bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Spatiotemporal Regulation of Tumor Angiogenesis by Circulating Chromogranin A Cleavage and Neuropilin-1 Engagement
Authors: Dallatomasina Alice , Gasparri Anna Maria , Colombo Barbara , Sacchi Angelina , Bianco Mimma , Daniele Tiziana , Esposito Antonio , Pastorino Fabio , Ponzoni Mirco , Marcucci Fabrizio , Curnis Flavio , Corti Angelo
Published: March 2024

Abstract
The unbalanced production of pro- and antiangiogenic factors in tumors can lead to aberrant vasculature morphology, angiogenesis, and disease progression. In this study, we report that disease progression in various murine models of solid tumors is associated with increased cleavage of full-length chromogranin A (CgA), a circulating vasoregulatory neurosecretory protein. Cleavage of CgA led to the exposure of the highly conserved PGPQLR site, which corresponds to residues 368–373 of human CgA1-373, a fragment that has proangiogenic activity. Antibodies against this site, unable to bind full-length CgA, inhibited angiogenesis and reduced tumor perfusion and growth. The PGPQLR sequence of the fragment, but not of the precursor, bound the VEGF-binding site of neuropilin-1; the C-terminal arginine (R373) of the sequence was crucial for binding. The proangiogenic activity of the CgA1-373 was blocked by anti-neuropilin-1 antibodies as well as by nicotinic acetylcholine receptor antagonists, suggesting that these receptors, in addition to neuropilin-1, play a role in the proangiogenic activity of CgA1-373. The R373 residue was enzymatically removed in plasma, causing loss of neuropilin-1 binding and gain of antiangiogenic activity. These results suggest that cleavage of the R373R374 site of circulating human CgA in tumors and the subsequent removal of R373 in the blood represent an important “on/off” switch for the spatiotemporal regulation of tumor angiogenesis and may serve as a novel therapeutic target.
Significance:
This work reveals that the interaction between fragmented chromogranin A and neuropilin-1 is required for tumor growth and represents a novel potential therapeutic target.
Data from Tumor pH and Protein Concentration Contribute to the Signal of Amide Proton Transfer Magnetic Resonance Imaging
Authors: Ray Kevin J. , Simard Manon A. , Larkin James R. , Coates James , Kinchesh Paul , Smart Sean C. , Higgins Geoff S. , Chappell Michael A. , Sibson Nicola R.
Published: March 2024

Abstract
Abnormal pH is a common feature of malignant tumors and has been associated clinically with suboptimal outcomes. Amide proton transfer magnetic resonance imaging (APT MRI) holds promise as a means to noninvasively measure tumor pH, yet multiple factors collectively make quantification of tumor pH from APT MRI data challenging. The purpose of this study was to improve our understanding of the biophysical sources of altered APT MRI signals in tumors. Combining in vivo APT MRI measurements with ex vivo histological measurements of protein concentration in a rat model of brain metastasis, we determined that the proportion of APT MRI signal originating from changes in protein concentration was approximately 66%, with the remaining 34% originating from changes in tumor pH. In a mouse model of hypopharyngeal squamous cell carcinoma (FaDu), APT MRI showed that a reduction in tumor hypoxia was associated with a shift in tumor pH. The results of this study extend our understanding of APT MRI data and may enable the use of APT MRI to infer the pH of individual patients' tumors as either a biomarker for therapy stratification or as a measure of therapeutic response in clinical settings.
Significance:
These findings advance our understanding of amide proton transfer magnetic resonance imaging (APT MRI) of tumors and may improve the interpretation of APT MRI in clinical settings.
Data from BET Inhibitors Potentiate Chemotherapy and Killing of SPOP-Mutant Colon Cancer Cells via Induction of DR5
Authors: Tan Xiao , Tong Jingshan , Wang Yi-Jun , Fletcher Rochelle , Schoen Robert E. , Yu Jian , Shen Liangfang , Zhang Lin
Published: March 2024

Abstract
Bromodomain and extraterminal domain (BET) family proteins such as BRD4 are epigenetic readers that control expression of a number of oncogenic proteins. Targeting this family of proteins has recently emerged as a promising anticancer approach. BET inhibitors (BETi), either alone or in combination with other anticancer agents, have exhibited efficacy in a variety of tumors. However, the molecular mechanisms underlying differential response to BETi are not well understood. In this study, we report that death receptor 5 (DR5), a key component of the extrinsic apoptotic pathway, is markedly induced in response to BRD4 depletion and BETi treatment in colorectal cancer cells. Induction of DR5, following BET inhibition, was mediated by endoplasmic reticulum stress and CHOP-dependent transcriptional activation. Enhanced DR5 induction was necessary for the chemosensitization and apoptotic effects of BETi and was responsible for increased BETi sensitivity in colorectal cancer cells containing a mutation in speckle-type POZ protein (SPOP), a subunit of BRD4 E3 ubiquitin ligase. In a colorectal cancer xenograft model, BETi combined with chemotherapy suppressed the tumor growth in a DR5-dependent manner and potently inhibited patient-derived xenograft tumor growth with enhanced DR5 induction and apoptosis. These findings suggest that BETi alone or in combination with chemotherapy is effective against colorectal cancer due to enhanced DR5 induction and apoptosis. DR5 induction may also serve as a useful marker for designing personalized treatment and improved colorectal cancer combination therapies.

Significance: These findings reveal how BET inhibition sensitizes chemotherapy and kills a subset of colon cancer cells with specific genetic alterations and may provide a new molecular marker for improving colon cancer therapies.
Data from mTORC2 Suppresses GSK3-Dependent Snail Degradation to Positively Regulate Cancer Cell Invasion and Metastasis
Authors: Zhang Shuo , Qian Guoqing , Zhang Qian-Qian , Yao Yuying , Wang Dongsheng , Chen Zhuo G. , Wang Li-Jing , Chen Mingwei , Sun Shi-Yong
Published: March 2024

Abstract
mTOR complex 1 (mTORC1) positively regulates cell invasion and metastasis by enhancing translation of Snail. A connection between mTOR complex 2 (mTORC2) and cell invasion and metastasis has also been suggested, yet the underlying biology or mechanism is largely unknown and thus is the focus of this study. Inhibition of mTOR with both mTOR inhibitors and knockdown of key components of mTORC, including rictor, Sin1, and raptor, decreased Snail protein levels. Inhibition of mTOR enhanced the rate of Snail degradation, which could be rescued by inhibition of the proteasome. Critically, inhibition of mTORC2 (by knocking down rictor) but not mTORC1 (by knocking down raptor) enhanced Snail degradation. Therefore, only mTORC2 inhibition induces Snail proteasomal degradation, resulting in eventual Snail reduction. Interestingly, inhibition of GSK3 but not SCF/β-TrCP rescued the Snail reduction induced by mTOR inhibitors, suggesting GSK3-dependent, but SCF/β-TrCP–independent proteasomal degradation of Snail. Accordingly, mTOR inhibitors elevated E-cadherin levels and suppressed cancer cell migration and invasion in vitro and metastasis in vivo. Collectively, this study reveals that mTORC2 positively regulates Snail stability to control cell invasion and metastasis.
Significance:
These findings delineate a new regulation mechanism of Snail, an important master regulator of epithelial–mesenchymal transition and invasion in cancers.
Data from Frizzled-7 Is Required for Wnt Signaling in Gastric Tumors with and Without Apc Mutations
Authors: Flanagan Dustin J. , Barker Nick , Costanzo Natasha S. Di , Mason Elizabeth A. , Gurney Austin , Meniel Valerie S. , Koushyar Sarah , Austin Chloe R. , Ernst Matthias , Pearson Helen B. , Boussioutas Alex , Clevers Hans , Phesse Toby J. , Vincan Elizabeth
Published: March 2024

Abstract
A subset of patients with gastric cancer have mutations in genes that participate in or regulate Wnt signaling at the level of ligand (Wnt) receptor (Fzd) binding. Moreover, increased Fzd expression is associated with poor clinical outcome. Despite these findings, there are no in vivo studies investigating the potential of targeting Wnt receptors for treating gastric cancer, and the specific Wnt receptor transmitting oncogenic Wnt signaling in gastric cancer is unknown. Here, we use inhibitors of Wnt/Fzd (OMP-18R5/vantictumab) and conditional gene deletion to test the therapeutic potential of targeting Wnt signaling in preclinical models of intestinal-type gastric cancer and ex vivo organoid cultures. Pharmacologic targeting of Fzd inhibited the growth of gastric adenomas in vivo. We identified Fzd7 to be the predominant Wnt receptor responsible for transmitting Wnt signaling in human gastric cancer cells and mouse models of gastric cancer, whereby Fzd7-deficient cells were retained in gastric adenomas but were unable to respond to Wnt signals and consequently failed to proliferate. Genetic deletion of Fzd7 or treatment with vantictumab was sufficient to inhibit the growth of gastric adenomas with or without mutations to Apc. Vantictumab is currently in phase Ib clinical trials for advanced pancreatic, lung, and breast cancer. Our data extend the scope of patients that may benefit from this therapeutic approach as we demonstrate that this drug will be effective in treating patients with gastric cancer regardless of APC mutation status.
Significance:
The Wnt receptor Fzd7 plays an essential role in gastric tumorigenesis irrespective of Apc mutation status, therefore targeting Wnt/Fzd7 may be of therapeutic benefit to patients with gastric cancer.
Data from miR-192-5p Silencing by Genetic Aberrations Is a Key Event in Hepatocellular Carcinomas with Cancer Stem Cell Features
Authors: Gu Yuanzhuo , Wei Xiyang , Sun Yulin , Gao Hongjun , Zheng Xin , Wong Linda L. , Jin Ling , Liu Niya , Hernandez Brenda , Peplowska Karolina , Zhao Xiaohang , Zhan Qi-Min , Feng Xin-Hua , Tang Zhao-You , Ji Junfang
Published: March 2024

Abstract
Various cancer stem cell (CSC) biomarkers have been identified for hepatocellular carcinoma (HCC), but little is known about the implications of heterogeneity and shared molecular networks within the CSC population. Through miRNA profile analysis in an HCC cohort (n = 241) for five groups of CSC+ HCC tissues, i.e., EpCAM+, CD90+, CD133+, CD44+, and CD24+ HCC, we identified a 14-miRNA signature commonly altered among these five groups of CSC+ HCC. miR-192-5p, the top-ranked CSC miRNA, was liver-abundant and -specific and markedly downregulated in all five groups of CSC+ HCC from two independent cohorts (n = 613). Suppressing miR-192-5p in HCC cells significantly increased multiple CSC populations and CSC-related features through targeting PABPC4. Both TP53 mutation and hypermethylation of the mir-192 promoter impeded transcriptional activation of miR-192-5p in HCC cell lines and primary CSC+ HCC. This study reveals the circuit from hypermethylation of the mir-192 promoter through the increase in PABPC4 as a shared genetic regulatory pathway in various groups of primary CSC+ HCC. This circuit may be the driver that steers liver cells toward hepatic CSC cells, leading to hepatic carcinogenesis.
Significance:
miR-192-5p and its regulatory pathway is significantly abolished in multiple groups of HCC expressing high levels of CSC markers, which may represent a key event for hepatic carcinogenesis.
Data from Mcl-1 Interacts with Akt to Promote Lung Cancer Progression
Authors: Chen Guo , Park Dongkyoo , Magis Andrew T. , Behera Madhusmita , Ramalingam Suresh S. , Owonikoko Taofeek K. , Sica Gabriel L. , Ye Keqiang , Zhang Chao , Chen Zhengjia , Curran Walter J. , Deng Xingming
Published: March 2024

Abstract
Mcl-1 is a unique antiapoptotic Bcl2 family protein that functions as a gatekeeper in manipulating apoptosis and survival in cancer cells. Akt is an oncogenic kinase that regulates multiple cellular functions and its activity is significantly elevated in human cancers. Here we discovered a cross-talk between Mcl-1 and Akt in promoting lung cancer cell growth. Depletion of endogenous Mcl-1 from human lung cancer cells using CRISPR/Cas9 or Mcl-1 shRNA significantly decreased Akt activity, leading to suppression of lung cancer cell growth in vitro and in xenografts. Mechanistically, Mcl-1 directly interacted via its PEST domain with Akt at the pleckstrin homology (PH) domain. It is known that the interactions between the PH domain and kinase domain (KD) are important for maintaining Akt in an inactive state. The binding of Mcl-1/PH domain disrupted intramolecular PH/KD interactions to activate Akt. Intriguingly, Mcl-1 expression correlated with Akt activity in tumor tissues from patients with non–small cell lung cancer. Using the Mcl-1–binding PH domain of Akt as a docking site, we identified a novel small molecule, PH-687, that directly targets the PH domain and disrupts Mcl-1/Akt binding, leading to suppression of Akt activity and growth inhibition of lung cancer in vitro and in vivo. By targeting the Mcl-1/Akt interaction, this mechanism-driven agent provides a highly attractive strategy for the treatment of lung cancer.
Significance:
These findings indicate that targeting Mcl-1/Akt interaction by employing small molecules such as PH-687 represents a potentially new and effective strategy for cancer treatment.
Data from Spindle Assembly Checkpoint Inhibition Can Resensitize p53-Null Stem Cells to Cancer Chemotherapy
Authors: Liu Changlong , Banister Carolyn E. , Buckhaults Phillip J.
Published: March 2024

Abstract
TP53 mutations are common in most human cancers, but few therapeutic options for TP53-mutant tumors exist. To identify potential therapeutic options for cancer patients with TP53 mutations, we profiled 127 FDA-approved chemotherapy drugs against human embryonic stem cells (hESC) in which we engineered TP53 deletion by genome editing. We identified 27 cancer therapeutic drugs for which TP53 mutations conferred resistance; most of these drugs target DNA synthesis or topoisomerase and cause DNA damage. We then performed a genome-wide CRISPR/Cas9 knockout screen in the TP53-null hESC in the presence and absence of sublethal concentrations of cisplatin and identified 137 genes whose loss selectively resensitized the p53-null cells to this chemotherapeutic agent. Gene ontology classification of the resensitizing loci revealed significant overrepresentation of spindle checkpoint pathway genes. Moreover, we confirmed that targeting ZNF207/BuGZ sensitizes p53-null hESC to cisplatin. These data indicate that targeted inhibition of spindle assembly checkpoints (SAC) and chromosomal organizing centers may provide a way to treat p53-deficient cancer cells with standard chemotherapy drugs. Development of small-molecule inhibitors of SAC proteins may be a useful strategy for rescuing DNA-damaging chemotherapeutics in TP53-mutant cancers.
Significance:
These findings show that inhibition of spindle assembly checkpoints and chromosomal organizing centers may provide a new way to treat p53-deficient cancer cells with standard chemotherapy drugs.
Data from Vitamin D–VDR Signaling Inhibits Wnt/β-Catenin–Mediated Melanoma Progression and Promotes Antitumor Immunity
Authors: Muralidhar Sathya , Filia Anastasia , Nsengimana Jérémie , Poźniak Joanna , O'Shea Sally J. , Diaz Joey M. , Harland Mark , Randerson-Moor Juliette A. , Reichrath Jörg , Laye Jonathan P. , van der Weyden Louise , Adams David J. , Bishop D.T. , Newton-Bishop Julia
Published: March 2024

Abstract
1α,25-Dihydroxyvitamin D3 signals via the vitamin D receptor (VDR). Higher serum vitamin D is associated with thinner primary melanoma and better outcome, although a causal mechanism has not been established. As patients with melanoma commonly avoid sun exposure, and consequent vitamin D deficiency might worsen outcomes, we interrogated 703 primary melanoma transcriptomes to understand the role of vitamin D–VDR signaling and replicated the findings in The Cancer Genome Atlas metastases. VDR expression was independently protective for melanoma-related death in both primary and metastatic disease. High tumor VDR expression was associated with upregulation of pathways mediating antitumor immunity and corresponding with higher imputed immune cell scores and histologically detected tumor-infiltrating lymphocytes. High VDR–expressing tumors had downregulation of proliferative pathways, notably Wnt/β-catenin signaling. Deleterious low VDR levels resulted from promoter methylation and gene deletion in metastases. Vitamin D deficiency (<25 nmol/L ∼ 10 ng/mL) shortened survival in primary melanoma in a VDR-dependent manner. In vitro functional validation studies showed that elevated vitamin D–VDR signaling inhibited Wnt/β-catenin signaling genes. Murine melanoma cells overexpressing VDR produced fewer pulmonary metastases than controls in tail-vein metastasis assays. In summary, vitamin D–VDR signaling contributes to controlling pro-proliferative/immunosuppressive Wnt/β-catenin signaling in melanoma and this is associated with less metastatic disease and stronger host immune responses. This is evidence of a causal relationship between vitamin D–VDR signaling and melanoma survival, which should be explored as a therapeutic target in primary resistance to checkpoint blockade.
Significance:
VDR expression could potentially be used as a biomarker to stratify patients with melanoma that may respond better to immunotherapy.
Data from The Goldilocks Window of Personalized Chemotherapy: Getting the Immune Response Just Right
Authors: Park Derek S. , Robertson-Tessi Mark , Luddy Kimberly A. , Maini Philip K. , Bonsall Michael B. , Gatenby Robert A. , Anderson Alexander R.A.
Published: March 2024

Abstract
The immune system is a robust and often untapped accomplice of many standard cancer therapies. A majority of tumors exist in a state of immune tolerance where the patient's immune system has become insensitive to the cancer cells. Because of its lymphodepleting effects, chemotherapy has the potential to break this tolerance. To investigate this, we created a mathematical modeling framework of tumor-immune dynamics. Our results suggest that optimal chemotherapy scheduling must balance two opposing objectives: maximizing tumor reduction while preserving patient immune function. Successful treatment requires therapy to operate in a “Goldilocks Window” where patient immune health is not overly compromised. By keeping therapy “just right,” we show that the synergistic effects of immune activation and chemotherapy can maximize tumor reduction and control.
Significance:
To maximize the synergy between chemotherapy and antitumor immune response, lymphodepleting therapy must be balanced in a “Goldilocks Window” of optimal dosing.
Data from ID1 Is Critical for Tumorigenesis and Regulates Chemoresistance in Glioblastoma
Authors: Sachdeva Rohit , Wu Megan , Smiljanic Sandra , Kaskun Oleksandra , Ghannad-Zadeh Kimia , Celebre Angela , Isaev Keren , Morrissy A. Sorana , Guan Jennifer , Tong Jiefei , Chan Jeffrey , Wilson Taylor M. , Al-Omaishi Sayf , Munoz David G. , Dirks Peter B. , Moran Michael F. , Taylor Michael D. , Reimand Jüri , Das Sunit
Published: March 2024

Abstract
Glioblastoma is the most common primary brain tumor in adults. While the introduction of temozolomide chemotherapy has increased long-term survivorship, treatment failure and rapid tumor recurrence remains universal. The transcriptional regulatory protein, inhibitor of DNA-binding-1 (ID1), is a key regulator of cell phenotype in cancer. We show that CRISPR-mediated knockout of ID1 in glioblastoma cells, breast adenocarcinoma cells, and melanoma cells dramatically reduced tumor progression in all three cancer systems through transcriptional downregulation of EGF, which resulted in decreased EGFR phosphorylation. Moreover, ID1-positive cells were enriched by chemotherapy and drove tumor recurrence in glioblastoma. Addition of the neuroleptic drug pimozide to inhibit ID1 expression enhanced the cytotoxic effects of temozolomide therapy on glioma cells and significantly prolonged time to tumor recurrence. Conclusively, these data suggest ID1 could be a promising therapeutic target in patients with glioblastoma.
Significance:
These findings show that the transcriptional regulator ID1 is critical for glioblastoma initiation and chemoresistance and that inhibition of ID1 enhances the effect of temozolomide, delays tumor recurrence, and prolongs survival.
Data from Macrophage-Derived IL1β and TNFα Regulate Arginine Metabolism in Neuroblastoma
Authors: Fultang Livingstone , Gamble Laura D. , Gneo Luciana , Berry Andrea M. , Egan Sharon A. , De Bie Fenna , Yogev Orli , Eden Georgina L. , Booth Sarah , Brownhill Samantha , Vardon Ashley , McConville Carmel M. , Cheng Paul N. , Norris Murray D. , Etchevers Heather C. , Murray Jayne , Ziegler David S. , Chesler Louis , Schmidt Ronny , Burchill Susan A. , Haber Michelle , De Santo Carmela , Mussai Francis
Published: March 2024

Abstract
Neuroblastoma is the most common childhood solid tumor, yet the prognosis for high-risk disease remains poor. We demonstrate here that arginase 2 (ARG2) drives neuroblastoma cell proliferation via regulation of arginine metabolism. Targeting arginine metabolism, either by blocking cationic amino acid transporter 1 (CAT-1)–dependent arginine uptake in vitro or therapeutic depletion of arginine by pegylated recombinant arginase BCT-100, significantly delayed tumor development and prolonged murine survival. Tumor cells polarized infiltrating monocytes to an M1-macrophage phenotype, which released IL1β and TNFα in a RAC-alpha serine/threonine-protein kinase (AKT)–dependent manner. IL1β and TNFα established a feedback loop to upregulate ARG2 expression via p38 and extracellular regulated kinases 1/2 (ERK1/2) signaling in neuroblastoma and neural crest–derived cells. Proteomic analysis revealed that enrichment of IL1β and TNFα in stage IV human tumor microenvironments was associated with a worse prognosis. These data thus describe an immune-metabolic regulatory loop between tumor cells and infiltrating myeloid cells regulating ARG2, which can be clinically exploited.
Significance:
These findings illustrate that cross-talk between myeloid cells and tumor cells creates a metabolic regulatory loop that promotes neuroblastoma progression.
Data from MUC1-C Activates the NuRD Complex to Drive Dedifferentiation of Triple-Negative Breast Cancer Cells
Authors: Hata Tsuyoshi , Rajabi Hasan , Takahashi Hidekazu , Yasumizu Yota , Li Wei , Jin Caining , Long Mark D. , Hu Qiang , Liu Song , Fushimi Atsushi , Yamashita Nami , Kui Ling , Hong Deli , Yamamoto Masaaki , Miyo Masaaki , Hiraki Masayuki , Maeda Takahiro , Suzuki Yozo , Samur Mehmet K. , Kufe Donald
Published: March 2024

Abstract
The NuRD chromatin remodeling and deacetylation complex, which includes MTA1, MBD3, CHD4, and HDAC1 among other components, is of importance for development and cancer progression. The oncogenic mucin 1 (MUC1) C-terminal subunit (MUC1-C) protein activates EZH2 and BMI1 in the epigenetic reprogramming of triple-negative breast cancer (TNBC). However, there is no known link between MUC1-C and chromatin remodeling complexes. Here, we showed that MUC1-C binds directly to the MYC HLH-LZ domain and identified a previously unrecognized MUC1-C→MYC pathway that regulates the NuRD complex. MUC1-C/MYC complexes selectively activated the MTA1 and MBD3 genes and posttranscriptionally induced CHD4 expression in basal- but not luminal-type BC cells. In turn, MUC1-C formed complexes with these NuRD components on the ESR1 promoter. Downregulating MUC1-C decreased MTA1/MBD3/CHD4/HDAC1 occupancy and increased H3K27 acetylation on the ESR1 promoter, with induction of ESR1 expression and downstream estrogen response pathways. Targeting MUC1-C and these NuRD components also induced expression of FOXA1, GATA3, and other markers associated with the luminal phenotype. These findings support a model in which MUC1-C activates the NuRD complex to drive dedifferentiation and reprogramming of TNBC cells.
Significance:
MUC1-C directly interacts with MYC to activate the NuRD complex, mediating regulation of the estrogen receptor in triple-negative breast cancer cells.
Data from p300 Mediates Muscle Wasting in Lewis Lung Carcinoma
Authors: Sin Thomas K. , Zhu James Z. , Zhang Guohua , Li Yi-Ping
Published: March 2024

Abstract
C/EBPβ is a key mediator of cancer-induced skeletal muscle wasting. However, the signaling mechanisms that activate C/EBPβ in the cancer milieu are poorly defined. Here, we report cancer-induced muscle wasting requires the transcriptional cofactor p300, which is critical for the activation of C/EBPβ. Conditioned media from diverse types of tumor cells as well as recombinant HSP70 and HSP90 provoked rapid acetylation of C/EBPβ in myotubes, particularly at its Lys39 residue. Overexpression of C/EBPβ with mutated Lys39 impaired Lewis lung carcinoma (LLC)–induced activation of the C/EBPβ-dependent catabolic response, which included upregulation of E3 ligases UBR2 and atrogin1/MAFbx, increased LC3-II, and loss of muscle proteins both in myotubes and mouse muscle. Silencing p300 in myotubes or overexpressing a dominant negative p300 mutant lacking acetyltransferase activity in mouse muscle attenuated LLC tumor–induced muscle catabolism. Administration of pharmacologic p300 inhibitor C646, but not PCAF/GCN5 inhibitor CPTH6, spared LLC tumor–bearing mice from muscle wasting. Furthermore, mice with muscle-specific p300 knockout were resistant to LLC tumor–induced muscle wasting. These data suggest that p300 is a key mediator of LLC tumor–induced muscle wasting whose acetyltransferase activity may be targeted for therapeutic benefit in this disease.
Significance:
These findings demonstrate that tumor-induced muscle wasting in mice is abrogated by knockout, mutation of Lys39 or Asp1399, and pharmacologic inhibition of p300.
Data from Differential Subcellular Localization Regulates Oncogenic Signaling by ROS1 Kinase Fusion Proteins
Authors: Neel Dana S. , Allegakoen David V. , Olivas Victor , Mayekar Manasi K. , Hemmati Golzar , Chatterjee Nilanjana , Blakely Collin M. , McCoach Caroline E. , Rotow Julia K. , Le Anh , Karachaliou Niki , Rosell Rafael , Riess Jonathan W. , Nichols Robert , Doebele Robert C. , Bivona Trever G.
Published: March 2024

Abstract
Chromosomal rearrangements involving receptor tyrosine kinases (RTK) are a clinically relevant oncogenic mechanism in human cancers. These chimeric oncoproteins often contain the C-terminal kinase domain of the RTK joined in cis to various N-terminal, nonkinase fusion partners. The functional role of the N-terminal fusion partner in RTK fusion oncoproteins is poorly understood. Here, we show that distinct N-terminal fusion partners drive differential subcellular localization, which imparts distinct cell signaling and oncogenic properties of different, clinically relevant ROS1 RTK fusion oncoproteins. SDC4-ROS1 and SLC34A2-ROS1 fusion oncoproteins resided on endosomes and activated the MAPK pathway. CD74-ROS1 variants that localized instead to the endoplasmic reticulum (ER) showed compromised activation of MAPK. Forced relocalization of CD74-ROS1 from the ER to endosomes restored MAPK signaling. ROS1 fusion oncoproteins that better activate MAPK formed more aggressive tumors. Thus, differential subcellular localization controlled by the N-terminal fusion partner regulates the oncogenic mechanisms and output of certain RTK fusion oncoproteins.
Significance:
ROS1 fusion oncoproteins exhibit differential activation of MAPK signaling according to subcellular localization, with ROS1 fusions localized to endosomes, the strongest activators of MAPK signaling.
Data from Loss of E-Cadherin Inhibits CD103 Antitumor Activity and Reduces Checkpoint Blockade Responsiveness in Melanoma
Authors: Shields Bradley D. , Koss Brian , Taylor Erin M. , Storey Aaron J. , West Kirk L. , Byrum Stephanie D. , Mackintosh Samuel G. , Edmondson Rick , Mahmoud Fade , Shalin Sara C. , Tackett Alan J.
Published: March 2024

Abstract
Identifying controlling features of responsiveness to checkpoint blockade therapies is an urgent goal in oncology research. Our group and others have previously shown melanoma tumors resistant to checkpoint blockade display features of mesenchymal transition, including E-cadherin loss. Here, we present the first in vivo evidence that E-cadherin from tumor cells facilitate immune attack, using a B16F10 melanoma mouse model in which E-cadherin is exogenously expressed (B16.Ecad). We find, compared with vector control, B16.Ecad exhibits delayed tumor growth, reduced metastatic potential, and increased overall survival in vivo. Transplantation of B16.Ecad into Rag1−/− and CD103−/− mice abrogated the tumor growth delay. This indicates the anti-melanoma response against B16.Ecad is both immune and CD103+ mediated. Moreover, B16.Ecad showed increased responsiveness to combination immune checkpoint blockade (ICB) compared with vector control. This work establishes a rationale for ICB responses observed in high E-cadherin–expressing tumors and suggests therapeutic advancement through amplifying CD103+ immune cell subsets.

Significance: These findings identify the mechanism behind checkpoint blockade resistance observed in melanoma that has undergone mesenchymal transition and suggest activation of CD103+ immune cells as a therapeutic strategy against other E-cadherin–expressing malignancies.
Data from Inhibition of Notch Signaling Enhances Chemosensitivity in B-cell Precursor Acute Lymphoblastic Leukemia
Authors: Takam Kamga Paul , Dal Collo Giada , Midolo Martina , Adamo Annalisa , Delfino Pietro , Mercuri Angela , Cesaro Simone , Mimiola Elda , Bonifacio Massimiliano , Andreini Angelo , Chilosi Marco , Krampera Mauro
Published: March 2024

Abstract
Notch3 and Notch4 support survival of primary B-cell acute lymphoblastic leukemia (B-ALL) cells, suggesting a role for Notch signaling in drug response. Here we used in vitro, in silico, and in vivo mouse xenograft model-based approaches to define the role of the Notch pathway in B-ALL chemosensitivity. We observed significant Notch receptor and ligand expression in B-ALL primary cells and cell lines. Primary leukemia cells from high-risk patients overexpressed Notch3, Notch4, and Jagged2 while displaying a reduction in expression levels of Notch1-4 following chemotherapy. We then analyzed in vitro cell survival of B-ALL cells treated with conventional chemotherapeutic agents alone or in combination with Notch signaling inhibitors. Gamma-secretase inhibitors (GSI) and anti-Notch4 were all capable of potentiating drug-induced cell death in B-ALL cells by upregulating intracellular levels of reactive oxygen species, which in turn modulated mTOR, NF-κB, and ERK expression. In NOG-mouse-based xenograft models of B-ALL, co-administration of the Notch inhibitor GSI-XII with the chemotherapeutic agent Ara-C lowered bone marrow leukemic burden compared with DMSO or Ara-C alone, thus prolonging mouse survival. Overall, our results support the potential effectiveness of Notch inhibitors in patients with B-ALL.

Significance: Inhibition of Notch signaling enhances the chemosensitivity of B-ALL cells, suggesting Notch inhibition as a potential therapeutic strategy to improve the outcome of patients with B-ALL.
Data from Prolactin Promotes Fibrosis and Pancreatic Cancer Progression
Authors: Tandon Manuj , Coudriet Gina M. , Criscimanna Angela , Socorro Mairobys , Eliliwi Mouhanned , Singhi Aatur D. , Cruz-Monserrate Zobeida , Bailey Peter , Lotze Michael T. , Zeh Herbert , Hu Jing , Goffin Vincent , Gittes George K. , Biankin Andrew V. , Esni Farzad
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is associated with significant fibrosis. Recent findings have highlighted the profibrotic activity of tissue-resident macrophages in the pancreatic cancer microenvironment. Here, we show that neoplastic pancreatic epithelium, as well as a subset of tissue-resident macrophages, expresses the prolactin-receptor (PRLR). High mobility group box 1–induced prolactin expression in the pancreas maintained FAK1 and STAT3 phosphorylation within the epithelium and stroma. Gain-of-function and loss-of-function experiments demonstrated the essential role of prolactin in promoting collagen deposition and fibrosis. Finally, the signaling cascade downstream of prolactin/PRLR activated STAT3 rather than STAT5 in PDAC. These findings suggest that targeting prolactin together with IL6, a known major activator of STAT3, could represent a novel therapeutic strategy for treating pancreatic cancer.
Significance:
Prolactin is a key factor in the cross-talk between the stroma and neoplastic epithelium, functioning to promote fibrosis and PDAC progression.
Data from Roles and Regulation of Long Noncoding RNAs in Hepatocellular Carcinoma
Authors: Lim Lee Jin , Wong Samuel Y.S. , Huang Feiyang , Lim Sheng , Chong Samuel S. , Ooi London Lucien , Kon Oi Lian , Lee Caroline G.
Published: March 2024

Abstract
Next-generation sequencing has uncovered thousands of long noncoding RNAs (lncRNA). Many are reported to be aberrantly expressed in various cancers, including hepatocellular carcinoma (HCC), and play key roles in tumorigenesis. This review provides an in-depth discussion of the oncogenic mechanisms reported to be associated with deregulated HCC-associated lncRNAs. Transcriptional expression of lncRNAs in HCC is modulated through transcription factors, or epigenetically by aberrant histone acetylation or DNA methylation, and posttranscriptionally by lncRNA transcript stability modulated by miRNAs and RNA-binding proteins. Seventy-four deregulated lncRNAs have been identified in HCC, of which, 52 are upregulated. This review maps the oncogenic roles of these deregulated lncRNAs by integrating diverse datasets including clinicopathologic features, affected cancer phenotypes, associated miRNA and/or protein-interacting partners as well as modulated gene/protein expression. Notably, 63 deregulated lncRNAs are significantly associated with clinicopathologic features of HCC. Twenty-three deregulated lncRNAs associated with both tumor and metastatic clinical features were also tumorigenic and prometastatic in experimental models of HCC, and eight of these mapped to known cancer pathways. Fifty-two upregulated lncRNAs exhibit oncogenic properties and are associated with prominent hallmarks of cancer, whereas 22 downregulated lncRNAs have tumor-suppressive properties. Aberrantly expressed lncRNAs in HCC exert pleiotropic effects on miRNAs, mRNAs, and proteins. They affect multiple cancer phenotypes by altering miRNA and mRNA expression and stability, as well as through effects on protein expression, degradation, structure, or interactions with transcriptional regulators. Hence, these insights reveal novel lncRNAs as potential biomarkers and may enable the design of precision therapy for HCC.
Data from Early Loss of Histone H2B Monoubiquitylation Alters Chromatin Accessibility and Activates Key Immune Pathways That Facilitate Progression of Ovarian Cancer
Authors: Hooda Jagmohan , Novak Marián , Salomon Matthew P. , Matsuba Chikako , Ramos Romela I. , MacDuffie Emily , Song Melissa , Hirsch Michelle S. , Lester Jenny , Parkash Vinita , Karlan Beth Y. , Oren Moshe , Hoon Dave S. , Drapkin Ronny
Published: March 2024

Abstract
Recent insights supporting the fallopian tube epithelium (FTE) and serous tubal intraepithelial carcinomas (STIC) as the tissue of origin and the precursor lesion, respectively, for the majority of high-grade serous ovarian carcinomas (HGSOC) provide the necessary context to study the mechanisms that drive the development and progression of HGSOC. Here, we investigate the role of the E3 ubiquitin ligase RNF20 and histone H2B monoubiquitylation (H2Bub1) in serous tumorigenesis and report that heterozygous loss of RNF20 defines the majority of HGSOC tumors. At the protein level, H2Bub1 was lost or downregulated in a large proportion of STIC and invasive HGSOC tumors, implicating RNF20/H2Bub1 loss as an early event in the development of serous ovarian carcinoma. Knockdown of RNF20, with concomitant loss of H2Bub1, was sufficient to enhance cell migration and clonogenic growth of FTE cells. To investigate the mechanisms underlying these effects, we performed ATAC-seq and RNA-seq in RNF20 knockdown FTE cell lines. Loss of RNF20 and H2Bub1 was associated with a more open chromatin conformation, leading to upregulation of immune signaling pathways, including IL6. IL6 was one of the key cytokines significantly upregulated in RNF20- and H2Bub1-depleted FTE cells and imparted upon these cells an enhanced migratory phenotype. These studies provide mechanistic insight into the observed oncogenic phenotypes triggered by the early loss of H2Bub1.
Significance:
Loss of RNF20 and H2Bub1 contributes to transformation of the fallopian tube epithelium and plays a role in the initiation and progression of high-grade serous ovarian cancer.
Data from MUC1-C Integrates Chromatin Remodeling and PARP1 Activity in the DNA Damage Response of Triple-Negative Breast Cancer Cells
Authors: Yamamoto Masaaki , Jin Caining , Hata Tsuyoshi , Yasumizu Yota , Zhang Yan , Hong Deli , Maeda Takahiro , Miyo Masaaki , Hiraki Masayuki , Suzuki Yozo , Hinohara Kunihiko , Rajabi Hasan , Kufe Donald
Published: March 2024

Abstract
The oncogenic MUC1-C protein is overexpressed in triple-negative breast cancer (TNBC) cells and contributes to their epigenetic reprogramming and chemoresistance. Here we show that targeting MUC1-C genetically or pharmacologically with the GO-203 inhibitor, which blocks MUC1-C nuclear localization, induced DNA double-strand breaks and potentiated cisplatin (CDDP)-induced DNA damage and death. MUC1-C regulated nuclear localization of the polycomb group proteins BMI1 and EZH2, which formed complexes with PARP1 during the DNA damage response. Targeting MUC1-C downregulated BMI1-induced H2A ubiquitylation, EZH2-driven H3K27 trimethylation, and activation of PARP1. As a result, treatment with GO-203 synergistically sensitized both mutant and wild-type BRCA1 TNBC cells to the PARP inhibitor olaparib. These findings uncover a role for MUC1-C in the regulation of PARP1 and identify a therapeutic strategy for enhancing the effectiveness of PARP inhibitors against TNBC.
Significance:
These findings demonstrate that targeting MUC1-C disrupts epigenetics of the PARP1 complex, inhibits PARP1 activity, and is synergistic with olaparib in TNBC cells.
Data from Cys34 Adductomics Links Colorectal Cancer with the Gut Microbiota and Redox Biology
Authors: Grigoryan Hasmik , Schiffman Courtney , Gunter Marc J. , Naccarati Alessio , Polidoro Silvia , Dagnino Sonia , Dudoit Sandrine , Vineis Paolo , Rappaport Stephen M.
Published: March 2024

Abstract
Chronic inflammation is an established risk factor for colorectal cancer. To study reactive products of gut inflammation and redox signaling on colorectal cancer development, we used untargeted adductomics to detect adduct features in prediagnostic serum from the EPIC Italy cohort. We focused on modifications to Cys34 in human serum albumin, which is responsible for scavenging small reactive electrophiles that might initiate cancers. Employing a combination of statistical methods, we selected seven Cys34 adducts associated with colorectal cancer, as well as body mass index (BMI; a well-known risk factor). Five adducts were more abundant in colorectal cancer cases than controls and clustered with each other, suggesting a common pathway. Because two of these adducts were Cys34 modifications by methanethiol, a microbial–human cometabolite, and crotonaldehyde, a product of lipid peroxidation, these findings further implicate infiltration of gut microbes into the intestinal mucosa and the corresponding inflammatory response as causes of colorectal cancer. The other two associated adducts were Cys34 disulfides of homocysteine that were less abundant in colorectal cancer cases than controls and may implicate homocysteine metabolism as another causal pathway. The selected adducts and BMI ranked higher as potentially causal factors than variables previously associated with colorectal cancer (smoking, alcohol consumption, physical activity, and total meat consumption). Regressions of case–control differences in adduct levels on days to diagnosis showed no statistical evidence that disease progression, rather than causal factors at recruitment, contributed to the observed differences. These findings support the hypothesis that infiltration of gut microbes into the intestinal mucosa and the resulting inflammation are causal factors for colorectal cancer.
Significance:
Infiltration of gut microbes into the intestinal mucosa and the resulting inflammation are causal factors for colorectal cancer.
Data from Epidemiologic and Clinical Analysis of Cervical Cancer Using Data from the Population-Based Osaka Cancer Registry
Authors: Yagi Asami , Ueda Yutaka , Kakuda Mamoru , Tanaka Yusuke , Ikeda Sayaka , Matsuzaki Shinya , Kobayashi Eiji , Morishima Toshitaka , Miyashiro Isao , Fukui Keisuke , Ito Yuri , Nakayama Tomio , Kimura Tadashi
Published: March 2024

Abstract
Cervical cancer screening rate is extremely low and the governmental recommendation of HPV vaccine has been suspended for 5 years in Japan. Here, we utilized data from the Osaka Cancer Registry, collected between 1976 and 2012, to evaluate cervical cancer trends in Japan. Age-adjusted incidence, relative survival, and conditional survival rates were calculated using multiple imputation methods and period analyses in 25,826 cervical cancer cases. Association of survival rates and clinical factors, including patients' age, clinical stage, and treatment procedures, were also analyzed. A trend for significantly decreasing age-adjusted incidence of cervical cancer (per 100,000) began in 1976 but reversed after 2000, increasing significantly to date (annual percent change = 3.8, 95% confidence interval, 2.7–4.8; age-adjusted rate: 28.0 in 1976, 9.1 in 2000, 14.1 in 2012). The 10-year relative survival rate improved significantly after 2002, especially in cases of “localized” and “adjacent organs” disease; this was likely due to the introduction of concurrent chemotherapy and radiation. The conditional 5-year relative survival rate improved significantly yearly until the fourth survival year. In the surgery-based group, we observed no age-dependent differences in outcomes. Unexpectedly, however, prognosis for younger age groups was poorer in the radiation-based treatment group. These results indicate that although relative survival rates have recently increased, treatment for more advanced cases with distant metastasis requires further improvement. In addition, this study is the first to suggest that age might be an important predictor of radiotherapy resistance in cervical cancer.

Significance: A large-cohort analysis of cervical cancer cases reveals that age-adjusted incidence in Japan has increased since 2000 and that age may negatively correlate with resistance to radiotherapy.
Data from The Pro-Oncogenic Adaptor CIN85 Acts as an Inhibitory Binding Partner of Hypoxia-Inducible Factor Prolyl Hydroxylase 2
Authors: Kozlova Nina , Mennerich Daniela , Samoylenko Anatoly , Dimova Elitsa Y. , Koivunen Peppi , Biterova Ekaterina , Richter Kati , Hassinen Antti , Kellokumpu Sakari , Manninen Aki , Miinalainen Ilkka , Glumoff Virpi , Ruddock Lloyd , Drobot Lyudmyla Borysivna , Kietzmann Thomas
Published: March 2024

Abstract
The EGFR adaptor protein, CIN85, has been shown to promote breast cancer malignancy and hypoxia-inducible factor (HIF) stability. However, the mechanisms underlying cancer promotion remain ill defined. Here we show that CIN85 is a novel binding partner of the main HIF-prolyl hydroxylase, PHD2, but not of PHD1 or PHD3. Mechanistically, the N-terminal SRC homology 3 domains of CIN85 interacted with the proline-arginine–rich region within the N-terminus of PHD2, thereby inhibiting PHD2 activity and HIF degradation. This activity is essential in vivo, as specific loss of the CIN85–PHD2 interaction in CRISPR/Cas9-edited cells affected growth and migration properties, as well as tumor growth in mice. Overall, we discovered a previously unrecognized tumor growth checkpoint that is regulated by CIN85-PHD2 and uncovered an essential survival function in tumor cells by linking growth factor adaptors with hypoxia signaling.
Significance:
This study provides unprecedented evidence for an oxygen-independent mechanism of PHD2 regulation that has important implications in cancer cell survival.
Data from MEK Inhibition Modulates Cytokine Response to Mediate Therapeutic Efficacy in Lung Cancer
Authors: Xie Mengyu , Zheng Hong , Madan-Lala Ranjna , Dai Wenjie , Gimbrone Nicholas T. , Chen Zhihua , Kinose Fumi , Blackstone Sarah A. , Smalley Keiran S.M. , Cress W. Douglas , Haura Eric B. , Rix Uwe , Beg Amer A.
Published: March 2024

Abstract
Activating mutations in BRAF, a key mediator of RAS signaling, are present in approximately 50% of melanoma patients. Pharmacologic inhibition of BRAF or the downstream MAP kinase MEK is highly effective in treating BRAF-mutant melanoma. In contrast, RAS pathway inhibitors have been less effective in treating epithelial malignancies, such as lung cancer. Here, we show that treatment of melanoma patients with BRAF and MEK inhibitors (MEKi) activated tumor NF-κB activity. MEKi potentiated the response to TNFα, a potent activator of NF-κB. In both melanoma and lung cancer cells, MEKi increased cell-surface expression of TNFα receptor 1 (TNFR1), which enhanced NF-κB activation and augmented expression of genes regulated by TNFα and IFNγ. Screening of 289 targeted agents for the ability to increase TNFα and IFNγ target gene expression demonstrated that this was a general activity of inhibitors of MEK and ERK kinases. Treatment with MEKi led to acquisition of a novel vulnerability to TNFα and IFNγ-induced apoptosis in lung cancer cells that were refractory to MEKi killing and augmented cell-cycle arrest. Abolishing the expression of TNFR1 on lung cancer cells impaired the antitumor efficacy of MEKi, whereas the administration of TNFα and IFNγ in MEKi-treated mice enhanced the antitumor response. Furthermore, immunotherapeutics known to induce expression of these cytokines synergized with MEKi in eradicating tumors. These findings define a novel cytokine response modulatory function of MEKi that can be therapeutically exploited.
Significance:
Lung cancer cells are rendered sensitive to MEK inhibitors by TNFα and IFNγ, providing a strong mechanistic rationale for combining immunotherapeutics, such as checkpoint blockers, with MEK inhibitor therapy for lung cancer.

See related commentary by Havel, p. 5699