bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Risk SNP-Mediated Enhancer–Promoter Interaction Drives Colorectal Cancer through Both FADS2 and AP002754.2
Authors: Tian Jianbo , Lou Jiao , Cai Yimin , Rao Meilin , Lu Zequn , Zhu Ying , Zou Danyi , Peng Xiating , Wang Haoxue , Zhang Ming , Niu Siyuan , Li Yue , Zhong Rong , Chang Jiang , Miao Xiaoping
Published: March 2023

Abstract
Although genome-wide association studies (GWAS) have identified more than 100 colorectal cancer risk loci, most of the biological mechanisms associated with these loci remain unclear. Here we first performed a comprehensive expression quantitative trait loci analysis in colorectal cancer tissues adjusted for multiple confounders to test the determinants of germline variants in established GWAS susceptibility loci on mRNA and long noncoding RNA (lncRNA) expression. Combining integrative functional genomic/epigenomic analyses and a large-scale population study consisting of 6,024 cases and 10,022 controls, we then prioritized rs174575 with a C>G change as a potential causal candidate for colorectal cancer at 11q12.2, as its G allele was associated with an increased risk of colorectal cancer (OR = 1.26; 95% confidence interval = 1.17–1.36; P = 2.57 × 10–9). rs174575 acted as an allele-specific enhancer to distally facilitate expression of both FADS2 and lncRNA AP002754.2 via long-range enhancer–promoter interaction loops, which were mediated by E2F1. AP002754.2 further activated a transcriptional activator that upregulated FADS2 expression. FADS2, in turn, was overexpressed in colorectal cancer tumor tissues and functioned as a potential oncogene that facilitated colorectal cancer cell proliferation and xenograft growth in vitro and in vivo by increasing the metabolism of PGE2, an oncogenic molecule involved in colorectal cancer tumorigenesis. Our findings represent a novel mechanism by which a noncoding variant can facilitate long-range genome interactions to modulate the expression of multiple genes including not only mRNA, but also lncRNA, which provides new insights into the understanding of colorectal cancer etiology.
Significance:
This study provides an oncogenic regulatory circuit among several oncogenes including E2F1, FADS2, and AP002754.2 underlying the association of rs174575 with colorectal cancer risk, which is driven by long-range enhancer–promoter interaction loops.
Data from A Proof of Concept for Biomarker-Guided Targeted Therapy against Ovarian Cancer Based on Patient-Derived Tumor Xenografts
Authors: Palmer Adam C. , Plana Deborah , Gao Hui , Korn Joshua M. , Yang Guizhi , Green John , Zhang Xiamei , Velazquez Roberto , McLaughlin Margaret E. , Ruddy David A. , Kowal Colleen , Muszynski Julie , Bullock Caroline , Rivera Stacy , Rakiec Daniel P. , Elliott GiNell , Fordjour Paul , Meyer Ronald , Loo Alice , Kurth Esther , Engelman Jeffrey A. , Bitter Hans , Sellers William R. , Williams Juliet A. , Sorger Peter K.
Published: March 2023

Abstract
Advanced ovarian cancers are a leading cause of cancer-related death in women and are currently treated with surgery and chemotherapy. This standard of care is often temporarily successful but exhibits a high rate of relapse, after which, treatment options are few. Here we investigate whether biomarker-guided use of multiple targeted therapies, including small molecules and antibody–drug conjugates, is a viable alternative. A panel of patient-derived ovarian cancer xenografts (PDX), similar in genetics and chemotherapy responsiveness to human tumors, was exposed to 21 monotherapies and combination therapies. Three monotherapies and one combination were found to be active in different subsets of PDX. Analysis of gene expression data identified biomarkers associated with responsiveness to each of the three targeted therapies, none of which directly inhibits an oncogenic driver. While no single treatment had as high a response rate as chemotherapy, nearly 90% of PDXs were eligible for and responded to at least one biomarker-guided treatment, including tumors resistant to standard chemotherapy. The distribution of biomarker positivity in The Cancer Genome Atlas data suggests the potential for a similar precision approach in human patients.
Significance:
This study exploits a panel of patient-derived xenografts to demonstrate that most ovarian tumors can be matched to effective biomarker-guided treatments.
Data from Wnt-Induced Stabilization of KDM4C Is Required for Wnt/β-Catenin Target Gene Expression and Glioblastoma Tumorigenesis
Authors: Chen Yaohui , Fang Runping , Yue Chen , Chang Guoqiang , Li Peng , Guo Qing , Wang Jing , Zhou Aidong , Zhang Sicong , Fuller Gregory N. , Shi Xiaobing , Huang Suyun
Published: March 2023

Abstract
Wnt/β-catenin signaling activates the transcription of target genes to regulate stem cells and cancer development. However, the contribution of epigenetic regulation to this process is unknown. Here, we report that Wnt activation stabilizes the epigenetic regulator KDM4C that promotes tumorigenesis and survival of human glioblastoma cells by epigenetically activating the transcription of Wnt target genes. KDM4C protein expression was upregulated in human glioblastomas, and its expression directly correlated with Wnt activity and Wnt target gene expression. KDM4C was essential for Wnt-induced gene expression and tumorigenesis of glioblastoma cells. In the absence of Wnt3a, protein kinase R phosphorylated KDM4C at Ser918, inducing KDM4C ubiquitination and degradation. Wnt3a stabilized KDM4C through inhibition of GSK3-dependent protein kinase R activity. Stabilized KDM4C accumulated in the nucleus and bound to and demethylated TCF4-associated histone H3K9 by interacting with β-catenin, promoting HP1γ removal and transcriptional activation. These findings reveal that Wnt–KDM4C–β-catenin signaling represents a novel mechanism for the transcription of Wnt target genes and regulation of tumorigenesis, with important clinical implications.
Significance:
These findings identify the Wnt–KDM4C–β-catenin signaling axis as a critical mechanism for glioma tumorigenesis that may serve as a new therapeutic target in glioblastoma.
Data from Mevalonate Pathway Provides Ubiquinone to Maintain Pyrimidine Synthesis and Survival in p53-Deficient Cancer Cells Exposed to Metabolic Stress
Authors: Kaymak Irem , Maier Carina R. , Schmitz Werner , Campbell Andrew D. , Dankworth Beatrice , Ade Carsten P. , Walz Susanne , Paauwe Madelon , Kalogirou Charis , Marouf Hecham , Rosenfeldt Mathias T. , Gay David M. , McGregor Grace H. , Sansom Owen J. , Schulze Almut
Published: March 2023

Abstract
Oncogene activation and loss of tumor suppressor function changes the metabolic activity of cancer cells to drive unrestricted proliferation. Moreover, cancer cells adapt their metabolism to sustain growth and survival when access to oxygen and nutrients is restricted, such as in poorly vascularized tumor areas. We show here that p53-deficient colon cancer cells exposed to tumor-like metabolic stress in spheroid culture activated the mevalonate pathway to promote the synthesis of ubiquinone. This was essential to maintain mitochondrial electron transport for respiration and pyrimidine synthesis in metabolically compromised environments. Induction of mevalonate pathway enzyme expression in the absence of p53 was mediated by accumulation and stabilization of mature SREBP2. Mevalonate pathway inhibition by statins blocked pyrimidine nucleotide biosynthesis and induced oxidative stress and apoptosis in p53-deficient cancer cells in spheroid culture. Moreover, ubiquinone produced by the mevalonate pathway was essential for the growth of p53-deficient tumor organoids. In contrast, inhibition of intestinal hyperproliferation by statins in an Apc/KrasG12D-mutant mouse model was independent of de novo pyrimidine synthesis. Our results highlight the importance of the mevalonate pathway for maintaining mitochondrial electron transfer and biosynthetic activity in cancer cells exposed to metabolic stress. They also demonstrate that the metabolic output of this pathway depends on both genetic and environmental context.
Significance:
These findings suggest that p53-deficient cancer cells activate the mevalonate pathway via SREBP2 and promote the synthesis of ubiquinone that plays an essential role in reducing oxidative stress and supports the synthesis of pyrimidine nucleotide.
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 2023

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 Long Noncoding RNA TINCR-Mediated Regulation of Acetyl-CoA Metabolism Promotes Nasopharyngeal Carcinoma Progression and Chemoresistance
Authors: Zheng Zi-Qi , Li Zhi-Xuan , Guan Jia-Li , Liu Xu , Li Jun-Yan , Chen Yue , Lin Li , Kou Jia , Lv Jia-Wei , Zhang Lu-Lu , Zhou Guan-Qun , Liu Rui-Qi , Chen FoPing , He Xiao-Jun , Li Ying-Qin , Li Feng , Xu Si-Si , Ma Jun , Liu Na , Sun Ying
Published: March 2023

Abstract
Frontier evidence suggests that dysregulation of long noncoding RNAs (lncRNA) is ubiquitous in all human tumors, indicating that lncRNAs might have essential roles in tumorigenesis. Therefore, an in-depth study of the roles of lncRNA in nasopharyngeal carcinoma (NPC) carcinogenesis might be helpful to provide novel therapeutic targets. Here we report that lncRNA TINCR was significantly upregulated in NPC and was associated positively with poor survival. Silencing TINCR inhibited NPC progression and cisplatin resistance. Mechanistically, TINCR bound ACLY and protected it from ubiquitin degradation to maintain total cellular acetyl-CoA levels. Accumulation of cellular acetyl-CoA promoted de novo lipid biosynthesis and histone H3K27 acetylation, which ultimately regulated the peptidyl arginine deiminase 1 (PADI1)–MAPK–MMP2/9 pathway. In addition, insulin-like growth factor 2 mRNA-binding protein 3 interacted with TINCR and slowed its decay, which partially accounted for TINCR upregulation in NPC. These findings demonstrate that TINCR acts as a crucial driver of NPC progression and chemoresistance and highlights the newly identified TINCR–ACLY–PADI1–MAPK–MMP2/9 axis as a potential therapeutic target in NPC.
Significance:
TINCR-mediated regulation of a PADI1–MAPK–MMP2/9 signaling pathway plays a critical role in NPC progression and chemoresistance, marking TINCR as a viable therapeutic target in this disease.
Data from Rb and p53 Execute Distinct Roles in the Development of Pancreatic Neuroendocrine Tumors
Authors: Yamauchi Yuki , Kodama Yuzo , Shiokawa Masahiro , Kakiuchi Nobuyuki , Marui Saiko , Kuwada Takeshi , Sogabe Yuko , Tomono Teruko , Mima Atsushi , Morita Toshihiro , Matsumori Tomoaki , Ueda Tatsuki , Tsuda Motoyuki , Nishikawa Yoshihiro , Kuriyama Katsutoshi , Sakuma Yojiro , Ota Yuji , Maruno Takahisa , Uza Norimitsu , Masuda Atsuhiro , Tatsuoka Hisato , Yabe Daisuke , Minamiguchi Sachiko , Masui Toshihiko , Inagaki Nobuya , Uemoto Shinji , Chiba Tsutomu , Seno Hiroshi
Published: March 2023

Abstract
Pancreatic neuroendocrine tumors (PanNET) were classified into grades (G) 1 to 3 by the World Health Organization in 2017, but the precise mechanisms of PanNET initiation and progression have remained unclear. In this study, we used a genetically engineered mouse model to investigate the mechanisms of PanNET formation. Although pancreas-specific deletion of the Rb gene (Pdx1-Cre;Rbf/f) in mice did not affect pancreatic exocrine cells, the α-cell/β-cell ratio of islet cells was decreased at 8 months of age. During long-term observation (18–20 months), mice formed well-differentiated PanNET with a Ki67-labeling index of 2.7%. In contrast, pancreas-specific induction of a p53 mutation (Pdx1-Cre;Trp53R172H) had no effect on pancreatic exocrine and endocrine tissues, but simultaneous induction of a p53 mutation with Rb gene deletion (Pdx1-Cre;Trp53R172H;Rb f/f) resulted in the formation of aggressive PanNET with a Ki67-labeling index of 24.7% over the short-term (4 months). In Pdx1-Cre;Trp53R172H;Rbf/f mice, mRNA expression of Pten and Tsc2, negative regulators of the mTOR pathway, significantly decreased in the islet cells, and activation of the mTOR pathway was confirmed in subsequently formed PanNET. Thus, by manipulating Rb and p53 genes, we established a multistep progression model from dysplastic islet to indolent PanNET and aggressive metastatic PanNET in mice. These observations suggest that Rb and p53 have distinct roles in the development of PanNET.
Significance:
Pancreas-specific manipulation of Rb and p53 genes induced malignant transformation of islet cells, reproducing stepwise progression from microadenomas to indolent (grade 1) and subsequent aggressive PanNETs (grade 2–3).
Data from Transcriptionally Active Androgen Receptor Splice Variants Promote Hepatocellular Carcinoma Progression
Authors: Dauki Anees M. , Blachly James S. , Kautto Esko A. , Ezzat Sameera , Abdel-Rahman Mohamed H. , Coss Christopher C.
Published: March 2023

Abstract
Owing to the marked sexual dimorphism of hepatocellular carcinoma (HCC), sex hormone receptor signaling has been implicated in numerous aspects of liver cancer pathogenesis. We sought to reconcile the clear contribution of androgen receptor (AR) activity that has been established in preclinical models of HCC with the clinical failure of AR antagonists in patients with advanced HCC by evaluating potential resistance mechanisms to AR-targeted therapy. The AR locus was interrogated for resistance-causing genomic modifications using publicly available primary HCC datasets (1,019 samples). Analysis of HCC tumor and cell line RNA-seq data revealed enriched expression of constitutively active, treatment-refractory AR splice variants (AR-SV). HCC cell lines expressed C-terminal–truncated AR-SV; 28 primary HCC samples abundantly expressed AR-SV. Low molecular weight AR species were nuclear localized and constitutively active. Furthermore, AR/AR-SV signaling promoted AR-mediated HCC cell progression and conferred resistance to AR antagonists. Ligand-dependent and -independent AR signaling mediated HCC epithelial-to-mesenchymal transition by regulating the transcription factor SLUG. These data suggest that AR-SV expression in HCC drives HCC progression and resistance to traditional AR antagonists. Novel therapeutic approaches that successfully target AR-SVs may be therapeutically beneficial for HCC.
Significance:
Treatment-refractory, constitutively active androgen receptor splice variants promote hepatocellular carcinoma progression by regulating the epithelial-to-mesenchymal transition pathway.
Data from Postpartum Involution and Cancer: An Opportunity for Targeted Breast Cancer Prevention and Treatments?
Authors: Borges Virginia F. , Lyons Traci R. , Germain Doris , Schedin Pepper
Published: March 2023

Abstract
Childbirth at any age confers a transient increased risk for breast cancer in the first decade postpartum and this window of adverse effect extends over two decades in women with late-age first childbirth (>35 years of age). Crossover to the protective effect of pregnancy is dependent on age at first pregnancy, with young mothers receiving the most benefit. Furthermore, breast cancer diagnosis during the 5- to 10-year postpartum window associates with high risk for subsequent metastatic disease. Notably, lactation has been shown to be protective against breast cancer incidence overall, with varying degrees of protection by race, multiparity, and lifetime duration of lactation. An effect for lactation on breast cancer outcome after diagnosis has not been described. We discuss the most recent data and mechanistic insights underlying these epidemiologic findings. Postpartum involution of the breast has been identified as a key mediator of the increased risk for metastasis in women diagnosed within 5–10 years of a completed pregnancy. During breast involution, immune avoidance, increased lymphatic network, extracellular matrix remodeling, and increased seeding to the liver and lymph node work as interconnected pathways, leading to the adverse effect of a postpartum diagnosis. We al discuss a novel mechanism underlying the protective effect of breastfeeding. Collectively, these mechanistic insights offer potential therapeutic avenues for the prevention and/or improved treatment of postpartum breast cancer.
Data from A Feedback Circuitry between Polycomb Signaling and Fructose-1, 6-Bisphosphatase Enables Hepatic and Renal Tumorigenesis
Authors: Liao Kun , Deng Shuye , Xu Liyan , Pan Wenfeng , Yang Shiyu , Zheng Fufu , Wu Xingui , Hu Hongrong , Liu Zhijun , Luo Junhang , Zhang Rui , Kuang Dong-Ming , Dong Jiajun , Wu Yi , Zhang Hui , Zhou Penghui , Bei Jin-Xin , Xu Yang , Ji Yin , Wang Peng , Ju Huai-Qiang , Xu Rui-Hua , Li Bo
Published: March 2023

Abstract
Suppression of gluconeogenesis elevates glycolysis and is commonly observed in tumors derived from gluconeogenic tissues including liver and kidney, yet the definitive regulatory mechanism remains elusive. Here, we screened an array of transcription regulators and identified the enhancer of zeste homolog 2 (EZH2) as a key factor that inhibits gluconeogenesis in cancer cells. Specifically, EZH2 repressed the expression of a rate-limiting gluconeogenic enzyme fructose-1, 6-bisphosphatase 1 (FBP1) and promoted tumor growth primarily through FBP1 suppression. Furthermore, EZH2 was upregulated by genotoxins that commonly induce hepatic and renal tumorigenesis. Genotoxin treatments augmented EZH2 acetylation, leading to reduced association between EZH2 and its E3 ubiquitin ligase SMURF2. Consequently, EZH2 became less ubiquitinated and more stabilized, promoting FBP1 attenuation and tumor formation. Intriguingly, FBP1 physically interacted with EZH2, competed for EZH2 binding, and dissembled the polycomb complex. Therefore, FBP1 suppresses polycomb-initiated transcriptional responses and constitutes a double-negative feedback loop indispensable for EZH2-promoted tumorigenesis. Finally, EZH2 and FBP1 levels were inversely correlated in tumor tissues and accurately predicted patient survival. This work reveals an unexpected cross-talk between epigenetic and metabolic events, and identifies a new feedback circuitry that highlights EZH2 inhibitors as liver and kidney cancer therapeutics.
Significance:
A novel feedback loop involving EZH2 and suppression of the gluconeogenesis enzyme FBP1 promotes hepatocellular cancer growth.

See related commentary by Leithner, p. 657
Data from Futibatinib Is a Novel Irreversible FGFR 1–4 Inhibitor That Shows Selective Antitumor Activity against FGFR-Deregulated Tumors
Authors: Sootome Hiroshi , Fujita Hidenori , Ito Kenjiro , Ochiiwa Hiroaki , Fujioka Yayoi , Ito Kimihiro , Miura Akihiro , Sagara Takeshi , Ito Satoru , Ohsawa Hirokazu , Otsuki Sachie , Funabashi Kaoru , Yashiro Masakazu , Matsuo Kenichi , Yonekura Kazuhiko , Hirai Hiroshi
Published: March 2023

Abstract
FGFR signaling is deregulated in many human cancers, and FGFR is considered a valid target in FGFR-deregulated tumors. Here, we examine the preclinical profile of futibatinib (TAS-120; 1-[(3S)-[4-amino-3-[(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3, 4-d] pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one), a structurally novel, irreversible FGFR1–4 inhibitor. Among a panel of 296 human kinases, futibatinib selectively inhibited FGFR1–4 with IC50 values of 1.4 to 3.7 nmol/L. Futibatinib covalently bound the FGFR kinase domain, inhibiting FGFR phosphorylation and, in turn, downstream signaling in FGFR-deregulated tumor cell lines. Futibatinib exhibited potent, selective growth inhibition of several tumor cell lines (gastric, lung, multiple myeloma, bladder, endometrial, and breast) harboring various FGFR genomic aberrations. Oral administration of futibatinib led to significant dose-dependent tumor reduction in various FGFR-driven human tumor xenograft models, and tumor reduction was associated with sustained FGFR inhibition, which was proportional to the administered dose. The frequency of appearance of drug-resistant clones was lower with futibatinib than a reversible ATP-competitive FGFR inhibitor, and futibatinib inhibited several drug-resistant FGFR2 mutants, including the FGFR2 V565I/L gatekeeper mutants, with greater potency than any reversible FGFR inhibitors tested (IC50, 1.3–50.6 nmol/L). These results indicate that futibatinib is a novel orally available, potent, selective, and irreversible inhibitor of FGFR1–4 with a broad spectrum of antitumor activity in cell lines and xenograft models. These findings provide a strong rationale for testing futibatinib in patients with tumors oncogenically driven by FGFR genomic aberrations, with phase I to III trials ongoing.
Significance:
Preclinical characterization of futibatinib, an irreversible FGFR1–4 inhibitor, demonstrates selective and potent antitumor activity against FGFR-deregulated cancer cell lines and xenograft models, supporting clinical evaluation in patients with FGFR-driven tumors.
Data from NAMPT Inhibition Suppresses Cancer Stem-like Cells Associated with Therapy-Induced Senescence in Ovarian Cancer
Authors: Nacarelli Timothy , Fukumoto Takeshi , Zundell Joseph A. , Fatkhutdinov Nail , Jean Stephanie , Cadungog Mark G. , Borowsky Mark E. , Zhang Rugang
Published: March 2023

Abstract
Epithelial ovarian cancer (EOC) is the most lethal of gynecologic malignancies. The standard-of-care treatment for EOC is platinum-based chemotherapy such as cisplatin. Platinum-based chemotherapy induces cellular senescence. Notably, therapy-induced senescence contributes to chemoresistance by inducing cancer stem-like cells (CSC). However, therapeutic approaches targeting senescence-associated CSCs remain to be explored. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT) inhibition suppresses senescence-associated CSCs induced by platinum-based chemotherapy in EOC. Clinically applicable NAMPT inhibitors suppressed the outgrowth of cisplatin-treated EOC cells both in vitro and in vivo. Moreover, a combination of the NAMPT inhibitor FK866 and cisplatin improved the survival of EOC-bearing mice. These phenotypes correlated with inhibition of the CSCs signature, which consists of elevated expression of ALDH1A1 and stem-related genes, high aldehyde dehydrogenase activity, and CD133 positivity. Mechanistically, NAMPT regulates EOC CSCs in a paracrine manner through the senescence-associated secretory phenotype. Our results suggest that targeting NAMPT using clinically applicable NAMPT inhibitors, such as FK866, in conjunction with platinum-based chemotherapy represents a promising therapeutic strategy by suppressing therapy-induced senescence-associated CSCs.
Significance:
This study highlights the importance of NAMPT-mediated NAD+ biosynthesis in the production of cisplatin-induced senescence-associated cancer stem cells, as well as tumor relapse after cisplatin treatment.
Data from Acquired Resistance to HER2-Targeted Therapies Creates Vulnerability to ATP Synthase Inhibition
Authors: Gale Molly , Li Yao , Cao Jian , Liu Zongzhi Z. , Holmbeck Marissa A. , Zhang Meiling , Lang Sabine M. , Wu Lizhen , Do Carmo Mariana , Gupta Swati , Aoshima Keisuke , DiGiovanna Michael P. , Stern David F. , Rimm David L. , Shadel Gerald S. , Chen Xiang , Yan Qin
Published: March 2023

Abstract
Acquired resistance to HER2-targeted therapies occurs frequently in HER2+ breast tumors and new strategies for overcoming resistance are needed. Here, we report that resistance to trastuzumab is reversible, as resistant cells regained sensitivity to the drug after being cultured in drug-free media. RNA-sequencing analysis showed that cells resistant to trastuzumab or trastuzumab + pertuzumab in combination increased expression of oxidative phosphorylation pathway genes. Despite minimal changes in mitochondrial respiration, these cells exhibited increased expression of ATP synthase genes and selective dependency on ATP synthase function. Resistant cells were sensitive to inhibition of ATP synthase by oligomycin A, and knockdown of ATP5J or ATP5B, components of ATP synthase complex, rendered resistant cells responsive to a low dose of trastuzumab. Furthermore, combining ATP synthase inhibitor oligomycin A with trastuzumab led to regression of trastuzumab-resistant tumors in vivo. In conclusion, we identify a novel vulnerability of cells with acquired resistance to HER2-targeted antibody therapies and reveal a new therapeutic strategy to overcome resistance.
Significance:
These findings implicate ATP synthase as a novel potential target for tumors resistant to HER2-targeted therapies.
Data from RNA-Binding Protein ZFP36L1 Suppresses Hypoxia and Cell-Cycle Signaling
Authors: Loh Xin-Yi , Sun Qiao-Yang , Ding Ling-Wen , Mayakonda Anand , Venkatachalam Nachiyappan , Yeo Mei-Shi , Silva Tiago C. , Xiao Jin-Fen , Doan Ngan B. , Said Jonathan W. , Ran Xue-Bin , Zhou Si-Qin , Dakle Pushkar , Shyamsunder Pavithra , Koh Angele Pei-Fern , Huang Ruby Yun-Ju , Berman Benjamin P. , Tan Soo-Yong , Yang Henry , Lin De-Chen , Koeffler H. Phillip
Published: March 2023

Abstract
ZFP36L1 is a tandem zinc-finger RNA-binding protein that recognizes conserved adenylate-uridylate–rich elements (ARE) located in 3′untranslated regions (UTR) to mediate mRNA decay. We hypothesized that ZFP36L1 is a negative regulator of a posttranscriptional hub involved in mRNA half-life regulation of cancer-related transcripts. Analysis of in silico data revealed that ZFP36L1 was significantly mutated, epigenetically silenced, and downregulated in a variety of cancers. Forced expression of ZFP36L1 in cancer cells markedly reduced cell proliferation in vitro and in vivo, whereas silencing of ZFP36L1 enhanced tumor cell growth. To identify direct downstream targets of ZFP36L1, systematic screening using RNA pull-down of wild-type and mutant ZFP36L1 as well as whole transcriptome sequencing of bladder cancer cells {plus minus} tet-on ZFP36L1 was performed. A network of 1,410 genes was identified as potential direct targets of ZFP36L1. These targets included a number of key oncogenic transcripts such as HIF1A, CCND1, and E2F1. ZFP36L1 specifically bound to the 3′UTRs of these targets for mRNA degradation, thus suppressing their expression. Dual luciferase reporter assays and RNA electrophoretic mobility shift assays showed that wild-type, but not zinc-finger mutant ZFP36L1, bound to HIF1A 3′UTR and mediated HIF1A mRNA degradation, leading to reduced expression of HIF1A and its downstream targets. Collectively, our findings reveal an indispensable role of ZFP36L1 as a posttranscriptional safeguard against aberrant hypoxic signaling and abnormal cell-cycle progression.
Significance:
RNA-binding protein ZFP36L1 functions as a tumor suppressor by regulating the mRNA stability of a number of mRNAs involved in hypoxia and cell-cycle signaling.
Data from Stromal SNAI2 Is Required for ERBB2 Breast Cancer Progression
Authors: Blanco-Gómez Adrián , Hontecillas-Prieto Lourdes , Corchado-Cobos Roberto , García-Sancha Natalia , Salvador Nélida , Castellanos-Martín Andrés , Sáez-Freire María del Mar , Mendiburu-Eliçabe Marina , Alonso-López Diego , De Las Rivas Javier , Lorente Mar , García-Casas Ana , Del Carmen Sofía , Abad-Hernández María del Mar , Cruz-Hernández Juan Jesús , Rodríguez-Sánchez César Augusto , Claros-Ampuero Juncal , García-Cenador Begoña , García-Criado Javier , Orimo Akira , Gridley Thomas , Pérez-Losada Jesús , Castillo-Lluva Sonia
Published: March 2023

Abstract
SNAI2 overexpression appears to be associated with poor prognosis in breast cancer, yet it remains unclear in which breast cancer subtypes this occurs. Here we show that excess SNAI2 is associated with a poor prognosis of luminal B HER2+/ERBB2+ breast cancers in which SNAI2 expression in the stroma but not the epithelium correlates with tumor proliferation. To determine how stromal SNAI2 might influence HER2+ tumor behavior, Snai2-deficient mice were crossed with a mouse line carrying the ErbB2/Neu protooncogene to generate HER2+/ERBB2+ breast cancer. Tumors generated in this model expressed SNAI2 in the stroma but not the epithelium, allowing for the role of stromal SNAI2 to be studied without interference from the epithelial compartment. The absence of SNAI2 in the stroma of HER2+/ERBB2+ tumors is associated with: (i) lower levels of cyclin D1 (CCND1) and reduced tumor epithelium proliferation; (ii) higher levels of AKT and a lower incidence of metastasis; (iii) lower levels of angiopoietin-2 (ANGPT2), and more necrosis. Together, these results indicate that the loss of SNAI2 in cancer-associated fibroblasts limits the production of some cytokines, which influences AKT/ERK tumor signaling and subsequent proliferative and metastatic capacity of ERBB2+ breast cancer cells. Accordingly, SNAI2 expression in the stroma enhanced the tumorigenicity of luminal B HER2+/ERBB2+ breast cancers. This work emphasizes the importance of stromal SNAI2 in breast cancer progression and patients' prognosis.
Significance:
Stromal SNAI2 expression enhances the tumorigenicity of luminal B HER2+ breast cancers and can identify a subset of patients with poor prognosis, making SNAI2 a potential therapeutic target for this disease.
Data from Y Chromosome LncRNA Are Involved in Radiation Response of Male Non–Small Cell Lung Cancer Cells
Authors: Brownmiller Tayvia , Juric Jamie A. , Ivey Abby D. , Harvey Brandon M. , Westemeier Emily S. , Winters Michael T. , Stevens Alyson M. , Stanley Alana N. , Hayes Karen E. , Sprowls Samuel A. , Ammer Amanda S. Gatesman , Walker Mackenzee , Bey Erik A. , Wu Xiaoliang , Lim Zuan-Fu , Zhu Lin , Wen Sijin , Hu Gangqing , Ma Patrick C. , Martinez Ivan
Published: March 2023

Abstract
Numerous studies have implicated changes in the Y chromosome in male cancers, yet few have investigated the biological importance of Y chromosome noncoding RNA. Here we identify a group of Y chromosome–expressed long noncoding RNA (lncRNA) that are involved in male non–small cell lung cancer (NSCLC) radiation sensitivity. Radiosensitive male NSCLC cell lines demonstrated a dose-dependent induction of linc-SPRY3-2/3/4 following irradiation, which was not observed in radioresistant male NSCLC cell lines. Cytogenetics revealed the loss of chromosome Y (LOY) in the radioresistant male NSCLC cell lines. Gain- and loss-of-function experiments indicated that linc-SPRY3-2/3/4 transcripts affect cell viability and apoptosis. Computational prediction of RNA binding proteins (RBP) motifs and UV-cross-linking and immunoprecipitation (CLIP) assays identified IGF2BP3, an RBP involved in mRNA stability, as a binding partner for linc-SPRY3-2/3/4 RNA. The presence of linc-SPRY3-2/3/4 reduced the half-life of known IGF2BP3 binding mRNA, such as the antiapoptotic HMGA2 mRNA, as well as the oncogenic c-MYC mRNA. Assessment of Y chromosome in NSCLC tissue microarrays and expression of linc-SPRY3-2/3/4 in NSCLC RNA-seq and microarray data revealed a negative correlation between the loss of the Y chromosome or linc-SPRY3-2/3/4 and overall survival. Thus, linc-SPRY3-2/3/4 expression and LOY could represent an important marker of radiotherapy in NSCLC.
Significance:
This study describes previously unknown Y chromosome–expressed lncRNA regulators of radiation response in male NSCLC and show a correlation between loss of chromosome Y and radioresistance.
Data from A Division of Labor between YAP and TAZ in Non–Small Cell Lung Cancer
Authors: Shreberk-Shaked Michal , Dassa Bareket , Sinha Sanju , Di Agostino Silvia , Azuri Ido , Mukherjee Saptaparna , Aylon Yael , Blandino Giovanni , Ruppin Eytan , Oren Moshe
Published: March 2023

Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. The paralogous transcriptional cofactors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ, also called WWTR1), the main downstream effectors of the Hippo signal transduction pathway, are emerging as pivotal determinants of malignancy in lung cancer. Traditionally, studies have tended to consider YAP and TAZ as functionally redundant transcriptional cofactors with similar biological impact. However, there is growing evidence that each of them also possesses distinct attributes. Here we sought to systematically characterize the division of labor between YAP and TAZ in non–small cell lung cancer (NSCLC), the most common histological subtype of lung cancer. Representative NSCLC cell lines as well as patient-derived data showed that the two paralogs orchestrated nonoverlapping transcriptional programs in this cancer type. YAP preferentially regulated gene sets associated with cell division and cell-cycle progression, whereas TAZ preferentially regulated genes associated with extracellular matrix organization. Depletion of YAP resulted in growth arrest, whereas its overexpression promoted cell proliferation. Likewise, depletion of TAZ compromised cell migration, whereas its overexpression enhanced migration. The differential effects of YAP and TAZ on key cellular processes were also associated with differential response to anticancer therapies. Uncovering the different activities and downstream effects of YAP and TAZ may thus facilitate better stratification of patients with lung cancer for anticancer therapies.
Significance:
Thease findings show that oncogenic paralogs YAP and TAZ have distinct roles in NSCLC and are associated with differential response to anticancer drugs, knowledge that may assist lung cancer therapy decisions.
Data from An Allosteric PRC2 Inhibitor Targeting EED Suppresses Tumor Progression by Modulating the Immune Response
Authors: Dong Hongping , Liu Shaojun , Zhang Xuejie , Chen Sheng , Kang Lijing , Chen Yanni , Ma Shichao , Fu Xianlei , Liu Yanchao , Zhang Hailong , Zou Bin
Published: March 2023

Abstract
Aberrant activity of polycomb repressive complex 2 (PRC2) is involved in a wide range of human cancer progression. The WD40 repeat-containing protein EED is a core component of PRC2 and enhances PRC2 activity through interaction with H3K27me3. In this study, we report the discovery of a class of pyrimidone compounds, represented by BR-001, as potent allosteric inhibitors of PRC2. X-ray co-crystallography showed that BR-001 directly binds EED in the H3K27me3-binding pocket. BR-001 displayed antitumor potency in vitro and in vivo. In Karpas422 and Pfeiffer xenograft mouse models, twice daily oral dosing with BR-001 resulted in robust antitumor activity. BR-001 was also efficacious in syngeneic CT26 colon tumor-bearing mice; oral dosing of 30 mg/kg of BR-001 led to 59.3% tumor growth suppression and increased frequency of effector CD8+ T-cell infiltrates in tumors. Pharmacodynamic analysis revealed that CXCL10 was highly upregulated, suggesting that CXCL10 triggers the trafficking of CD8+ T cells toward tumor sites. Our results demonstrate for the first time that inhibition of EED modulates the tumor immune microenvironment to induce regression of colon tumors and therefore has the potential to be used in combination with immune-oncology therapy.
Significance:
BR-001, a potent inhibitor of the EED subunit of the PRC2 complex, suppresses tumor progression by modulating the tumor microenvironment.
Data from YAP and AP-1 Cooperate to Initiate Pancreatic Cancer Development from Ductal Cells in Mice
Authors: Park Jaeoh , Eisenbarth David , Choi Wonyoung , Kim Hail , Choi Chan , Lee Dahye , Lim Dae-Sik
Published: March 2023

Abstract
The development of pancreatic cancer is heavily dependent upon the aberrant activation of KRAS signaling. Among the downstream targets of KRAS, the effectors of the Hippo pathway YAP and TAZ (YAP/TAZ) are crucial during cancer initiation and progression. However, little is known about the cell type-specific effects of YAP/TAZ on the development of pancreatic cancer. Here we clarify the unique consequences of YAP/TAZ activation in the ductal cell population of the pancreas by generating mice with pancreatic duct cell-specific, inducible knockouts of Lats1 and Lats2, the main kinases upstream of YAP/TAZ. Oncogenic activation of YAP by deletion of Lats1/2 in ductal cells led to the rapid transformation of the pancreas, which was accompanied by a robust increase in the expression of YAP and AP-1 target genes. Pharmacologic inhibition of AP-1 activity induced death in Lats1/2 knockout organoids and attenuated YAP-dependent transformation of the pancreas in vivo. Both YAP and AP-1 were activated during the development of KRAS-dependent cancer in mice and human patients with pancreatic ductal adenocarcinoma, suggesting that this signaling hub represents an important mediator of pancreatic cancer development and progression. Collectively, these data define a YAP-dependent mechanism of pancreatic cancer cell development and suggest that inhibition of AP-1 can suppress this development.
Significance:
A pancreatic ductal cell-specific knockout mouse model featuring constitutively active YAP allows for the study of YAP-dependent transformation of the pancreas and for screening pharmacologically active inhibitors.
Data from BRG1 Loss Predisposes Lung Cancers to Replicative Stress and ATR Dependency
Authors: Gupta Manav , Concepcion Carla P. , Fahey Caroline G. , Keshishian Hasmik , Bhutkar Arjun , Brainson Christine F. , Sanchez-Rivera Francisco J. , Pessina Patrizia , Kim Jonathan Y. , Simoneau Antoine , Paschini Margherita , Beytagh Mary C. , Stanclift Caroline R. , Schenone Monica , Mani D.R. , Li Chendi , Oh Audris , Li Fei , Hu Hai , Karatza Angeliki , Bronson Roderick T. , Shaw Alice T. , Hata Aaron N. , Wong Kwok-Kin , Zou Lee , Carr Steven A. , Jacks Tyler , Kim Carla F.
Published: March 2023

Abstract
Inactivation of SMARCA4/BRG1, the core ATPase subunit of mammalian SWI/SNF complexes, occurs at very high frequencies in non–small cell lung cancers (NSCLC). There are no targeted therapies for this subset of lung cancers, nor is it known how mutations in BRG1 contribute to lung cancer progression. Using a combination of gain- and loss-of-function approaches, we demonstrate that deletion of BRG1 in lung cancer leads to activation of replication stress responses. Single-molecule assessment of replication fork dynamics in BRG1-deficient cells revealed increased origin firing mediated by the prelicensing protein, CDC6. Quantitative mass spectrometry and coimmunoprecipitation assays showed that BRG1-containing SWI/SNF complexes interact with RPA complexes. Finally, BRG1-deficient lung cancers were sensitive to pharmacologic inhibition of ATR. These findings provide novel mechanistic insight into BRG1-mutant lung cancers and suggest that their dependency on ATR can be leveraged therapeutically and potentially expanded to BRG1-mutant cancers in other tissues.
Significance:
These findings indicate that inhibition of ATR is a promising therapy for the 10% of non-small cell lung cancer patients harboring mutations in SMARCA4/BRG1.
Data from Exosomal Noncoding RNAs and Tumor Drug Resistance
Authors: Guo Chengyao , Liu Jinbo , Zhou Quanbo , Song Junmin , Zhang Zhiyong , Li Zhen , Wang Guixian , Yuan Weitang , Sun Zhenqiang
Published: March 2023

Abstract
Tumor drug resistance is a major challenge in the treatment of cancer. Noncoding RNAs (ncRNA) play a role in the progression of drug resistance. Recent studies have indicated that exosomes, with their in vitro and in vivo compatibility, are the best natural carrier of ncRNA, and their transport of ncRNA into cells could regulate drug resistance. Exosomal ncRNA impact drug resistance through participation in drug efflux, regulation of signaling pathways, and modification of the tumor microenvironment. In this review, we evaluate the mechanism of exosomal ncRNA related to tumor drug resistance, their role in different tumors, and potential clinical applications.
Data from Tumor Cell–Derived IL1β Promotes Desmoplasia and Immune Suppression in Pancreatic Cancer
Authors: Das Shipra , Shapiro Beny , Vucic Emily A. , Vogt Sandra , Bar-Sagi Dafna
Published: March 2023

Abstract
Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy typified by a highly stromal and weakly immunogenic tumor microenvironment that promotes tumor evolution and contributes to therapeutic resistance. Here, we demonstrate that PDA tumor cell–derived proinflammatory cytokine IL1β is essential for the establishment of the protumorigenic PDA microenvironment. Tumor cell–derived IL1β promoted the activation and secretory phenotype of quiescent pancreatic stellate cells and established an immunosuppressive milieu mediated by M2 macrophages, myeloid-derived suppressor cells, CD1dhiCD5+ regulatory B cells, and Th17 cells. Loss of tumor cell–derived IL1 signaling in tumor stroma enabled intratumoral infiltration and activation of CD8+ cytotoxic T cells, attenuated growth of pancreatic neoplasia, and conferred survival advantage to PDA-bearing mice. Accordingly, antibody-mediated neutralization of IL1β significantly enhanced the antitumor activity of α-PD-1 and was accompanied by increased tumor infiltration of CD8+ T cells. Tumor cell expression of IL1β in vivo was driven by microbial-dependent activation of toll-like receptor 4 (TLR4) signaling and subsequent engagement of the NLRP3 inflammasome. Collectively, these findings identify a hitherto unappreciated role for tumor cell–derived IL1β in orchestrating an immune-modulatory program that supports pancreatic tumorigenesis.
Significance:
These findings identify a new modality for immune evasion in PDA that depends on IL1β production by tumor cells through TLR4-NLRP3 inflammasome activation. Targeting this axis might provide an effective PDA therapeutic strategy.
Data from Identification of a Small-Molecule Inhibitor That Disrupts the SIX1/EYA2 Complex, EMT, and Metastasis
Authors: Zhou Hengbo , Blevins Melanie A. , Hsu Jessica Y. , Kong Deguang , Galbraith Matthew D. , Goodspeed Andrew , Culp-Hill Rachel , Oliphant Michael U.J. , Ramirez Dominique , Zhang Lingdi , Trinidad-Pineiro Jennyvette , Mathews Griner Lesley , King Rebecca , Barnaeva Elena , Hu Xin , Southall Noel T. , Ferrer Marc , Gustafson Daniel L. , Regan Daniel P. , D'Alessandro Angelo , Costello James C. , Patnaik Samarjit , Marugan Juan , Zhao Rui , Ford Heide L.
Published: March 2023

Abstract
Metastasis is the major cause of mortality for patients with cancer, and dysregulation of developmental signaling pathways can significantly contribute to the metastatic process. The Sine oculis homeobox homolog 1 (SIX1)/eyes absent (EYA) transcriptional complex plays a critical role in the development of multiple organs and is typically downregulated after development is complete. In breast cancer, aberrant expression of SIX1 has been demonstrated to stimulate metastasis through activation of TGFβ signaling and subsequent induction of epithelial–mesenchymal transition (EMT). In addition, SIX1 can induce metastasis via non-cell autonomous means, including activation of GLI-signaling in neighboring tumor cells and activation of VEGFC–induced lymphangiogenesis. Thus, targeting SIX1 would be expected to inhibit metastasis while conferring limited side effects. However, transcription factors are notoriously difficult to target, and thus novel approaches to inhibit their action must be taken. Here we identified a novel small molecule compound, NCGC00378430 (abbreviated as 8430), that reduces the SIX1/EYA2 interaction. 8430 partially reversed transcriptional and metabolic profiles mediated by SIX1 overexpression and reversed SIX1-induced TGFβ signaling and EMT. 8430 was well tolerated when delivered to mice and significantly suppressed breast cancer–associated metastasis in vivo without significantly altering primary tumor growth. Thus, we have demonstrated for the first time that pharmacologic inhibition of the SIX1/EYA2 complex and associated phenotypes is sufficient to suppress breast cancer metastasis.
Significance:
These findings identify and characterize a novel inhibitor of the SIX1/EYA2 complex that reverses EMT phenotypes suppressing breast cancer metastasis.
Data from A Deep Learning Framework Identifies Pathogenic Noncoding Somatic Mutations from Personal Prostate Cancer Genomes
Authors: Wang Cheng , Li Jingjing
Published: March 2023

Abstract
Our understanding of noncoding mutations in cancer genomes has been derived primarily from mutational recurrence analysis by aggregating clinical samples on a large scale. These cohort-based approaches cannot directly identify individual pathogenic noncoding mutations from personal cancer genomes. Therefore, although most somatic mutations are localized in the noncoding cancer genome, their effects on driving tumorigenesis and progression have not been systematically explored and noncoding somatic alleles have not been leveraged in current clinical practice to guide personalized screening, diagnosis, and treatment. Here, we present a deep learning framework to capture pathogenic noncoding mutations in personal cancer genomes, which perturb gene regulation by altering chromatin architecture. We deployed the system specifically for localized prostate cancer by integrating large-scale prostate cancer genomes and the prostate-specific epigenome. We exhaustively evaluated somatic mutations in each patient's genome and agnostically identified thousands of somatic alleles altering the prostate epigenome. Functional genomic analyses subsequently demonstrated that affected genes displayed differential expression in prostate tumor samples, were vulnerable to expression alterations, and were convergent onto androgen receptor–mediated signaling pathways. Accumulation of pathogenic regulatory mutations in these affected genes was predictive of clinical observations, suggesting potential clinical utility of this approach. Overall, the deep learning framework has significantly expanded our view of somatic mutations in the vast noncoding genome, uncovered novel genes in localized prostate cancer, and will foster the development of personalized screening and therapeutic strategies for prostate cancer.
Significance:
This study's characterization of the noncoding genome in prostate cancer reveals mutational signatures predictive of clinical observations, which may serve as a powerful prognostic tool in this disease.