bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from A Protease-Activated Fluorescent Probe Allows Rapid Visualization of Keratinocyte Carcinoma during Excision
Authors: Walker Ethan , Liu Yiqiao , Kim InYoung , Biro Mark , Iyer Sukanya Raj , Ezaldein Harib , Scott Jeffrey , Merati Miesha , Mistur Rachel , Zhou Bo , Straight Brian , Yim Joshua J. , Bogyo Matthew , Mann Margaret , Wilson David L. , Basilion James P. , Popkin Daniel L.
Published: March 2024

Abstract
Keratinocyte carcinomas, including basal and squamous cell carcinomas, are the most common human cancers worldwide. While 75% of all keratinocyte carcinoma (4 million annual cases in the United States) are treated with conventional excision, this surgical modality has much lower cure rates than Mohs micrographic surgery, likely due to the bread-loaf histopathologic assessment that visualizes <1% of the tissue margins. A quenched protease-activated fluorescent probe 6qcNIR, which produces a signal only in the protease-rich tumor microenvironment, was topically applied to 90 specimens ex vivo immediately following excision. “Puzzle-fit” analysis was used to correlate the fluorescent images with histology. Probe-dependent fluorescent images correlated with cancer determined by conventional histology. Point-of-care fluorescent detection of skin cancer had a clinically relevant sensitivity of 0.73 and corresponding specificity of 0.88. Importantly, clinicians were effectively trained to read fluorescent images within 15 minutes with reliability and confidence, resulting in sensitivities of 62%–78% and specificities of 92%–97%. Fluorescent imaging using 6qcNIR allows 100% tumor margin assessment by generating en face images that correlate with histology and may be used to overcome the limitations of conventional bread-loaf histology. The utility of 6qcNIR was validated in a busy real-world clinical setting, and clinicians were trained to effectively read fluorescent margins with a short guided instruction, highlighting clinical adaptability. When used in conventional excision, this approach may result in higher cure rates at a lower cost by allowing same-day reexcision when needed, reducing patient anxiety and improving compliance by expediting postsurgical specimen assessment.
Significance:
A fluorescent-probe-tumor-visualization platform was developed and validated in human keratinocyte carcinoma excision specimens that may provide simple, rapid, and global assessment of margins during skin cancer excision, allowing same-day reexcision when needed.
Data from Acetylation of CCAR2 Establishes a BET/BRD9 Acetyl Switch in Response to Combined Deacetylase and Bromodomain Inhibition
Authors: Rajendran Praveen , Johnson Gavin , Li Li , Chen Ying-Shiuan , Dashwood Mohaiza , Nguyen Nhung , Ulusan Ahmet , Ertem Furkan , Zhang Mutian , Li Jia , Sun Deqiang , Huang Yun , Wang Shan , Leung Hon-Chiu , Lieberman David , Beaver Laura , Ho Emily , Bedford Mark , Chang Kyle , Vilar Eduardo , Dashwood Roderick
Published: March 2024

Abstract
There continues to be interest in targeting epigenetic “readers, writers, and erasers” for the treatment of cancer and other pathologies. However, a mechanistic understanding is frequently lacking for the synergy observed when combining deacetylase and bromodomain inhibitors. Here we identify cell cycle and apoptosis regulator 2 (CCAR2) as an early target for acetylation in colon cancer cells treated with sulforaphane. N-terminal acetylation of CCAR2 diminished its interactions with histone deacetylase 3 and β-catenin, interfering with Wnt coactivator functions of CCAR2, including in cells harboring genetically encoded CCAR2 acetylation. Protein domain arrays and pull-down assays identified acetyl “reader” proteins that recognized CCAR2 acetylation sites, including BRD9 and members of the bromodomain and extraterminal domain (BET) family. Treatment with the BET inhibitor JQ1 synergized with sulforaphane in colon cancer cells and suppressed tumor development effectively in a preclinical model of colorectal cancer. Studies with sulforaphane+JQ1 in combination implicated a BET/BRD9 acetyl switch and a shift in the pool of acetyl “reader” proteins in favor of BRD9-regulated target genes.
Significance:
These results highlight the competition that exists among the “readers” of acetylated histone and nonhistone proteins and provide a mechanistic basis for potential new therapeutic avenues involving epigenetic combination treatments.
Data from EIF3H Orchestrates Hippo Pathway–Mediated Oncogenesis via Catalytic Control of YAP Stability
Authors: Zhou Zhuan , Zhou Honghong , Ponzoni Luca , Luo Aiping , Zhu Rui , He Mingjing , Huang Yi , Guan Kun-Liang , Bahar Ivet , Liu Zhihua , Wan Yong
Published: March 2024

Abstract
EIF3H is presumed to be a critical translational initiation factor. Here, our unbiased screening for tumor invasion factors has identified an unexpected role for EIF3H as a deubiquitylating enzyme that dictates breast tumor invasion and metastasis by modulating the Hippo–YAP pathway. EIF3H catalyzed YAP for deubiquitylation, resulting in its stabilization. Structure-based molecular modeling and simulations coupled with biochemical characterization unveiled a unique catalytic mechanism for EIF3H in dissociating polyubiquitin chains from YAP through a catalytic triad consisting of Asp90, Asp91, and Gln121. Trp119 and Tyr 140 on EIF3H directly interacted with the N-terminal region of YAP1, facilitating complex formation of EIF3H and YAP1 for YAP1 deubiquitylation. Stabilization of YAP via elevated EIF3H promoted tumor invasion and metastasis. Interference of EIF3H-mediated YAP deubiquitylation blocked YAP-induced tumor progression and metastasis in breast cancer models. These findings point to a critical role for YAP regulation by EIF3H in tumor invasion and metastasis.
Significance:
This work demonstrates that EIF3H is a novel bona fide deubiquitinase that counteracts YAP ubiquitylation and proteolysis, and stabilization of YAP by EIF3H promotes tumor invasion and metastasis.
Data from A Custom Genotyping Array Reveals Population-Level Heterogeneity for the Genetic Risks of Prostate Cancer and Other Cancers in Africa
Authors: Harlemon Maxine , Ajayi Olabode , Kachambwa Paidamoyo , Kim Michelle S. , Simonti Corinne N. , Quiver Melanie H. , Petersen Desiree C. , Mittal Anuradha , Fernandez Pedro W. , Hsing Ann W. , Baichoo Shakuntala , Agalliu Ilir , Jalloh Mohamed , Gueye Serigne M. , Snyper Nana Yaa F. , Adusei Ben , Mensah James E. , Abrahams Afua O.D. , Adebiyi Akindele O. , Orunmuyi Akin T. , Aisuodionoe-Shadrach Oseremen I. , Nwegbu Maxwell M. , Joffe Maureen , Chen Wenlong C. , Irusen Hayley , Neugut Alfred I. , Quintana Yuri , Seutloali Moleboheng , Fadipe Mayowa B. , Warren Christopher , Woehrmann Marcos H. , Zhang Peng , Ongaco Chrissie M. , Mawhinney Michelle , McBride Jo , Andrews Caroline V. , Adams Marcia , Pugh Elizabeth , Rebbeck Timothy R. , Petersen Lindsay N. , Lachance Joseph
Published: March 2024

Abstract
Although prostate cancer is the leading cause of cancer mortality for African men, the vast majority of known disease associations have been detected in European study cohorts. Furthermore, most genome-wide association studies have used genotyping arrays that are hindered by SNP ascertainment bias. To overcome these disparities in genomic medicine, the Men of African Descent and Carcinoma of the Prostate (MADCaP) Network has developed a genotyping array that is optimized for African populations. The MADCaP Array contains more than 1.5 million markers and an imputation backbone that successfully tags over 94% of common genetic variants in African populations. This array also has a high density of markers in genomic regions associated with cancer susceptibility, including 8q24. We assessed the effectiveness of the MADCaP Array by genotyping 399 prostate cancer cases and 403 controls from seven urban study sites in sub-Saharan Africa. Samples from Ghana and Nigeria clustered together, whereas samples from Senegal and South Africa yielded distinct ancestry clusters. Using the MADCaP array, we identified cancer-associated loci that have large allele frequency differences across African populations. Polygenic risk scores for prostate cancer were higher in Nigeria than in Senegal. In summary, individual and population-level differences in prostate cancer risk were revealed using a novel genotyping array.
Significance:
This study presents an Africa-specific genotyping array, which enables investigators to identify novel disease associations and to fine-map genetic loci that are associated with prostate and other cancers.
Data from Long-Term Gemcitabine Treatment Reshapes the Pancreatic Tumor Microenvironment and Sensitizes Murine Carcinoma to Combination Immunotherapy
Authors: Principe Daniel R. , Narbutis Matthew , Kumar Sandeep , Park Alex , Viswakarma Navin , Dorman Matthew J. , Kamath Suneel D. , Grippo Paul J. , Fishel Melissa L. , Hwang Rosa F. , Thummuri Dinesh , Underwood Patrick W. , Munshi Hidayatullah G. , Trevino Jose G. , Rana Ajay
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death with a median survival time of 6–12 months. Most patients present with disseminated disease and the majority are offered palliative chemotherapy. With no approved treatment modalities for patients who progress on chemotherapy, we explored the effects of long-term gemcitabine administration on the tumor microenvironment to identify potential therapeutic options for chemorefractory PDAC. Using a combination of mouse models, primary cell line–derived xenografts, and established tumor cell lines, we first evaluated chemotherapy-induced alterations in the tumor secretome and immune surface proteins by high throughput proteomic arrays. In addition to enhancing antigen presentation and immune checkpoint expression, gemcitabine consistently increased the synthesis of CCL/CXCL chemokines and TGFβ-associated signals. These secreted factors altered the composition of the tumor stroma, conferring gemcitabine resistance to cancer-associated fibroblasts in vitro and further enhancing TGFβ1 biosynthesis. Combined gemcitabine and anti-PD-1 treatment in transgenic models of murine PDAC failed to alter disease course unless mice also underwent genetic or pharmacologic ablation of TGFβ signaling. In the setting of TGFβ signaling deficiency, gemcitabine and anti-PD-1 led to a robust CD8+ T-cell response and decrease in tumor burden, markedly enhancing overall survival. These results suggest that gemcitabine successfully primes PDAC tumors for immune checkpoint inhibition by enhancing antigen presentation only following disruption of the immunosuppressive cytokine barrier. Given the current lack of third-line treatment options, this approach warrants consideration in the clinical management of gemcitabine-refractory PDAC.
Significance:
These data suggest that long-term treatment with gemcitabine leads to extensive reprogramming of the pancreatic tumor microenvironment and that patients who progress on gemcitabine-based regimens may benefit from multidrug immunotherapy.

See related commentary by Carpenter et al., p. 3070
Data from Long Noncoding RNA MRPL23-AS1 Promotes Adenoid Cystic Carcinoma Lung Metastasis
Authors: Chen Chu-Wen , Fu Min , Du Zhi-Hao , Zhao Fei , Yang Wen-Wen , Xu Li-Hua , Li Sheng-Lin , Ge Xi-Yuan
Published: March 2024

Abstract
Lung metastasis is a major factor affecting long-term survival in patients with adenoid cystic carcinoma. Here, we showed that the long noncoding RNA (lncRNA) MRPL23 antisense RNA 1 (MRPL23-AS1) was highly expressed and correlated with lung metastasis and overall survival in patients with salivary adenoid cystic carcinoma (SACC). MRPL23-AS1 positively regulated epithelial–mesenchymal transition by forming an RNA–protein complex with enhancer of zeste homolog 2 (EZH2). MRPL23-AS1 increased the binding of EZH2 and H3K27me3 on the E-cadherin promoter region. Moreover, MRPL23-AS1 levels were higher in exosomes isolated from the blood plasma of patients with SACC, and exosomal MRPL23-AS1 affected pulmonary microvascular endothelial cells in an “exosomecrine” manner. MRPL23-AS1–enriched exosomes increased microvascular permeability and facilitated the metastasis of SACC in vivo. Collectively, these findings highlight a molecular mechanism of lung metastasis in SACC. MRPL23-AS1 may represent a biomarker and target for clinical intervention to control this intractable disease.
Significance:
This study identifies a novel metastasis-promoting lncRNA MRPL23-AS1, which mediates the transcriptional silencing of E-cadherin through forming an RNA–protein complex with EZH2.
Data from Intratumoral Genetic and Functional Heterogeneity in Pediatric Glioblastoma
Authors: Hoffman Mary , Gillmor Aaron H. , Kunz Daniel J. , Johnston Michael J. , Nikolic Ana , Narta Kiran , Zarrei Mehdi , King Jennifer , Ellestad Katrina , Dang Ngoc Ha , Cavalli Florence M.G. , Kushida Michelle M. , Coutinho Fiona J. , Zhu Yuankun , Luu Betty , Ma Yussanne , Mungall Andrew J. , Moore Richard , Marra Marco A. , Taylor Michael D. , Pugh Trevor J. , Dirks Peter B. , Strother Douglas , Lafay-Cousin Lucie , Resnick Adam C. , Scherer Stephen , Senger Donna L. , Simons Benjamin D. , Chan Jennifer A. , Morrissy A. Sorana , Gallo Marco
Published: March 2024

Abstract
Pediatric glioblastoma (pGBM) is a lethal cancer with no effective therapies. To understand the mechanisms of tumor evolution in this cancer, we performed whole-genome sequencing with linked reads on longitudinally resected pGBM samples. Our analyses showed that all diagnostic and recurrent samples were collections of genetically diverse subclones. Clonal composition rapidly evolved at recurrence, with less than 8% of nonsynonymous single-nucleotide variants being shared in diagnostic-recurrent pairs. To track the origins of the mutational events observed in pGBM, we generated whole-genome datasets for two patients and their parents. These trios showed that genetic variants could be (i) somatic, (ii) inherited from a healthy parent, or (iii) de novo in the germlines of pGBM patients. Analysis of variant allele frequencies supported a model of tumor growth involving slow-cycling cancer stem cells that give rise to fast-proliferating progenitor-like cells and to nondividing cells. Interestingly, radiation and antimitotic chemotherapeutics did not increase overall tumor burden upon recurrence. These findings support an important role for slow-cycling stem cell populations in contributing to recurrences, because slow-cycling cell populations are expected to be less prone to genotoxic stress induced by these treatments and therefore would accumulate few mutations. Our results highlight the need for new targeted treatments that account for the complex functional hierarchies and genomic heterogeneity of pGBM.
Significance:
This work challenges several assumptions regarding the genetic organization of pediatric GBM and highlights mutagenic programs that start during early prenatal development.
Data from Picosecond Infrared Laser Desorption Mass Spectrometry Identifies Medulloblastoma Subgroups on Intrasurgical Timescales
Authors: Woolman Michael , Kuzan-Fischer Claudia M. , Ferry Isabelle , Kiyota Taira , Luu Betty , Wu Megan , Munoz David G. , Das Sunit , Aman Ahmed , Taylor Michael D. , Rutka James T. , Ginsberg Howard J. , Zarrine-Afsar Arash
Published: March 2024

Abstract
Medulloblastoma (MB) is a pediatric malignant brain tumor composed of four different subgroups (WNT, SHH, Group 3, Group 4), each of which are a unique biological entity with distinct clinico-pathological, molecular, and prognostic characteristics. Although risk stratification of patients with MB based on molecular features may offer personalized therapies, conventional subgroup identification methods take too long and are unable to deliver subgroup information intraoperatively. This limitation prevents subgroup-specific adjustment of the extent or the aggressiveness of the tumor resection by the neurosurgeon. In this study, we investigated the potential of rapid tumor characterization with Picosecond infrared laser desorption mass spectrometry (PIRL-MS) for MB subgroup classification based on small molecule signatures. One hundred and thirteen ex vivo MB tumors from a local tissue bank were subjected to 10- to 15-second PIRL-MS data collection and principal component analysis with linear discriminant analysis (PCA-LDA). The MB subgroup model was established from 72 independent tumors; the remaining 41 de-identified unknown tumors were subjected to multiple, 10-second PIRL-MS samplings and real-time PCA-LDA analysis using the above model. The resultant 124 PIRL-MS spectra from each sampling event, after the application of a 95% PCA-LDA prediction probability threshold, yielded a 98.9% correct classification rate. Post-ablation histopathologic analysis suggested that intratumoral heterogeneity or sample damage prior to PIRL-MS sampling at the site of laser ablation was able to explain failed classifications. Therefore, upon translation, 10-seconds of PIRL-MS sampling is sufficient to allow personalized, subgroup-specific treatment of MB during surgery.
Significance:
This study demonstrates that laser-extracted lipids allow immediate grading of medulloblastoma tumors into prognostically important subgroups in 10 seconds, providing medulloblastoma pathology in an actionable manner during surgery.
Data from USP10 Promotes Proliferation of Hepatocellular Carcinoma by Deubiquitinating and Stabilizing YAP/TAZ
Authors: Zhu Hong , Yan Fangjie , Yuan Tao , Qian Meijia , Zhou Tianyi , Dai Xiaoyang , Cao Ji , Ying Meidan , Dong Xiaowu , He Qiaojun , Yang Bo
Published: March 2024

Abstract
Yes-associated protein (YAP) and its paralog, transcriptional coactivator with PDZ-binding motif (TAZ), play pivotal roles in promoting the progression of hepatocellular carcinoma. However, the regulatory mechanism underpinning aberrant activation of YAP/TAZ in hepatocellular carcinoma remains unclear. In this study, we globally profiled the contribution of deubiquitinating enzymes (DUB) to both transcriptional activity and protein abundance of YAP/TAZ in hepatocellular carcinoma models and identified ubiquitin-specific peptidase 10 (USP10) as a potent YAP/TAZ-activating DUB. Mechanistically, USP10 directly interacted with and stabilized YAP/TAZ by reverting their proteolytic ubiquitination. Depletion of USP10 enhanced polyubiquitination of YAP/TAZ, promoted their proteasomal degradation, and ultimately arrested the proliferation of hepatocellular carcinoma in vitro and in vivo. Expression levels of USP10 positively correlated with the abundance of YAP/TAZ in hepatocellular carcinoma patient samples as well as in N-nitrosodiethylamine (DEN)-induced liver cancer mice models. Collectively, this study establishes the causal link between USP10 and hyperactivated YAP/TAZ in hepatocellular carcinoma cells and provides a rationale for potential therapeutic interventions in the treatment of patients with hepatocellular carcinoma harboring a high level of YAP/TAZ.
Significance:
These findings identify USP10 as a DUB of YAP/TAZ and its role in hepatocellular carcinoma progression, which may serve as a potential therapeutic target for hepatocellular carcinoma treatment.
Data from Host Wnt5a Potentiates Microenvironmental Regulation of Ovarian Cancer Metastasis
Authors: Asem Marwa , Young Allison M. , Oyama Carlysa , Claure De La Zerda Alejandro , Liu Yueying , Yang Jing , Hilliard Tyvette S. , Johnson Jeffery , Harper Elizabeth I. , Guldner Ian , Zhang Siyuan , Page-Mayberry Toni , Kaliney William J. , Stack M. Sharon
Published: March 2024

Abstract
The noncanonical Wnt ligand Wnt5a is found in high concentrations in ascites of women with ovarian cancer. In this study, we elucidated the role of Wnt5a in ovarian cancer metastasis. Wnt5a promoted ovarian tumor cell adhesion to peritoneal mesothelial cells as well as migration and invasion, leading to colonization of peritoneal explants. Host components of the ovarian tumor microenvironment, notably peritoneal mesothelial cells and visceral adipose, secreted Wnt5a. Conditional knockout of host WNT5A significantly reduced peritoneal metastatic tumor burden. Tumors formed in WNT5A knockout mice had elevated cytotoxic T cells, increased M1 macrophages, and decreased M2 macrophages, indicating that host Wnt5a promotes an immunosuppressive microenvironment. The Src family kinase Fgr was identified as a downstream effector of Wnt5a. These results highlight a previously unreported role for host-expressed Wnt5a in ovarian cancer metastasis and suggest Fgr as a novel target for inhibition of ovarian cancer metastatic progression.

Significance: This study establishes host-derived Wnt5a, expressed by peritoneal mesothelial cells and adipocytes, as a primary regulator of ovarian cancer intraperitoneal metastatic dissemination and identifies Fgr kinase as novel target for inhibition of metastasis.
Data from Targeting the E3 Ubiquitin Ligase PJA1 Enhances Tumor-Suppressing TGFβ Signaling
Authors: Chen Jian , Mitra Abhisek , Li Shulin , Song Shumei , Nguyen Bao-Ngoc , Chen Jiun-Sheng , Shin Ji-Hyun , Gough Nancy R. , Lin Paul , Obias Vincent , He Aiwu Ruth , Yao Zhixing , Malta Tathiane M. , Noushmehr Houtan , Latham Patricia S. , Su Xiaoping , Rashid Asif , Mishra Bibhuti , Wu Ray-Chang , Mishra Lopa
Published: March 2024

Abstract
RING-finger E3 ligases are instrumental in the regulation of inflammatory cascades, apoptosis, and cancer. However, their roles are relatively unknown in TGFβ/SMAD signaling. SMAD3 and its adaptors, such as β2SP, are important mediators of TGFβ signaling and regulate gene expression to suppress stem cell–like phenotypes in diverse cancers, including hepatocellular carcinoma (HCC). Here, PJA1, an E3 ligase, promoted ubiquitination and degradation of phosphorylated SMAD3 and impaired a SMAD3/β2SP-dependent tumor-suppressing pathway in multiple HCC cell lines. In mice deficient for SMAD3 (Smad3+/−), PJA1 overexpression promoted the transformation of liver stem cells. Analysis of genes regulated by PJA1 knockdown and TGFβ1 signaling revealed 1,584 co-upregulated genes and 1,280 co-downregulated genes, including many implicated in cancer. The E3 ligase inhibitor RTA405 enhanced SMAD3-regulated gene expression and reduced growth of HCC cells in culture and xenografts of HCC tumors, suggesting that inhibition of PJA1 may be beneficial in treating HCC or preventing HCC development in at-risk patients.

Significance: These findings provide a novel mechanism regulating the tumor suppressor function of TGFβ in liver carcinogenesis.
Data from Prophylactic In Vivo Hematopoietic Stem Cell Gene Therapy with an Immune Checkpoint Inhibitor Reverses Tumor Growth in Syngeneic Mouse Tumor Models
Authors: Li Chang , Course Meredith M. , McNeish Iain A. , Drescher Charles W. , Valdmanis Paul N. , Lieber André
Published: March 2024

Abstract
Population-wide testing for cancer-associated mutations has established that more than one-fifth of ovarian and breast carcinomas are associated with inherited risk. Salpingo-oophorectomy and/or mastectomy are currently the only effective options offered to women with high-risk germline mutations. Our goal here is to develop a long-lasting approach that provides immunoprophylaxis for mutation carriers. Our approach leverages the fact that at early stages, tumors recruit hematopoietic stem/progenitor cells (HSPC) from the bone marrow and differentiate them into tumor-supporting cells. We developed a technically simple technology to genetically modify HSPCs in vivo. The technology involves HSPC mobilization and intravenous injection of an integrating HDAd5/35++ vector. In vivo HSPC transduction with a GFP-expressing vector and subsequent implantation of syngeneic tumor cells showed >80% GFP marking in tumor-infiltrating leukocytes. To control expression of transgenes, we developed a miRNA regulation system that is activated only when HSPCs are recruited to and differentiated by the tumor. We tested our approach using the immune checkpoint inhibitor anti-PD-L1-γ1 as an effector gene. In in vivo HSPC-transduced mice with implanted mouse mammary carcinoma (MMC) tumors, after initial tumor growth, tumors regressed and did not recur. Conventional treatment with an anti-PD-L1 mAb had no significant antitumor effect, indicating that early, self-activating expression of anti-PD-L1-γ1 can overcome the immunosuppressive environment in MMC tumors. The efficacy and safety of this approach was further validated in an ovarian cancer model with typical germline mutations (ID8 p53−/− brca2−/−), both in a prophylactic and therapeutic setting. This HSPC gene therapy approach has potential for clinical translation.
Significance:
Considering the limited prophylactic options that are currently offered to women with high-risk germ-line mutations, the in vivo HSPC gene therapy approach is a promising strategy that addresses a major medical problem.
Data from ARRB1-Promoted NOTCH1 Degradation Is Suppressed by OncomiR miR-223 in T-cell Acute Lymphoblastic Leukemia
Authors: Shu Yi , Wang Yi , Lv Wen-Qiong , Peng Dan-Yi , Li Juan , Zhang Hang , Jiang Guang-Jie , Yang Bi-Jie , Liu Shan , Zhang Jia , Chen Yan-Hua , Tang Shi , Wan Ke-Xing , Yuan Jun-Tao , Guo Wei , Fu Guo , Qi Xin-Kun , Liu Zhi-Dai , Liu Hai-Yan , Yang Chao , Zhang Ling-Huan , Liu Fang-Jie , Yu Jie , Zhang Peng-Hui , Qu Bin , Zhao Hui , He Tong-Chuan , Zou Lin
Published: March 2024

Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is a type of aggressive leukemia with inferior prognosis. Although activating mutations of NOTCH1 are observed in most T-ALL cases, these mutations alone are not sufficient to drive the full development of T-ALL. β-Arrestins (ARRB) are versatile and multifunctional adapter proteins that regulate diverse cellular functions, including promoting the development of cancer. However, the role of ARRBs in T-ALL has largely remained elusive. In this study, we showed that ARRB1 is expressed at low levels in assayed T-ALL clinical samples and cell lines. Exogenous ARRB1 expression inhibited T-ALL proliferation and improved the survival of T-ALL xenograft animals. ARRB1 facilitated NOTCH1 ubiquitination and degradation through interactions with NOTCH1 and DTX1. Mechanistically, the oncogenic miRNA (oncomiR) miR-223 targets the 3′-UTR of ARRB1 (BUTR) and inhibits its expression in T-ALL. Furthermore, overexpression of the ARRB1-derived miR-223 sponge suppressed T-ALL cell proliferation and induced apoptosis. Collectively, these results demonstrate that ARRB1 acts as a tumor suppressor in T-ALL by promoting NOTCH1 degradation, which is inhibited by elevated miR-223, suggesting that ARRB1 may serve as a valid drug target in the development of novel T-ALL therapeutics.

Significance: These findings highlight a novel tumor suppressive function of the adaptor protein β-arrestin1 in T-ALL.
Data from DMDRMR-Mediated Regulation of m6A-Modified CDK4 by m6A Reader IGF2BP3 Drives ccRCC Progression
Authors: Gu Yinmin , Niu Shaoxi , Wang Yang , Duan Liqiang , Pan Yongbo , Tong Zhou , Zhang Xu , Yang Zhenyu , Peng Bo , Wang Xiaodong , Han Xiaoqi , Li Yuxin , Cheng Tianyou , Liu Yajuan , Shang Lina , Liu Tongfeng , Yang Xiwang , Sun Minxuan , Jiang Siyuan , Zhang Chang , Zhang Ning , Ye Qinong , Gao Shan
Published: March 2024

Abstract
Aberrant N6-methyladenosine (m6A) modification has emerged as a driver of tumor initiation and progression, yet how long noncoding RNAs (lncRNA) are involved in the regulation of m6A remains unknown. Here we utilize data from 12 cancer types from The Cancer Genome Atlas to comprehensively map lncRNAs that are potentially deregulated by DNA methylation. A novel DNA methylation–deregulated and RNA m6A reader–cooperating lncRNA (DMDRMR) facilitated tumor growth and metastasis in clear cell renal cell carcinoma (ccRCC). Mechanistically, DMDRMR bound insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) to stabilize target genes, including the cell-cycle kinase CDK4 and three extracellular matrix components (COL6A1, LAMA5, and FN1), by specifically enhancing IGF2BP3 activity on them in an m6A-dependent manner. Consequently, DMDRMR and IGF2BP3 enhanced the G1–S transition, thus promoting cell proliferation in ccRCC. In patients with ccRCC, high coexpression of DMDRMR and IGF2BP3 was associated with poor outcomes. Our findings reveal that DMDRMR cooperates with IGF2BP3 to regulate target genes in an m6A-dependent manner and may represent a potential diagnostic, prognostic, and therapeutic target in ccRCC.
Significance:
This study demonstrates that the lncRNA DMDRMR acts as a cofactor for IGF2BP3 to stabilize target genes in an m6A-dependent manner, thus exerting essential oncogenic roles in ccRCC.
Data from A GRN Autocrine-Dependent FAM135B/AKT/mTOR Feedforward Loop Promotes Esophageal Squamous Cell Carcinoma Progression
Authors: Dong Dezuo , Zhang Weimin , Xiao Wenchang , Wu Qingnan , Cao Yiren , Gao Xiaohan , Huang Lijie , Wang Yan , Chen Jie , Wang Weihu , Zhan Qimin
Published: March 2024

Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most common and deadly diseases. In our previous comprehensive genomics study, we found that family with sequence similarity 135 member B (FAM135B) was a novel cancer-related gene, yet its biological functions and molecular mechanisms remain unclear. In this study, we demonstrate that the protein levels of FAM135B are significantly higher in ESCC tissues than in precancerous tissues, and high expression of FAM135B correlates with poorer clinical prognosis. Ectopic expression of FAM135B promoted ESCC cell proliferation in vitro and in vivo, likely through its direct interaction with growth factor GRN, thus forming a feedforward loop with AKT/mTOR signaling. Patients with ESCC with overexpression of both FAM135B and GRN had worse prognosis; multivariate Cox model analysis indicated that high expression of both FAM135B and GRN was an independent prognostic factor for patients with ESCC. FAM135B transgenic mice bore heavier tumor burden than wild-type mice and survived a relatively shorter lifespan after 4-nitroquinoline 1-oxide treatment. In addition, serum level of GRN in transgenic mice was higher than in wild-type mice, suggesting that serum GRN levels might provide diagnostic discrimination for patients with ESCC. These findings suggest that the interaction between FAM135B and GRN plays critical roles in the regulation of ESCC progression and both FAM135B and GRN might be potential therapeutic targets and prognostic factors in ESCC.
Significance:
These findings investigate the mechanisms of FAM135B in promoting ESCC progression and suggest new potential prognostic biomarkers and therapeutic targets in patients with ESCC.
Data from Hypoxic Glioma Stem Cell–Derived Exosomes Containing Linc01060 Promote Progression of Glioma by Regulating the MZF1/c-Myc/HIF1α Axis
Authors: Li Junjun , Liao Tingting , Liu Hongya , Yuan Hongliang , Ouyang Taohui , Wang Jiajing , Chai Songshan , Li Jinsong , Chen Jingchao , Li Xiang , Zhao Hongyang , Xiong Nanxiang
Published: March 2024

Abstract
Glioma stem cells (GSC) are a subpopulation of tumor cells with special abilities to proliferate and differentiate in gliomas. They are one of the main causes of tumor recurrence, especially under hypoxic conditions. Although long noncoding RNAs (lncRNA) are known to be involved in numerous biological processes and are implied in the occurrence of certain diseases, their role in tumor development and progression remains poorly understood. Here we explored the mechanisms by which lncRNA derived from hypoxic GSCs (H-GSC) cause glioma progression. Isolation and identification of the Linc01060 gene, the exosomes containing them, and the proteins from tumor cells regulating the gene allowed for studying the effects of Linc01060 on proliferation and glycometabolism. H-GSC exerted their effects by transferring exosomes to glioma cells, resulting in a significant increase in Linc01060 levels. Mechanistically, Linc01060 directly interacted with the transcription factor myeloid zinc finger 1 (MZF1) and enhanced its stability. Linc01060 facilitated nuclear translocation of MZF1 and promoted MZF1-mediated c-Myc transcriptional activities. In addition, c-Myc enhanced the accumulation of the hypoxia-inducible factor-1 alpha (HIF1α) at the posttranscriptional level. HIF1α bound the hormone response elements of the Linc01060 promoter, upregulating the transcription of Linc01060 gene. Clinically, Linc01060 was upregulated in glioma and was significantly correlated with tumor grade and poor clinical prognosis. Overall, these data show that secretion of Linc01060-containing exosomes from H-GSCs activates prooncogenic signaling pathways in glioma cells to promote disease progression.
Significance:
These findings suggest that inhibition of Linc01060-containing exosomes or targeting the Linc01060/MZF1/c-Myc/HIF1α axis may be an effective therapeutic strategy in glioma.
Data from E7386, a Selective Inhibitor of the Interaction between β-Catenin and CBP, Exerts Antitumor Activity in Tumor Models with Activated Canonical Wnt Signaling
Authors: Yamada Kazuhiko , Hori Yusaku , Inoue Satoshi , Yamamoto Yuji , Iso Kentaro , Kamiyama Hiroshi , Yamaguchi Atsumi , Kimura Takayuki , Uesugi Mai , Ito Junichi , Matsuki Masahiro , Nakamoto Kazutaka , Harada Hitoshi , Yoneda Naoki , Takemura Atsushi , Kushida Ikuo , Wakayama Naomi , Kubara Kenji , Kato Yu , Semba Taro , Yokoi Akira , Matsukura Masayuki , Odagami Takenao , Iwata Masao , Tsuruoka Akihiko , Uenaka Toshimitsu , Matsui Junji , Matsushima Tomohiro , Nomoto Kenichi , Kouji Hiroyuki , Owa Takashi , Funahashi Yasuhiro , Ozawa Yoichi
Published: March 2024

Abstract
The Wnt/β-catenin signaling pathway plays crucial roles in embryonic development and the development of multiple types of cancer, and its aberrant activation provides cancer cells with escape mechanisms from immune checkpoint inhibitors. E7386, an orally active selective inhibitor of the interaction between β-catenin and CREB binding protein, which is part of the Wnt/β-catenin signaling pathway, disrupts the Wnt/β-catenin signaling pathway in HEK293 and adenomatous polyposis coli (APC)-mutated human gastric cancer ECC10 cells. It also inhibited tumor growth in an ECC10 xenograft model and suppressed polyp formation in the intestinal tract of ApcMin/+ mice, in which mutation of Apc activates the Wnt/β-catenin signaling pathway. E7386 demonstrated antitumor activity against mouse mammary tumors developed in mouse mammary tumor virus (MMTV)-Wnt1 transgenic mice. Gene expression profiling using RNA sequencing data of MMTV-Wnt1 tumor tissue from mice treated with E7386 showed that E7386 downregulated genes in the hypoxia signaling pathway and immune responses related to the CCL2, and IHC analysis showed that E7386 induced infiltration of CD8+ cells into tumor tissues. Furthermore, E7386 showed synergistic antitumor activity against MMTV-Wnt1 tumor in combination with anti-PD-1 antibody. In conclusion, E7386 demonstrates clear antitumor activity via modulation of the Wnt/β-catenin signaling pathway and alteration of the tumor and immune microenvironments, and its antitumor activity can be enhanced in combination with anti-PD-1 antibody.
Significance:
These findings demonstrate that the novel anticancer agent, E7386, modulates Wnt/β-catenin signaling, altering the tumor immune microenvironment and exhibiting synergistic antitumor activity in combination with anti-PD-1 antibody.
Data from KDM5B Is Essential for the Hyperactivation of PI3K/AKT Signaling in Prostate Tumorigenesis
Authors: Li Guoliang , Kanagasabai Thanigaivelan , Lu Wenfu , Zou Mike R. , Zhang Shang-Min , Celada Sherly I. , Izban Michael G. , Liu Qi , Lu Tao , Ballard Billy R. , Zhou Xinchun , Adunyah Samuel E. , Matusik Robert J. , Yan Qin , Chen Zhenbang
Published: March 2024

Abstract
KDM5B (lysine[K]-specific demethylase 5B) is frequently upregulated in various human cancers including prostate cancer. KDM5B controls H3K4me3/2 levels and regulates gene transcription and cell differentiation, yet the contributions of KDM5B to prostate cancer tumorigenesis remain unknown. In this study, we investigated the functional role of KDM5B in epigenetic dysregulation and prostate cancer progression in cultured cells and in mouse models of prostate epithelium–specific mutant Pten/Kdm5b. Kdm5b deficiency resulted in a significant delay in the onset of prostate cancer in Pten-null mice, whereas Kdm5b loss alone caused no morphologic abnormalities in mouse prostates. At 6 months of age, the prostate weight of Pten/Kdm5b mice was reduced by up to 70% compared with that of Pten mice. Pathologic analysis revealed Pten/Kdm5b mice displayed mild morphologic changes with hyperplasia in prostates, whereas age-matched Pten littermates developed high-grade prostatic intraepithelial neoplasia and prostate cancer. Mechanistically, KDM5B governed PI3K/AKT signaling in prostate cancer in vitro and in vivo. KDM5B directly bound the PIK3CA promoter, and KDM5B knockout resulted in a significant reduction of P110α and PIP3 levels and subsequent decrease in proliferation of human prostate cancer cells. Conversely, KDM5B overexpression resulted in increased PI3K/AKT signaling. Loss of Kdm5b abrogated the hyperactivation of AKT signaling by decreasing P110α/P85 levels in Pten/Kdm5b mice. Taken together, our findings reveal that KDM5B acts as a key regulator of PI3K/AKT signaling; they also support the concept that targeting KDM5B is a novel and effective therapeutic strategy against prostate cancer.
Significance:
This study demonstrates that levels of histone modification enzyme KDM5B determine hyperactivation of PI3K/AKT signaling in prostate cancer and that targeting KDM5B could be a novel strategy against prostate cancer.
Data from Patterns of Human Leukocyte Antigen Class I and Class II Associations and Cancer
Authors: Liu Zhiwei , Derkach Andriy , Yu Kelly J. , Yeager Meredith , Chang Yu-Sun , Chen Chien-Jen , Gyllensten Ulf , Lan Qing , Lee Mei-Hsuan , McKay James D. , Rothman Nathaniel , Yang Hwai-I , Hildesheim Allan , Pfeiffer Ruth M.
Published: March 2024

Abstract
Human leukocyte antigen (HLA) gene variation is associated with risk of cancers, particularly those with infectious etiology or hematopoietic origin, given its role in immune presentation. Previous studies focused primarily on HLA allele/haplotype-specific associations. To answer whether associations are driven by HLA class I (essential for T-cell cytotoxicity) or class II (important for T-cell helper responses) genes, we analyzed GWAS from 24 case–control studies and consortia comprising 27 cancers (totaling >71,000 individuals). Associations for most cancers with infectious etiology or of hematopoietic origin were driven by multiple HLA regions, suggesting that both cytotoxic and helper T-cell responses are important. Notable exceptions were observed for nasopharyngeal carcinoma, an EBV-associated cancer, and CLL/SLL forms of non-Hodgkin lymphomas; these cancers were associated with HLA class I region only and HLA class II region only, implying the importance of cytotoxic T-cell responses for the former and CD4+ T-cell helper responses for the latter. Our findings suggest that increased understanding of the pattern of HLA associations for individual cancers could lead to better insights into specific mechanisms involved in cancer pathogenesis.
Significance:
GWAS of >71,000 individuals across 27 cancer types suggest that patterns of HLA Class I and Class II associations may provide etiologic insights for cancer.
Data from A Positive Feedback Loop of AKR1C3-Mediated Activation of NF-κB and STAT3 Facilitates Proliferation and Metastasis in Hepatocellular Carcinoma
Authors: Zhou Qingqing , Tian Wei , Jiang Zhiyuan , Huang Tingting , Ge Chao , Liu Tengfei , Zhao Fangyu , Chen Taoyang , Cui Ying , Li Hong , Yao Ming , Li Jinjun , Tian Hua
Published: March 2024

Abstract
AKR1C3 is an enzyme belonging to the aldo-ketoreductase family, the members of which catalyze redox transformations involved in biosynthesis, intermediary metabolism, and detoxification. AKR1C3 plays an important role in tumor progression and metastasis, however, little is known about the function and the molecular mechanism underlying the role of AKR1C3 in hepatocellular carcinoma (HCC). In this study, we report that AKR1C3 is significantly upregulated in HCC and that increased AKR1C3 is associated with poor survival. AKR1C3 positively regulated HCC cell proliferation and metastasis in vitro and in vivo. AKR1C3 promoted tumor proliferation and metastasis by activating NF-κB signaling. Furthermore, AKR1C3 regulated NF-κB activity by modulating TRAF6 and inducing its autoubiquitination in HCC cells. Activation of NF-κB released proinflammatory factors that facilitated the phosphorylation of STAT3 and increased tumor cell proliferation and invasion. Gain- and loss-of-function experiments showed that AKR1C3 promoted tumor proliferation and invasion via the IL6/STAT3 pathway. STAT3 also directly bound the AKR1C3 promoter and increased transcription of AKR1C3, thereby establishing a positive regulatory feedback loop. Treatment with the AKR1C3 inhibitors indocin and medroxyprogesterone acetate inhibited tumor growth and invasion and promoted apoptosis in HCC cells. Collectively, these results indicate that a AKR1C3/NF-κB/STAT3 signaling loop results in HCC cell proliferation and metastasis and could be a promising therapeutic target in HCC.
Significance:
These findings elucidate a novel AKR1C3-driven signaling loop that regulates proliferation and metastasis in HCC, providing potential prognostic and therapeutic targets in this disease.
Data from EPHB2 Activates β-Catenin to Enhance Cancer Stem Cell Properties and Drive Sorafenib Resistance in Hepatocellular Carcinoma
Authors: Leung Hoi Wing , Leung Carmen Oi Ning , Lau Eunice Y. , Chung Katherine Po Sin , Mok Etienne H. , Lei Martina Mang Leng , Leung Rainbow Wing Hei , Tong Man , Keng Vincent W. , Ma Cong , Zhao Qian , Ng Irene Oi Lin , Ma Stephanie , Lee Terence K.
Published: March 2024

Abstract
The survival benefit derived from sorafenib treatment for patients with hepatocellular carcinoma (HCC) is modest due to acquired resistance. Targeting cancer stem cells (CSC) is a possible way to reverse drug resistance, however, inhibitors that specifically target liver CSCs are limited. In this study, we established two sorafenib-resistant, patient-derived tumor xenografts (PDX) that mimicked development of acquired resistance to sorafenib in patients with HCC. RNA-sequencing analysis of sorafenib-resistant PDXs and their corresponding mock controls identified EPH receptor B2 (EPHB2) as the most significantly upregulated kinase. EPHB2 expression increased stepwise from normal liver tissue to fibrotic liver tissue to HCC tissue and correlated with poor prognosis. Endogenous EPHB2 knockout showed attenuation of tumor development in mice. EPHB2 regulated the traits of liver CSCs; similarly, sorted EPHB2High HCC cells were endowed with enhanced CSC properties when compared with their EPHB2-Low counterparts. Mechanistically, EPHB2 regulated cancer stemness and drug resistance by driving the SRC/AKT/GSK3β/β-catenin signaling cascade, and EPHB2 expression was regulated by TCF1 via promoter activation, forming a positive Wnt/β-catenin feedback loop. Intravenous administration of rAAV-8-shEPHB2 suppressed HCC tumor growth and significantly sensitized HCC cells to sorafenib in an NRAS/AKT-driven HCC immunocompetent mouse model. Targeting a positive feedback loop involving the EPHB2/β-catenin axis may be a possible therapeutic strategy to combat acquired drug resistance in HCC.
Significance:
This study identifies a EPHB2/β-catenin/TCF1 positive feedback loop that augments cancer stemness and sorafenib resistance in HCC, revealing a targetable axis to combat acquired drug resistance in HCC.
Data from SNAI2-Mediated Repression of BIM Protects Rhabdomyosarcoma from Ionizing Radiation
Authors: Wang Long , Hensch Nicole R. , Bondra Kathryn , Sreenivas Prethish , Zhao Xiang R. , Chen Jiangfei , Moreno Campos Rodrigo , Baxi Kunal , Vaseva Angelina V. , Sunkel Benjamin D. , Gryder Berkley E. , Pomella Silvia , Stanton Benjamin Z. , Zheng Siyuan , Chen Eleanor Y. , Rota Rossella , Khan Javed , Houghton Peter J. , Ignatius Myron S.
Published: March 2024

Abstract
Ionizing radiation (IR) and chemotherapy are mainstays of treatment for patients with rhabdomyosarcoma, yet the molecular mechanisms that underlie the success or failure of radiotherapy remain unclear. The transcriptional repressor SNAI2 was previously identified as a key regulator of IR sensitivity in normal and malignant stem cells through its repression of the proapoptotic BH3-only gene PUMA/BBC3. Here, we demonstrate a clear correlation between SNAI2 expression levels and radiosensitivity across multiple rhabdomyosarcoma cell lines. Modulating SNAI2 levels in rhabdomyosarcoma cells through its overexpression or knockdown altered radiosensitivity in vitro and in vivo. SNAI2 expression reliably promoted overall cell growth and inhibited mitochondrial apoptosis following exposure to IR, with either variable or minimal effects on differentiation and senescence, respectively. Importantly, SNAI2 knockdown increased expression of the proapoptotic BH3-only gene BIM, and chromatin immunoprecipitation sequencing experiments established that SNAI2 is a direct repressor of BIM/BCL2L11. Because the p53 pathway is nonfunctional in the rhabdomyosarcoma cells used in this study, we have identified a new, p53-independent SNAI2/BIM signaling axis that could potentially predict clinical responses to IR treatment and be exploited to improve rhabdomyosarcoma therapy.
Significance:
SNAI2 is identified as a major regulator of radiation-induced apoptosis in rhabdomyosarcoma through previously unknown mechanisms independent of p53.
Data from A Transcriptionally Distinct Subpopulation of Healthy Acinar Cells Exhibit Features of Pancreatic Progenitors and PDAC
Authors: Gopalan Vishaka , Singh Arashdeep , Rashidi Mehrabadi Farid , Wang Li , Ruppin Eytan , Arda H. Efsun , Hannenhalli Sridhar
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) tumors can originate either from acinar or ductal cells in the adult pancreas. We re-analyze multiple pancreas and PDAC single-cell RNA-seq datasets and find a subset of nonmalignant acinar cells, which we refer to as acinar edge (AE) cells, whose transcriptomes highly diverge from a typical acinar cell in each dataset. Genes upregulated among AE cells are enriched for transcriptomic signatures of pancreatic progenitors, acinar dedifferentiation, and several oncogenic programs. AE-upregulated genes are upregulated in human PDAC tumors, and consistently, their promoters are hypomethylated. High expression of these genes is associated with poor patient survival. The fraction of AE-like cells increases with age in healthy pancreatic tissue, which is not explained by clonal mutations, thus pointing to a nongenetic source of variation. The fraction of AE-like cells is also significantly higher in human pancreatitis samples. Finally, we find edge-like states in lung, liver, prostate, and colon tissues, suggesting that subpopulations of healthy cells across tissues can exist in pre-neoplastic states.
Significance:
These findings show “edge” epithelial cell states with oncogenic transcriptional activity in human organs without oncogenic mutations. In the pancreas, the fraction of acinar cells increases with age.