway and reduced expression of Dickkopf 3 (DKK3), a reported ligand for Wnt co-receptors. We demonstrate that MYC suppresses DKK3 transcription through one of miR-17-92 cluster miRNAs, miR-92a. We further examined the role of DKK3 by overexpression and knockdown and discovered that DKK3 suppresses Wnt signaling in Apc-null murine colonic organoids and human colon cancer cells despite the presence of downstream activating mutations in the Wnt pathway. Conversely, MYC overexpression in the same cell lines resulted in hyperactive Wnt signaling, acquisition of epithelial-to-mesenchymal transition markers, and enhanced migration/invasion in vitro and metastasis in a syngeneic orthotopic mouse colon cancer model.
Implications:
Our results suggest that the MYC→miR-92a-|DKK3 axis hyperactivates Wnt signaling, forming a feed-forward oncogenic loop.
Data from Epstein-Barr Virus Induces Lymphangiogenesis and Lympth Node Metastasis via Upregulation of VEGF-C in Nasopharyngeal Carcinoma
Authors: Li Deng-Ke , Chen Xing-Rui , Wang Li-Na , Wang Jia-Hong , Wen Yue-Ting , Zhou Zi-Ying , Li Ji-Ke , Liu Jing-Xian , Cai Lin-Bo , Zhong Shui-Sheng , Lyu Xiao-Ming , Damola Faleti Oluwasijibomi , Li Min-Ying , Zhang Jing-Jing , Zeng Yu-Mei , Wang Qian-Li , Zhang Qian-Bing , Lyu Hao , Fu Xiao-Yan , Wang Wei , Li Xin , Huang Zhong-Xi , Yao Kai-Tai
Published: April 2023

Abstract
Lymphatic metastasis is a common clinical symptom in nasopharyngeal carcinoma (NPC), the most common Epstein-Barr virus (EBV)-associated head and neck malignancy. However, the effect of EBV on NPC lymph node (LN) metastasis is still unclear. In this study, we demonstrated that EBV infection is strongly associated with advanced clinical N stage and lymphangiogenesis of NPC. We found that NPC cells infected with EBV promote LN metastasis by inducing cancer-associated lymphangiogenesis, whereas these changes were abolished upon clearance of EBV genomes. Mechanistically, EBV-induced VEGF-C contributed to lymphangiogenesis and LN metastasis, and PHLPP1, a target of miR-BART15, partially contributed to AKT/HIF1a hyperactivity and subsequent VEGF-C transcriptional activation. In addition, administration of anti-VEGF-C antibody or HIF1α inhibitors attenuated the lymphangiogenesis and LN metastasis induced by EBV. Finally, we verified the clinical significance of this prometastatic EBV/VEGF-C axis by determining the expression of PHLPP1, AKT, HIF1a, and VEGF-C in NPC specimens with and without EBV. These results uncover a reasonable mechanism for the EBV-modulated LN metastasis microenvironment in NPC, indicating that EBV is a potential therapeutic target for NPC with lymphatic metastasis.
Implications:
This research demonstrates that EBV induces lymphangiogenesis in NPC by regulating PHLPP1/p-AKT/HIF1a/VEGF-C, providing a new therapeutic target for NPC with lymphatic metastasis.
Data from Aggressive B-cell Lymphoma with MYC/TP53 Dual Alterations Displays Distinct Clinicopathobiological Features and Response to Novel Targeted Agents
Authors: Deng Manman , Xu-Monette Zijun Y. , Pham Lan V. , Wang Xudong , Tzankov Alexandar , Fang Xiaosheng , Zhu Feng , Visco Carlo , Bhagat Govind , Dybkaer Karen , Chiu April , Tam Wayne , Zu Youli , Hsi Eric D. , You Hua , Huh Jooryung , Ponzoni Maurilio , Ferreri Andrés J.M. , Møller Michael B. , Parsons Benjamin M. , Hagemeister Fredrick , van Krieken J. Han , Piris Miguel A. , Winter Jane N. , Li Yong , Xu Bing , Liu Phillip , Young Ken H.
Published: April 2023

Abstract
Diffuse large B-cell lymphoma (DLBCL) is the major type of aggressive B-cell lymphoma. High-grade B-cell lymphoma (HGBCL) with MYC/BCL2 double-hit (DH) represents a distinct entity with dismal prognosis after standard immunochemotherapy in the current WHO lymphoma classification. However, whether TP53 mutation synergizes with MYC abnormalities (MYC rearrangement and/or Myc protein overexpression) contributing to HGBCL-like biology and prognosis is not well investigated. In this study, patients with DLBCL with MYC/TP53 abnormalities demonstrated poor clinical outcome, high-grade morphology, and distinct gene expression signatures. To identify more effective therapies for this distinctive DLBCL subset, novel MYC/TP53/BCL-2–targeted agents were investigated in DLBCL cells with MYC/TP53 dual alterations or HGBCL-MYC/BCL2-DH. A BET inhibitor INCB057643 effectively inhibited cell viability and induced apoptosis in DLBCL/HGBCL cells regardless of MYC/BCL2/TP53 status. Combining INCB057643 with a MDM2-p53 inhibitor DS3032b significantly enhanced the cytotoxic effects in HGBCL-DH without TP53 mutation, while combining with the BCL-2 inhibitor venetoclax displayed potent therapeutic synergy in DLBCL/HGBCL cells with and without concurrent TP53 mutation. Reverse-phase protein arrays revealed the synergistic molecular actions by INCB057643, DS3032b and venetoclax to induce cell-cycle arrest and apoptosis and to inhibit AKT/MEK/ERK/mTOR pathways, as well as potential drug resistance mechanisms mediated by upregulation of Mcl-1 and RAS/RAF/MEK/ERK pathways. In summary, these findings support subclassification of DLBCL/HGBCL with dual MYC/TP53 alterations, which demonstrates distinct pathobiologic features and dismal survival with standard therapy, therefore requiring additional targeted therapies.
Implications:
The clinical and pharmacologic studies suggest recognizing DLBCL with concomitant TP53 mutation and MYC abnormalities as a distinctive entity necessary for precision oncology practice.
Visual Overview:
http://mcr.aacrjournals.org/content/molcanres/19/2/249/F1.large.jpg.
Data from O-GlcNAc Transferase – An Auxiliary Factor or a Full-blown Oncogene?
Authors: Itkonen Harri M. , Loda Massimo , Mills Ian G.
Published: April 2023

Abstract
The β-linked N-acetyl-d-glucosamine (GlcNAc) is a posttranslational modification of serine and threonine residues catalyzed by the enzyme O-GlcNAc transferase (OGT). Increased OGT expression is a feature of most human cancers and inhibition of OGT decreases cancer cell proliferation. Antiproliferative effects are attributed to posttranslational modifications of known regulators of cancer cell proliferation, such as MYC, FOXM1, and EZH2. In general, OGT amplifies cell-specific phenotype, for example, OGT overexpression enhances reprogramming efficiency of mouse embryonic fibroblasts into stem cells. Genome-wide screens suggest that certain cancers are particularly dependent on OGT, and understanding these addictions is important when considering OGT as a target for cancer therapy. The O-GlcNAc modification is involved in most cellular processes, which raises concerns of on-target undesirable effects of OGT-targeting therapy. Yet, emerging evidence suggest that, much like proteasome inhibitors, specific compounds targeting OGT elicit selective antiproliferative effects in cancer cells, and can prime malignant cells to other treatments. It is, therefore, essential to gain mechanistic insights on substrate specificity for OGT, develop reagents to more specifically enrich for O-GlcNAc–modified proteins, identify O-GlcNAc “readers,” and develop OGT small-molecule inhibitors. Here, we review the relevance of OGT in cancer progression and the potential targeting of this metabolic enzyme as a putative oncogene.
Data from Cross-talk between YAP and RAR-RXR Drives Expression of Stemness Genes to Promote 5-FU Resistance and Self-Renewal in Colorectal Cancer Cells
Authors: Bauzone Marjolaine , Souidi Mouloud , Dessein Anne-Frédérique , Wisztorski Maxence , Vincent Audrey , Gimeno Jean-Pascal , Monté Didier , Van Seuningen Isabelle , Gespach Christian , Huet Guillemette
Published: April 2023

Abstract
The mechanisms whereby the Hippo pathway effector YAP regulates cancer cell stemness, plasticity, and chemoresistance are not fully understood. We previously showed that in 5-fluorouracil (5-FU)–resistant colorectal cancer cells, the transcriptional coactivator YAP is differentially regulated at critical transitions connected with reversible quiescence/dormancy to promote metastasis. Here, we found that experimental YAP activation in 5-FU–sensitive and 5-FU–resistant HT29 colorectal cancer cells enhanced nuclear YAP localization and the transcript levels of the retinoic acid (RA) receptors RARα/γ and RAR target genes CYP26A1, ALDH1A3, and LGR5 through RA Response Elements (RARE). In these two cell models, constitutive YAP activation reinforced the expression of the stemness biomarkers and regulators ALDH1A3, LGR5, and OCT4. Conversely, YAP silencing, RAR/RXR inhibition by the pan-RAR antagonist BMS493, and vitamin A depletion downregulated stemness traits and self-renewal. Regarding the mechanisms engaged, proximity-dependent labeling, nuclear YAP pulldown coupled with mass spectrometry, and chromatin immunoprecipitation (ChIP)/re-ChIP experiments revealed: (i) the nuclear colocalization/interaction of YAP with RARγ and RXRs; and (ii) combined genomic co-occupancy of YAP, RARα/γ, and RXRα interactomes at proximal RAREs of LGR5 and ALDH1A3 promoters. Moreover, activation of the YAP/RAR-RXR cross-talk in colorectal cancer cells promoted RAR self-activation loops via vitamin A metabolism, RA, and active RAR ligands generated by ALDH1A3. Together, our data identify YAP as a bona fide RAR-RXR transcriptional coactivator that acts through RARE-activated stemness genes.
Implications:
Targeting the newly identified YAP/RAR-RXR cross-talk implicated in cancer cell stemness maintenance may lead to multitarget combination therapies for patients with colorectal cancer.
Data from Demethylation of the SFRP4 Promoter Drives Gastric Cancer Progression via the Wnt Pathway
Authors: Li Haojie , Zhao Junjie , Sun Jie , Tian Chenyu , Jiang Quan , Ding Chen , Gan Qiangjun , Shu Ping , Wang Xuefei , Qin Jing , Sun Yihong
Published: April 2023

Abstract
Wnt signaling is believed to be an important contributor to tumor development and has been reported to be modulated by secreted frizzled-related proteins (SFRP). Nevertheless, the role of secreted frizzled-related protein 4 (SFRP4) in tumorigenesis remains controversial. We aim to explore its biological function in gastric cancer. Genomes analysis based on the Gene Expression Omnibus (GEO) dataset was used to find the differential gene expression between different tumor–node–metastasis (TNM) stages of gastric cancer. IHC was used to determine the relationship between SFRP4 expression and clinicopathologic characteristics in patients with gastric cancer. The influence of SFRP4 on tumor progression was evaluated by CCK-8, colony formation, cell apoptosis, and cell cycle in vitro, as well as xenograft model in vivo. The methylation status of SFRPs was examined in gastric cancer specimens by quantitative methylation analysis. SFRP4 was most upregulated in advanced gastric cancer. High intratumoral SFRP4 expression, which was associated with tumor invasion and metastasis, was also a poor prognostic indicator for patients with gastric cancer. In vitro and in vivo studies revealed that SFRP4 could promote tumor growth; however, IWR-1 could suppress tumor growth mediated by SFRP4 overexpression. Mechanistic exploration found that SFRP4 was overexpressed by the decrease of promoter methylation and thus could competitively antagonize the inhibitory effect of SFRP1 on Wnt pathway activation and tumor progression in gastric cancer.
Implications:
In gastric cancer, the expression of SFRP4 was upregulated by decreased methylation. High intratumoral SFRP4 expression could activate the Wnt pathway to promote tumor progression and predict poor survival of patients with gastric cancer.
Data from Mutations in Noncoding Cis-Regulatory Elements Reveal Cancer Driver Cistromes in Luminal Breast Cancer
Authors: El Ghamrasni Samah , Quevedo Rene , Hawley James , Mazrooei Parisa , Hanna Youstina , Cirlan Iulia , Zhu Helen , Bruce Jeff P. , Oldfield Leslie E. , Yang S.Y. Cindy , Guilhamon Paul , Reimand Jüri , Cescon Dave W. , Done Susan J. , Lupien Mathieu , Pugh Trevor J.
Published: April 2023

Abstract
Whole-genome sequencing of primary breast tumors enabled the identification of cancer driver genes and noncoding cancer driver plexuses from somatic mutations. However, differentiating driver from passenger events among noncoding genetic variants remains a challenge. Herein, we reveal cancer-driver cis-regulatory elements linked to transcription factors previously shown to be involved in development of luminal breast cancers by defining a tumor-enriched catalogue of approximately 100,000 unique cis-regulatory elements from 26 primary luminal estrogen receptor (ER)+ progesterone receptor (PR)+ breast tumors. Integrating this catalog with somatic mutations from 350 publicly available breast tumor whole genomes, we uncovered cancer driver cistromes, defined as the sum of binding sites for a transcription factor, for ten transcription factors in luminal breast cancer such as FOXA1 and ER, nine of which are essential for growth in breast cancer with four exclusive to the luminal subtype. Collectively, we present a strategy to find cancer driver cistromes relying on quantifying the enrichment of noncoding mutations over cis-regulatory elements concatenated into a functional unit.
Implications:
Mapping the accessible chromatin of luminal breast cancer led to discovery of an accumulation of mutations within cistromes of transcription factors essential to luminal breast cancer. This demonstrates coopting of regulatory networks to drive cancer and provides a framework to derive insight into the noncoding space of cancer.
Data from PCBP2 Posttranscriptional Modifications Induce Breast Cancer Progression via Upregulation of UFD1 and NT5E
Authors: Wang Xiaonan , Guo Qianying , Wang Hao , Yuan Xiaodong , Wang Bijun , Lobie Peter E. , Zhu Tao , Tan Sheng , Wu Zhengsheng
Published: April 2023

Abstract
It is commonly accepted that cellular protein levels are primarily determined by mRNA levels. However, discordance between protein and mRNA expression has been implicated in many pathologic conditions including oncogenesis. The mechanisms involved in this discordance are complicated and far from understood. In this study, it was observed that the expression levels of poly(C) binding protein 2 (PCBP2) mRNA and protein were diametric in breast normal and cancer cell lines, paraffin-embedded and fresh tissue specimens, consistent with data from The Cancer Genome Atlas and the Clinical Proteomic Tumor Analysis Consortium. Moreover, PCBP2 protein expression was significantly associated with disease progression and poor outcome in patients with breast cancer. Depletion of PCBP2 protein inhibited cell proliferation, colony formation, migration, invasion, and in vivo tumor growth and metastasis. Forced expression of PCBP2 exhibited the opposite effect. Mechanistically, it was demonstrated that PCBP2 3′ untranslated region (3′UTR) was subject to alternative splicing and polyadenylation (APA) in breast cancer tissues and cell lines. Non-full-length 3′UTR PCBP2 transcripts yielded more protein than the full-length 3′UTR transcripts and enhanced the oncogenic and metastatic capacities of human breast cancer cells. Furthermore, UFD1 and NT5E were identified as genes downstream of PCBP2. PCBP2 promoted oncogenicity of breast cancer cells via upregulation of the expression of UFD1 and NT5E by direct binding to their 3′UTR-B portions.
Implications:
Findings demonstrate that APA of PCBP2 3′UTR contributes to its increased expression with subsequent promotion of breast cancer progression by regulating UFD1 and NT5E.
Visual Overview:
http://mcr.aacrjournals.org/content/molcanres/19/1/86/F1.large.jpg.
Data from CHK2 Inhibition Provides a Strategy to Suppress Hematologic Toxicity from PARP Inhibitors
Authors: Xu Zhen , Vandenberg Cassandra J. , Lieschke Elizabeth , Di Rago Ladina , Scott Clare L. , Majewski Ian J.
Published: April 2023

Abstract
Patients with cancer treated with PARP inhibitors (PARPi) experience various side effects, with hematologic toxicity being most common. Short-term treatment of mice with olaparib resulted in depletion of reticulocytes, B-cell progenitors, and immature thymocytes, whereas longer treatment induced broader myelosuppression. We performed a CRISPR/Cas9 screen that targeted DNA repair genes in Eμ-Myc pre-B lymphoma cell lines as a way to identify strategies to suppress hematologic toxicity from PARPi. The screen revealed that single-guide RNAs targeting the serine/threonine kinase checkpoint kinase 2 (CHK2) were enriched following olaparib treatment. Genetic or pharmacologic inhibition of CHK2-blunted PARPi response in lymphoid and myeloid cell lines, and in primary murine pre-B/pro-B cells. Using a Cas9 base editor, we found that blocking CHK2-mediated phosphorylation of p53 also impaired olaparib response. Our results identify the p53 pathway as a major determinant of the acute response to PARPi in normal blood cells and demonstrate that targeting CHK2 can short circuit this response. Cotreatment with a CHK2 inhibitor did not antagonize olaparib response in ovarian cancer cell lines. Selective inhibition of CHK2 may spare blood cells from the toxic influence of PARPi and broaden the utility of these drugs.
Implications:
We reveal that genetic or pharmacologic inhibition of CHK2 may offer a way to alleviate the toxic influence of PARPi in the hematologic system.
Data from Bidirectional Regulatory Cross-Talk between Cell Context and Genomic Aberrations Shapes Breast Tumorigenesis
Authors: Kumar Brijesh , Bhat-Nakshatri Poornima , Maguire Calli , Jacobsen Max , Temm Constance J. , Sandusky George , Nakshatri Harikrishna
Published: April 2023

Abstract
Breast cancers are classified into five intrinsic subtypes and 10 integrative clusters based on gene expression patterns and genomic aberrations, respectively. Although the cell-of-origin, adaptive plasticity, and genomic aberrations shape dynamic transcriptomic landscape during cancer progression, how interplay between these three core elements governs obligatory steps for a productive cancer progression is unknown. Here, we used genetic ancestry-mapped immortalized breast epithelial cell lines generated from breast biopsies of healthy women that share gene expression profiles of luminal A, normal-like, and basal-like intrinsic subtypes of breast cancers and breast cancer relevant oncogenes to develop breast cancer progression model. Using flow cytometry, mammosphere growth, signaling pathway, DNA damage response, and in vivo tumorigenicity assays, we provide evidence that establishes cell context–dependent effects of oncogenes in conferring plasticity, self-renewal/differentiation, intratumor heterogeneity, and metastatic properties. In contrast, oncogenic aberrations, independent of cell context, shaped response to DNA damage-inducing agents. Collectively, this study reveals how the same set of genomic aberration can have distinct effects on tumor characteristics based on cell-of-origin of tumor and highlights the need to utilize multiple “normal” epithelial cell types to decipher oncogenic properties of a gene of interest. In addition, by creating multiple isogenic cell lines ranging from primary cells to metastatic variants, we provide resources to elucidate cell-intrinsic properties and cell-oncogene interactions at various stages of cancer progression.
Implications:
Our findings demonstrate that how an interplay between the normal cell type that encountered genomic aberrations and type of genomic aberration influences heterogeneity, self-renewal/differentiation, and tumor properties including propensity for metastasis.
Data from Nestin Is Required for Spindle Assembly and Cell-Cycle Progression in Glioblastoma Cells
Authors: Wang Qinglin , Wu Hao , Hu Jian , Fu Haijuan , Qu Yanghui , Yang Yijun , Cai Kathy Q. , Efimov Andrey , Wu Minghua , Yen Tim , Wang Yuan , Yang Zeng-Jie
Published: April 2023

Abstract
Nestin, a class IV intermediate filament protein, is generally considered as a putative marker of neural stem and progenitor cells in the central nervous system. Glioma is a common type of adult brain tumors, and glioblastoma (GBM) represents the most aggressive form of glioma. Here, we report that Nestin expression is significantly upregulated in human GBM, compared with other types of glioma. Nestin knockdown or deletion in U251 cells and tumor cells from GBM patients derived xenografts resulted in G2–M arrest, finally leading to apoptosis in tumor cells. Using proximity-dependent biotin identification method, we identified βII-tubulin as an interacting protein of Nestin in U251 cells. Nestin stabilized βII-tubulin in U251 cells through physical interaction. Knockdown of Nestin or βII-tubulin disrupted spindle morphology in tumor cells. Our studies further revealed that Nestin deficiency in U251 cells and GBM PDX cells repressed tumor growth upon transplantation. Finally, we found that Nestin deficiency sensitized GBM cells to microtubule-destabilizing drugs such as vinblastine and vincristine. Our studies demonstrate the essential functions and underlying mechanisms of Nestin in the growth and drug response of GBM cells.
Implications:
Through interaction with βII-tubulin, Nestin facilitates cell-cycle progression and spindle assembly of tumor cells in glioblastoma.
Data from Caspase 9b Drives Cellular Transformation, Lung Inflammation, and Lung Tumorigenesis
Authors: Kim Minjung , Vu Ngoc T. , Wang Xue , Bulut Gamze B. , Wang Min-Hsuan , Uram-Tuculescu Cora , Pillappa Raghavendra , Kim Sungjune , Chalfant Charles E.
Published: April 2023

Abstract
Caspase 9 undergoes alternative splicing to produce two opposing isoforms: proapoptotic Caspase 9a and pro-survival Caspase 9b (C9b). Previously, our laboratory reported that C9b is expressed in majority of non–small cell lung cancer tumors and directly activates the NF-κB pathway. In this study, the role of C9b in activation of the NF-κB pathway in vivo, lung inflammation and immune responses, and lung tumorigenesis were examined. Specifically, a transgenic mouse model expressing human C9b in the lung pneumocytes developed inflammatory lung lesions, which correlated with enhanced activation of the NF-κB pathway and increased influx of immunosuppressive myeloid-derived suppressor cells in contrast to wild-type mice. C9b mice presented with facial dermatitis, a thickened and disorganized dermis, enhanced collagen depth, and increased serum levels of IL6. C9b mice also developed spontaneous lung tumors, and C9b cooperated with oncogenic KRAS in lung tumorigenesis. C9b expression also cooperated with oncogenic KRAS and p53 downregulation to drive the full cell transformation of human bronchial epithelial cells (e.g., tumor formation).
Implications:
Our findings show that C9b can directly activate NF-κB pathway in vivo to modulate lung inflammation, immune cell influx, and peripheral immune responses, which demonstrates that C9b is key factor in driving cell transformation and lung tumorigenesis.
Data from Liver Endothelium Promotes HER3-Mediated Cell Survival in Colorectal Cancer with Wild-Type and Mutant KRAS
Authors: Rathore Moeez , Zhang Wei , Wright Michel'le , Bhattacharya Rajat , Fan Fan , Vaziri-Gohar Ali , Winter Jordan , Wang Zhenghe , Markowitz Sanford D. , Willis Joseph , Ellis Lee M. , Wang Rui
Published: April 2023

Abstract
We previously identified that human epidermal growth factor receptor 3 (HER3, also known as ERBB3) is a key mediator in liver endothelial cell (EC) promoting colorectal cancer growth and chemoresistance, and suggested HER3-targeted therapy as a strategy for treating patients with metastatic colorectal cancer in the liver. Meanwhile, KRAS mutations occur in 40%–50% of metastatic colorectal cancer and render colorectal cancer resistant to therapies targeting the other HER family protein epidermal growth factor receptor (EGFR). It is necessary to elucidate the roles of KRAS mutation status in HER3-mediated cell survival and colorectal cancer response to HER3 inhibition. In the present study, we used primary ECs isolated from non-neoplastic liver tissues to recapitulate the liver EC microenvironment. We demonstrated that liver EC-secreted factors activated colorectal cancer-associated HER3, and increased colorectal cancer cell survival in vitro and promoted colorectal cancer patient-derived xenograft tumor growth in vivo. Moreover, we determined that blocking HER3, either by siRNA knockdown or the humanized antibody seribantumab, blocked EC-induced colorectal cancer survival in vitro in both KRAS wild-type and mutant colorectal cancer cells, and the HER3 antibody seribantumab significantly decreased colorectal cancer tumor growth and sensitized tumors to chemotherapy in an orthotopic xenograft model with colorectal cancer tumors developed in the liver. In summary, our findings demonstrated that blocking HER3 had significant effects on attenuating liver EC-induced colorectal cancer cell survival independent of the KRAS mutation status.
Implications:
This body of work highlighted a potential strategy of using HER3 antibodies in combination with standard chemotherapy agents for treating patients with either KRAS wild-type or KRAS mutant metastatic colorectal cancer.
Data from VPRBP Functions Downstream of the Androgen Receptor and OGT to Restrict p53 Activation in Prostate Cancer
Authors: Poulose Ninu , Forsythe Nicholas , Polonski Adam , Gregg Gemma , Maguire Sarah , Fuchs Marc , Minner Sarah , Sauter Guido , McDade Simon S. , Mills Ian G.
Published: April 2023

Abstract
Androgen receptor (AR) is a major driver of prostate cancer initiation and progression. O-GlcNAc transferase (OGT), the enzyme that catalyzes the covalent addition of UDP-N-acetylglucosamine (UDP-GlcNAc) to serine and threonine residues of proteins, is often highly expressed in prostate cancer with its expression correlated with high Gleason score. In this study, we have identified an AR and OGT coregulated factor, Vpr (HIV-1) binding protein (VPRBP) also known as DDB1 and CUL4 Associated Factor 1 (DCAF1). We show that VPRBP is regulated by the AR at the transcript level, and stabilized by OGT at the protein level. VPRBP knockdown in prostate cancer cells led to a significant decrease in cell proliferation, p53 stabilization, nucleolar fragmentation, and increased p53 recruitment to the chromatin. In human prostate tumor samples, VPRBP protein overexpression correlated with AR amplification, OGT overexpression, a shorter time to postoperative biochemical progression and poor clinical outcome. In clinical transcriptomic data, VPRBP expression was positively correlated with the AR and also with AR activity gene signatures.
Implications:
In conclusion, we have shown that VPRBP/DCAF1 promotes prostate cancer cell proliferation by restraining p53 activation under the influence of the AR and OGT.
Data from TWEAK–Fn14–RelB Signaling Cascade Promotes Stem Cell–like Features that Contribute to Post-Chemotherapy Ovarian Cancer Relapse
Authors: Holmberg Ryne , Robinson Mikella , Gilbert Samuel F. , Lujano-Olazaba Omar , Waters Jennifer A. , Kogan Emily , Velasquez Candyd Lace R. , Stevenson Denay , Cruz Luisjesus S. , Alexander Logan J. , Lara Jacqueline , Mu Emily M. , Camillo Jared Rafael , Bitler Benjamin G. , Huxford Tom , House Carrie D.
Published: April 2023

Abstract
Disease recurrence in high-grade serous ovarian cancer may be due to cancer stem–like cells (CSC) that are resistant to chemotherapy and capable of reestablishing heterogeneous tumors. The alternative NF-κB signaling pathway is implicated in this process; however, the mechanism is unknown. Here we show that TNF-like weak inducer of apoptosis (TWEAK) and its receptor, Fn14, are strong inducers of alternative NF-κB signaling and are enriched in ovarian tumors following chemotherapy treatment. We further show that TWEAK enhances spheroid formation ability, asymmetric division capacity, and expression of SOX2 and epithelial-to-mesenchymal transition genes VIM and ZEB1 in ovarian cancer cells, phenotypes that are enhanced when TWEAK is combined with carboplatin. Moreover, TWEAK in combination with chemotherapy induces expression of the CSC marker CD117 in CD117− cells. Blocking the TWEAK–Fn14–RelB signaling cascade with a small-molecule inhibitor of Fn14 prolongs survival following carboplatin chemotherapy in a mouse model of ovarian cancer. These data provide new insights into ovarian cancer CSC biology and highlight a signaling axis that should be explored for therapeutic development.
Implications:
This study identifies a unique mechanism for the induction of ovarian cancer stem cells that may serve as a novel therapeutic target for preventing relapse.
Data from Origins and Timing of Emerging Lesions in Advanced Renal Cell Carcinoma
Authors: Wallace Andrew , Porten Sima P. , Lo Amy A. , Oreper Daniel , Lounsbury Nicolas , Havnar Charles , Pechuan-Jorge Ximo , Zill Oliver A. , Meng Maxwell V.
Published: April 2023

Abstract
Renal cell carcinoma (RCC) with venous tumor thrombus (VTT) arising from the primary tumor occurs in approximately 10% of cases and is thought to represent more advanced disease. The intravascular nature of VTT suggests that it may serve as a source for hematogenous metastases. RCC with VTT and distant metastasis provides unique opportunities to examine the origins and emergence timing of these distinct tumor lesions, and to identify molecular correlates with disease state. We performed multi-region exome and RNA-sequencing analysis of 16 patients with RCC with VTT, with eight patients also having sequenced metastasis, to identify genomic alterations, biological pathways, and evolutionary processes contributing to VTT and metastasis, and to ask whether metastasis arises directly from or independent of VTT. No specific genomic alterations were associated with VTT. Hallmark copy-number alterations (deletions of 14q, 8p, and 4q) were associated with metastasis and disease recurrence, and secondary driver alterations tended to accumulate in metastatic lineages. Mismatch repair mutational signatures co-occurred across most tumors, suggesting a role for intracellular DNA damage in RCC. Robust phylogenetic timing analysis indicated that metastasis typically emerged before VTT, rather than deriving from it, with the earliest metastases predicted to emerge years before diagnosis. As a result, VTT in metastatic cases frequently derived from a metastatic lineage. Relative to the primary tumor, VTT upregulated immediate-early genes and transcriptional targets of the TNFα/NF-κB pathway, whereas metastases upregulated MTOR and transcriptional targets downstream of mTORC1 activation.
Implications:
These results suggest that VTT and metastasis formation occur independently, VTT presence alone does not necessarily imply more advanced disease with inevitably poor prognosis.
Data from Uveal Melanoma Exosomes Induce a Prometastatic Microenvironment through Macrophage Migration Inhibitory Factor
Authors: Ambrosini Grazia , Rai Alex J. , Carvajal Richard D. , Schwartz Gary K.
Published: April 2023

Abstract
Uveal melanoma is a rare melanoma subtype different from cutaneous melanoma, with high incidence of liver metastasis and poor prognosis. Cancer cell–derived extracellular vesicles have been shown to induce proinflammatory and prometastatic signaling in the tumor microenvironment and at distant sites. The characterization of uveal melanoma exosome cargo and its role in metastatic spread is essential to identify targets and intervene in the early stages of metastatic development. Our study characterizes the proteomic content of uveal melanoma exosomes and identified the presence of markers with metastatic properties. We demonstrated that uveal melanoma exosomes induce activation of cell signaling pathways and the release of cytokines and growth factors from hepatocytes. These exosome-stimulated liver cells could in turn induce migration of uveal melanoma cells, confirming that the exosomes have a functional role in the cross-talk between these two cell types. We found that the proinflammatory cytokine macrophage migration inhibitory factor (MIF) was a major player in these mechanisms and its blockade inhibited cell migration in coculture with exosome-stimulated hepatocytes and prevented the development of metastases in vivo. Targeting MIF in the early stages of metastasis may represent a novel adjuvant drug therapy to prevent metastatic spread in uveal melanoma.
Implications:
This study provides the first in vivo evidence that MIF inhibition may serve as a novel adjuvant drug therapy to prevent metastasis in uveal melanoma.
Data from Epigenetic Regulation of Fanconi Anemia Genes Implicates PRMT5 Blockage as a Strategy for Tumor Chemosensitization
Authors: Du Changzheng , Li Steven W. , Singh Simranjit X. , Roso Kristen , Sun Michael A. , Pirozzi Christopher J. , Yang Rui , Li Jian-Liang , He Yiping
Published: April 2023

Abstract
Strengthened DNA repair pathways in tumor cells contribute to the development of resistance to DNA-damaging agents. Consequently, targeting proteins in these pathways is a promising strategy for tumor chemosensitization. Here, we show that the expression of a subset of Fanconi anemia (FA) genes is attenuated in glioblastoma tumor cells deficient in methylthioadenosine phosphorylase (MTAP), a common genetic alteration in a variety of cancers. Subsequent experiments in cell line models of different cancer types illustrate that this reduced transcription of FA genes can be recapitulated by blockage of Protein Arginine Methyltransferase 5 (PRMT5), a promising therapeutically targetable epigenetic regulator whose enzymatic activity is compromised in MTAP-deficient cells. Further analyses provide evidence to support that PRMT5 can function as an epigenetic regulator that contributes to the increased expression of FA genes in cancer cells. Most notably and consistent with the essential roles of FA proteins in resolving DNA damage elicited by interstrand crosslinking (ICL) agents, PRMT5 blockage, as well as MTAP loss, sensitizes tumor cells to ICL agents both in vitro and in xenografts. Collectively, these findings reveal a novel epigenetic mechanism underlying the upregulated expression of FA genes in cancer cells and suggest that therapeutically targeting PRMT5 can have an additional benefit of chemosensitizing tumor cells to ICL agents.
Implications:
PRMT5 positively regulates the expression of FA genes. Inhibition of PRMT5 attenuates FA-dependent DNA repair pathway and sensitizes tumor cells to ICL agents.
Data from DCLK1-Short Splice Variant Promotes Esophageal Squamous Cell Carcinoma Progression via the MAPK/ERK/MMP2 Pathway
Authors: Ge Yang , Fan Xiaona , Huang Xuying , Weygant Nathaniel , Xiao Zeru , Yan Rui , Liu Heshu , Liu Jian , An Guangyu , Yao Jiannan
Published: April 2023

Abstract
Cancer stem cell (CSC) marker doublecortin-like kinase 1 (DCLK1) contributes greatly to the malignancy of gastrointestinal cancers, and DCLK1-targeted agents have potential therapeutic value. However, the molecular pathways regulated by DCLK1-S (DCLK1 isoform 4), a shortened splice variant of DCLK1, still remain obscure. Here we found that the expression of DCLK1-S is significantly increased in human esophageal squamous cell carcinoma (ESCC) tissues and associated with malignant progression and poor prognosis. Functional studies indicated that silencing total of DCLK1 mediated by CRISPR/Cas9 inhibited ESCC cell proliferation, migration, and invasion. Conversely, these changes were largely reversed after DCLK1-S rescue or overexpression. More importantly, DCLK1-S significantly enhanced primary tumor formation and metastatic lung colonization in vivo. The Cancer Genome Atlas database and molecular analysis showed that DCLK1-S was closely related to the epithelial–mesenchymal transition (EMT) process in patients with ESCC. Further RNA sequencing and Kyoto Encyclopedia of Genes and Genomes analysis demonstrated that MAPK signaling pathway was significantly enriched. Our in vitro study proclaimed that DCLK1-S induced MMP2 expression in ESCC cells via MAPK/ERK signaling, leading to the activation of EMT. In addition, administration of ERK1/2 blocker SCH772984 attenuated the proliferative and migratory phenotype induced by DCLK1-S. In conclusion, these findings suggest that DCLK1-S may be a key molecule in MAPK/ERK/MMP2 pathway–mediated progression of ESCC, and that it has potential as a biomarker or therapeutic target to improve outcomes in patients with ESCC.
Implications
: DCLK1-S induces ESCC progression by activating the MAPK/ERK/MMP2 axis and may serve as a prognostic biomarker or therapeutic target for patients with ESCC.
Data from Reg4 Interacts with CD44 to Regulate Proliferation and Stemness of Colorectal and Pancreatic Cancer Cells
Authors: Bishnupuri Kumar S. , Sainathan Satheesh K. , Ciorba Matthew A. , Houchen Courtney W. , Dieckgraefe Brian K.
Published: April 2023

Abstract
Regenerating Gene 4 (Reg4) is highly upregulated in gastrointestinal (GI) malignancies including colorectal and pancreatic cancers. Numerous studies demonstrated an association between higher Reg4 expression and tumor aggressiveness, intrinsic resistance to apoptotic death, and poor outcomes from GI malignancies. However, the precise receptor and underlying signaling mechanism have remained unknown. Although we previously reported a Reg4-mediated induction of EGFR activity in colorectal cancer cells, a direct interaction between Reg4 and EGFR was not observed. This study is focused on identifying the cell surface binding partner of Reg4 and dissecting its role in colorectal cancer and pancreatic cancer growth and stem cell survival. In vitro models of human colorectal cancer and pancreatic cancer were used to evaluate the results. Results of this study find: (i) Reg4 interacts with CD44, a transmembrane protein expressed by a population of colorectal cancer and pancreatic cancer cells; (ii) Reg4 activates regulated intramembrane proteolysis of CD44 resulting in γ-secretase–mediated cleavage and release of the CD44 intracytoplasmic domain (CD44ICD) that functions as a transcriptional activator of D-type cyclins involved in the regulation of cancer cell proliferation and Klf4 and Sox2 expression involved in regulating pluripotency of cancer stem cells; and (iii) Reg4 significantly increases colorectal cancer and pancreatic cancer cell proliferation and their clonogenic potential in stem cell assays.
Implications:
These results suggest that pro-proliferative and pro-stemness effects of Reg4 are mediated through γ-secretase–mediated CD44/CD44ICD signaling, hence strategies to disrupt Reg4-CD44-γ-secretase-CD44ICD signaling axis may increase cancer cell susceptibility to chemo- and radiotherapeutics.
Data from Epigenetic Silencing of 15-Hydroxyprostaglandin Dehydrogenase by Histone Methyltransferase EHMT2/G9a in Cholangiocarcinoma
Authors: Zhang Jinqiang , Chen Weina , Ma Wenbo , Song Kyoungsub , Lee Sean , Han Chang , Wu Tong
Published: April 2023

Abstract
Cholangiocarcinoma (CCA) is a lethal malignancy with few therapeutic options. NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) has been shown to inhibit CCA cell growth in vitro and in xenograft models. However, the role of 15-PGDH in CCA development has not been investigated and the mechanism for 15-PGDH gene regulation remains unclear. Here, we evaluated the role of 15-PGDH in CCA development by using a mouse model with hydrodynamic tail vein injection of transposase-based plasmids expressing Notch1 intracellular domain and myr-Akt, with or without co-injection of 15-PGDH expression plasmids. Our results reveal that 15-PGDH overexpression effectively prevents CCA development. Through patient data mining and experimental approaches, we provide novel evidences that 15-PGDH is epigenetically silenced by histone methyltransferase G9a. We observe that 15-PGDH and G9a expressions are inversely correlated in both human and mouse CCAs. By using CCA cells and mouse models, we show that G9a inhibition restores 15-PGDH expression and inhibited CCA in vitro and in vivo. Mechanistically, our data indicate that G9a is recruited to 15-PGDH gene promoter via protein–protein interaction with the E-box binding Myc/Max heterodimer. The recruited G9a then silences 15-PGDH gene through enhanced methylation of H3K9. Our further experiments have led to the identification of STAT4 as a key transcription factor involved in the regulation of 15-PGDH by G9a. Collectively, our findings disclose a novel G9a-15PGDH signaling axis which is importantly implicated in CCA development and progression.
Implications:
The current study describes a novel G9a-15PGDH signaling axis which is importantly implicated in CCA development and progression.
Supplementary Table 1 from Combined Serum CA19-9 and miR-27a-3p in Peripheral Blood Mononuclear Cells to Diagnose Pancreatic Cancer
Authors: Wang Wan-Sheng , Liu Ling-Xiao , Li Guo-Ping , Chen Yi , Li Chang-Yu , Jin Da-Yong , Wang Xiao-Lin
Published: April 2023

PDF file - 144K, Eligibility criteria for selection of the subjects
Supplementary Table 3 from The Chemopreventive Effect of Mifepristone on Mammary Tumorigenesis Is Associated with an Anti-invasive and Anti-inflammatory Gene Signature
Authors: Yuan Hongyan , Upadhyay Geeta , Lu Jin , Kopelovich Levy , Glazer Robert I.
Published: April 2023

XLS file - 73K, Gene array data from MMTV-Pax8PPARg...
Supplementary Figure Legends 1-2 from The Chemopreventive Effect of Mifepristone on Mammary Tumorigenesis Is Associated with an Anti-invasive and Anti-inflammatory Gene Signature
Authors: Yuan Hongyan , Upadhyay Geeta , Lu Jin , Kopelovich Levy , Glazer Robert I.
Published: April 2023

PDF file - 64K
Supplementary Table 2 from Novel Susceptibility Loci for Second Primary Tumors/Recurrence in Head and Neck Cancer Patients: Large-Scale Evaluation of Genetic Variants
Authors: Wu Xifeng , Spitz Margaret R. , Lee J. Jack , Lippman Scott M. , Ye Yuanqing , Yang Hushan , Khuri Fadlo R. , Kim Edward , Gu Jian , Lotan Reuben , Hong Waun K.
Published: April 2023

Supplementary Table 2 from Novel Susceptibility Loci for Second Primary Tumors/Recurrence in Head and Neck Cancer Patients: Large-Scale Evaluation of Genetic Variants
Supplementary Table 1, Figures 1 - 4 from Dietary Immunosuppressants Do Not Enhance UV-Induced Skin Carcinogenesis, and Reveal Discordance between p53-Mutant Early Clones and Carcinomas
Authors: Voskamp Pieter , Bodmann Carolien A , Koehl Gudrun E , Rebel Heggert G. , Van Olderen Marjolein G.E. , Gaumann Andreas , El Ghalbzouri Abdoel , Tensen Cornelis P. , Bavinck Jan N. Bouwes , Willemze Rein , Geissler Edward K. , De Gruijl Frank R.
Published: April 2023

PDF file - 67K, Supplementary table 1; Primer sequences. Supplementary figure 1; Effects of immunosuppressive drugs on epidermal proliferation in HSEs (n=3-4) as % of Ki-67 positive (supra-)basal cells. Supplementary figure 2: Mice on Aza diet (A) show more extensive burning 72 hours after UV irradiation compared with mice on control diet (C). Supplementary figure 3; No effect of Aza on tumor yields induced by daily UVA irradiation.Supplementary figure 4; Tumor-free survival (Kaplan-Meier) plots of the different treatment groups (n=12-13),
Supplementary Video 2 from eRapa Restores a Normal Life Span in a FAP Mouse Model
Authors: Hasty Paul , Livi Carolina B. , Dodds Sherry G. , Jones Diane , Strong Randy , Javors Martin , Fischer Kathleen E. , Sloane Lauren , Murthy Kruthi , Hubbard Gene , Sun Lishi , Hurez Vincent , Curiel Tyler J. , Sharp Zelton Dave
Published: April 2023

AVI file - 9806K, A 42 ppm-fed ApcMin/+ female at 1087 days of age.
Supplementary Table 1 from Deficiency in the 15-kDa Selenoprotein Inhibits Tumorigenicity and Metastasis of Colon Cancer Cells
Authors: Irons Robert , Tsuji Petra A. , Carlson Bradley A. , Ouyang Ping , Yoo Min-Hyuk , Xu Xue-Ming , Hatfield Dolph L. , Gladyshev Vadim N. , Davis Cindy D.
Published: April 2023

Supplementary Table 1 from Deficiency in the 15-kDa Selenoprotein Inhibits Tumorigenicity and Metastasis of Colon Cancer Cells
Related Article from New Directions in Reducing Stress Effects on Cancer
Authors: Melhem-Bertrandt Amal , Sood Anil K.
Published: April 2023

Related Article from New Directions in Reducing Stress Effects on Cancer
Supplementary Materials and Methods, Figure Legends from Molecular Profiling of Premalignant Lesions in Lung Squamous Cell Carcinomas Identifies Mechanisms Involved in Stepwise Carcinogenesis
Authors: Ooi Aik T. , Gower Adam C. , Zhang Kelvin X. , Vick Jessica L. , Hong Longsheng , Nagao Brian , Wallace W. Dean , Elashoff David A. , Walser Tonya C. , Dubinett Steven M. , Pellegrini Matteo , Lenburg Marc E. , Spira Avrum , Gomperts Brigitte N.
Published: April 2023

PDF file - 85KB
Perspective on This Article from Endothelin Receptor Type B Gene Promoter Hypermethylation in Salivary Rinses Is Independently Associated with Risk of Oral Cavity Cancer and Premalignancy
Authors: Pattani Kavita Malhotra , Zhang Zhe , Demokan Semra , Glazer Chad , Loyo Myriam , Goodman Steven , Sidransky David , Bermudez Francisco , Jean-Charles Germain , McCaffrey Thomas , Padhya Tapan , Phelan Joan , Spivakovsky Silvia , Bowne Helen Yoo , Goldberg Judith D. , Rolnitzky Linda , Robbins Miriam , Kerr A. Ross , Sirois David , Califano Joseph A.
Published: April 2023

Perspective on This Article from Endothelin Receptor Type B Gene Promoter Hypermethylation in Salivary Rinses Is Independently Associated with Risk of Oral Cavity Cancer and Premalignancy
Supplementary Figure 4 from Increased Plasma Levels of the APC-Interacting Protein MAPRE1, LRG1, and IGFBP2 Preceding a Diagnosis of Colorectal Cancer in Women
Authors: Ladd Jon J. , Busald Tina , Johnson Melissa M. , Zhang Qing , Pitteri Sharon J. , Wang Hong , Brenner Dean E. , Lampe Paul D. , Kucherlapati Raju , Feng Ziding , Prentice Ross L. , Hanash Samir M.
Published: April 2023

PDF file - 70K, Correlations between different markers based on ELISA data of newly diagnosed samples.
Supplementary Table 1 from Spectrin Repeat Containing Nuclear Envelope 1 and Forkhead Box Protein E1 Are Promising Markers for the Detection of Colorectal Cancer in Blood
Authors: Melotte Veerle , Yi Joo Mi , Lentjes Marjolein H.F.M. , Smits Kim M. , Van Neste Leander , Niessen Hanneke E.C. , Wouters Kim A.D. , Louwagie Joost , Schuebel Kornel E. , Herman James G. , Baylin Stephen B. , van Criekinge Wim , Meijer Gerrit A. , Ahuja Nita , van Engeland Manon
Published: April 2023

Supplementary Table 1. Patient characteristics of training and test studies
Supplementary Figure S1 from Zerumbone Induces Heme Oxygenase-1 Expression in Mouse Skin and Cultured Murine Epidermal Cells through Activation of Nrf2
Authors: Shin Jun-Wan , Ohnishi Kohta , Murakami Akira , Lee Jeong-Sang , Kundu Joydeb Kumar , Na Hye-Kyung , Ohigashi Hajime , Surh Young-Joon
Published: April 2023

Supplementary Figure S1 from Zerumbone Induces Heme Oxygenase-1 Expression in Mouse Skin and Cultured Murine Epidermal Cells through Activation of Nrf2
Supplementary Data from Grape Seed Extract Efficacy against Azoxymethane-Induced Colon Tumorigenesis in A/J Mice: Interlinking miRNA with Cytokine Signaling and Inflammation
Authors: Derry Molly M. , Raina Komal , Balaiya Velmurugan , Jain Anil K. , Shrotriya Sangeeta , Huber Kendra M. , Serkova Natalie J. , Agarwal Rajesh , Agarwal Chapla
Published: April 2023

Supplementary Data from Grape Seed Extract Efficacy against Azoxymethane-Induced Colon Tumorigenesis in A/J Mice: Interlinking miRNA with Cytokine Signaling and Inflammation