bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from SNHG6 Acts as a Genome-Wide Hypomethylation Trigger via Coupling of miR-1297–Mediated S-Adenosylmethionine–Dependent Positive Feedback Loops
Authors: Guo Tao , Wang Hongling , Liu Pengpeng , Xiao Yushao , Wu Ping , Wang Yitao , Chen Baiyang , Zhao Qiu , Liu Zhisu , Liu Quanyan
Published: March 2024

Abstract
Aberrant genome-wide hypomethylation and long noncoding RNA (lncRNA) dysregulation are associated with hepatocarcinogenesis. However, whether a relationship between the two exists remains largely unknown. S-adenosylmethionine (SAMe)-dependent methylation is a critical factor in genomic methylation. We previously found that SNHG6 lncRNA acted as an oncogene in hepatocarcinogenesis and could be considered a potential prognostic indicator for hepatocellular carcinoma (HCC). Here we verify that SNHG6 leads to genome-wide hypomethylation in hepatoma cells and that SNHG6 negatively correlates with the steady-state SAMe concentration in vivo and in vitro. SNHG6 suppressed MAT1A protein expression by activating the miR-1297/FUS pathway to regulate nucleocytoplasmic shuttling of MAT1A mRNA. In addition, SNHG6 promoted expression of MAT2A by suppressing direct binding of miR-1297 to the MAT2A 3′UTR. SNHG6 regulated steady-state SAMe levels via coupling of two miR-1297–mediated SAMe-dependent positive feedback loops. Interestingly, the effect of SNHG6 on genome-wide methylation was inhibited by exogenous SAMe within a certain concentration range. These results suggest that single lncRNA dysregulation can lead to aberrant genome-wide hypomethylation by inhibiting SAMe production in HCC and that exogenous SAMe may be beneficial in the treatment of HCC.

Significance: These findings explore the role of SNHG6 lncRNA in suppressing production of the universal methyl donor SAMe and its impact on global DNA methylation levels in liver cancer and highlight the potential benefit of SAMe for the treatment of liver cancer. Cancer Res; 78(14); 3849–64. ©2018 AACR.
Data from BMX-Mediated Regulation of Multiple Tyrosine Kinases Contributes to Castration Resistance in Prostate Cancer
Authors: Chen Sen , Cai Changmeng , Sowalsky Adam G. , Ye Huihui , Ma Fen , Yuan Xin , Simon Nicholas I. , Gray Nathanael S. , Balk Steven P.
Published: March 2024

Abstract
Prostate cancer responds to therapies that suppress androgen receptor (AR) activity (androgen deprivation therapy, ADT) but invariably progresses to castration-resistant prostate cancer (CRPC). The Tec family nonreceptor tyrosine kinase BMX is activated downstream of PI3K and has been implicated in regulation of multiple pathways and in the development of cancers including prostate cancer. However, its precise mechanisms of action, and particularly its endogenous substrates, remain to be established. Here, we demonstrate that BMX expression in prostate cancer is suppressed directly by AR via binding to the BMX gene and that BMX expression is subsequently rapidly increased in response to ADT. BMX contributed to CRPC development in cell line and xenograft models by positively regulating the activities of multiple receptor tyrosine kinases through phosphorylation of a phosphotyrosine-tyrosine (pYY) motif in their activation loop, generating pYpY that is required for full kinase activity. To assess BMX activity in vivo, we generated a BMX substrate–specific antibody (anti-pYpY) and found that its reactivity correlated with BMX expression in clinical samples, supporting pYY as an in vivo substrate. Inhibition of BMX with ibrutinib (developed as an inhibitor of the related Tec kinase BTK) or another BMX inhibitor BMX-IN-1 markedly enhanced the response to castration in a prostate cancer xenograft model. These data indicate that increased BMX in response to ADT contributes to enhanced tyrosine kinase signaling and the subsequent emergence of CRPC, and that combination therapies targeting AR and BMX may be effective in a subset of patients.

Significance: The tyrosine kinase BMX is negatively regulated by androgen and contributes to castration-resistant prostate cancer by enhancing the phosphorylation and activation of multiple receptor tyrosine kinases following ADT. Cancer Res; 78(18); 5203–15. ©2018 AACR.
Data from HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes
Authors: Wang Sophia S. , Carrington Mary , Berndt Sonja I. , Slager Susan L. , Bracci Paige M. , Voutsinas Jenna , Cerhan James R. , Smedby Karin E. , Hjalgrim Henrik , Vijai Joseph , Morton Lindsay M. , Vermeulen Roel , Paltiel Ora , Vajdic Claire M. , Linet Martha S. , Nieters Alexandra , de Sanjose Silvia , Cozen Wendy , Brown Elizabeth E. , Turner Jennifer , Spinelli John J. , Zheng Tongzhang , Birmann Brenda M. , Flowers Christopher R. , Becker Nikolaus , Holly Elizabeth A. , Kane Eleanor , Weisenburger Dennis , Maynadie Marc , Cocco Pierluigi , Albanes Demetrius , Weinstein Stephanie J. , Teras Lauren R. , Diver W. Ryan , Lax Stephanie J. , Travis Ruth C. , Kaaks Rudolph , Riboli Elio , Benavente Yolanda , Brennan Paul , McKay James , Delfau-Larue Marie-Hélène , Link Brian K. , Magnani Corrado , Ennas Maria Grazia , Latte Giancarlo , Feldman Andrew L. , Doo Nicole Wong , Giles Graham G. , Southey Melissa C. , Milne Roger L. , Offit Kenneth , Musinsky Jacob , Arslan Alan A. , Purdue Mark P. , Adami Hans-Olov , Melbye Mads , Glimelius Bengt , Conde Lucia , Camp Nicola J. , Glenn Martha , Curtin Karen , Clavel Jacqueline , Monnereau Alain , Cox David G. , Ghesquières Hervé , Salles Gilles , Bofetta Paulo , Foretova Lenka , Staines Anthony , Davis Scott , Severson Richard K. , Lan Qing , Brooks-Wilson Angela , Smith Martyn T. , Roman Eve , Kricker Anne , Zhang Yawei , Kraft Peter , Chanock Stephen J. , Rothman Nathaniel , Hartge Patricia , Skibola Christine F.
Published: March 2024

Abstract
A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes.

Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.
Data from APC/C-CDH1–Regulated IDH3β Coordinates with the Cell Cycle to Promote Cell Proliferation
Authors: Wu Qingnan , Zhang Weimin , Xue Liyan , Wang Yan , Fu Ming , Ma Liying , Song Yongmei , Zhan Qi-Min
Published: March 2024

Abstract
Metabolic activities are often accompanied by cell-cycle progression, yet known connections between these two processes remain limited. Here, we identified the isocitrate dehydrogenase 3β (IDH3β) as a novel substrate of anaphase-promoting complex/cyclosome (APC/C)-CDH1 and an important regulator of the cell cycle. In esophageal squamous cell carcinoma (ESCC), IDH3β was posttranslationally upregulated in late G1 phase, and overexpression of IDH3β accelerated G1–S transition, contributing to the promotion of cell proliferation in vitro and in vivo. α-Ketoglutarate (α-KG), a crucial metabolite in tricarboxylic acid (TCA) cycle, was dependent on IDH3β level and partially accounted for IDH3β-mediated cell growth. IDH3β expression increased PFKFB3 protein levels and enhanced glucose uptake, and high expression of IDH3β correlated with poor survival in patients with ESCC, suggesting a potential application of IDH3β in prognosis. Overall, our results highlight a new molecular connection between cell-cycle regulation and the TCA cycle in ESCC.
Significance:
These findings show that IDH3β is an APC/C-CDH1 substrate and is expressed in a cell-cycle–dependent manner, highlighting novel molecular cross-talk between the TCA cycle and cell cycle in cancer cells.
Data from Mammary Precancerous Stem and Non-Stem Cells Evolve into Cancers of Distinct Subtypes
Authors: Bu Wen , Liu Zhenyu , Jiang Weiyu , Nagi Chandandeep , Huang Shixia , Edwards Dean P. , Jo Eunji , Mo Qianxing , Creighton Chad J. , Hilsenbeck Susan G. , Leavitt Andrew D. , Lewis Michael T. , Wong Stephen T. C. , Li Yi
Published: March 2024

Abstract
There are distinct cell subpopulations in normal epithelial tissue, including stem cells, progenitor cells, and more differentiated cells, all of which have been extensively studied for their susceptibility to tumorigenesis. However, normal cells usually have to progress through a precancerous lesion state before becoming a full-blown tumor. Precancerous early lesions are heterogeneous, and the cell subset that is the primary source of the eventual tumor remains largely unknown. By using mouse models that are tailored to address this question, we identified a keratin 6a-expressing precancerous stem cell (PcSC) subset and a more differentiated whey acidic protein-positive (WAP+) cell subset in mammary precancerous lesions initiated by the Wnt1 oncogene. Both cell subsets rapidly progressed to cancer upon introduction of constitutively active versions of either HRAS or BRAF. However, the resulting tumors were dramatically different in protein profiles and histopathology: keratin 6a+ precancerous cells gave rise to adenocarcinoma, whereas WAP+ cells yielded metaplastic carcinoma with severe squamous differentiation and more robust activation of MEK/ERK signaling. Therefore, both stem and non-stem cells in mammary precancerous lesions can contribute to the eventual cancers, but their differentiation status determines the resulting cancer phenotype. This work identifies a previously unknown player in cancer heterogeneity and suggests that cancer prevention should target precancerous cells broadly and not be limited to PcSC.
Significance:
This work uses a novel mouse mammary gland cancer model to show that tumors initiated from different precancerous mammary epithelial cells are distinct.
Data from Epigenetic Regulation of NAMPT by NAMPT-ASDrives Metastatic Progression in Triple-Negative Breast Cancer
Authors: Zhang Hanwen , Zhang Ning , Liu Ying , Su Peng , Liang Yiran , Li Yaming , Wang Xiaolong , Chen Tong , Song Xiaojin , Sang Yuting , Duan Yi , Zhang Jiashu , Wang Lijuan , Chen Bing , Zhao Wenjing , Guo Haiyang , Liu Zhaojian , Hu Guohong , Yang Qifeng
Published: March 2024

Abstract
Triple-negative breast cancer (TNBC) is highly heterogeneous and has a poor prognosis. It is therefore important to identify the underlying molecular mechanisms in order to develop novel therapeutic strategies. Although emerging research has revealed long noncoding RNAs (lncRNA) as vital to carcinogenesis and cancer progression, their functional involvement in TNBC has not been well defined. In this study, we utilized the The Cancer Genome Atlas (TCGA) database and analyzed clinical samples to show that the long noncoding antisense transcript of nicotinamide phosphoribosyltransferase (NAMPT), NAMPT-AS, is upregulated in TNBC and is associated with poor prognosis, lymph node involvement, metastasis, and advanced stage. NAMPT-AS was cotranscribed with NAMPT from a bidirectional promoter, where the distributions of H3K4me3 and H3K27Ac chromatin modifications were enriched based on ENCODE and FANTOM5, suggesting the potential enhancer-RNA characteristics of NAMPT-AS. NAMPT-AS epigenetically regulated the expression of NAMPT in two divergent ways: NAMPT-AS recruited POU2F2 to activate the transcription of NAMPT, and NAMPT-AS acted as a competing endogenous RNA to rescue NAMPT degradation from miR-548b-3p. NAMPT-AS/NAMPT promoted tumor progression and regulated autophagy through the mTOR pathway in vitro and in vivo. In a cohort of 480 breast cancer patients, NAMPT was associated with breast cancer–specific survival and overall survival. These results demonstrate that NAMPT-AS is an oncogenic lncRNA in TNBC that epigenetically activates NAMPT to promote tumor progression and metastasis. Furthermore, these data identify NAMPT-AS/NAMPT as promising therapeutic targets in patients with TNBC.
Significance:
Upregulation of the long noncoding antisense RNA of NAMPT gene (NAMPT-AS) is associated with metastasis and poor prognosis in TNBC.
Data from Anthropometric Risk Factors for Cancers of the Biliary Tract in the Biliary Tract Cancers Pooling Project
Authors: Jackson Sarah S. , Van Dyke Alison L. , Zhu Bin , Pfeiffer Ruth M. , Petrick Jessica L. , Adami Hans-Olov , Albanes Demetrius , Andreotti Gabriella , Beane Freeman Laura E. , Berrington de González Amy , Buring Julie E. , Chan Andrew T. , Chen Yu , Fraser Gary E. , Freedman Neal D. , Gao Yu-Tang , Gapstur Susan M. , Gaziano J. Michael , Giles Graham G. , Grant Eric J. , Grodstein Francine , Hartge Patricia , Jenab Mazda , Kitahara Cari M. , Knutsen Synnove F. , Koh Woon-Puay , Larsson Susanna C. , Lee I-Min , Liao Linda M. , Luo Juhua , McGee Emma E. , Milne Roger L. , Monroe Kristine R. , Neuhouser Marian L. , O’Brien Katie M. , Peters Ulrike , Poynter Jenny N. , Purdue Mark P. , Robien Kim , Sandler Dale P. , Sawada Norie , Schairer Catherine , Sesso Howard D. , Simon Tracey G. , Sinha Rashmi , Stolzenberg-Solomon Rachael Z. , Tsugane Shoichiro , Wang Renwei , Weiderpass Elisabete , Weinstein Stephanie J. , White Emily , Wolk Alicja , Yuan Jian-Min , Zeleniuch-Jacquotte Anne , Zhang Xuehong , McGlynn Katherine A. , Campbell Peter T. , Koshiol Jill
Published: March 2024

Abstract
Biliary tract cancers are rare but highly fatal with poorly understood etiology. Identifying potentially modifiable risk factors for these cancers is essential for prevention. Here we estimated the relationship between adiposity and cancer across the biliary tract, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC). We pooled data from 27 prospective cohorts with over 2.7 million adults. Adiposity was measured using baseline body mass index (BMI), waist circumference, hip circumference, waist-to-hip, and waist-to-height ratios. HRs and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusted for sex, education, race, smoking, and alcohol consumption with age as the time metric and the baseline hazard stratified by study. During 37,883,648 person-years of follow-up, 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases occurred. For each 5 kg/m2 increase in BMI, there were risk increases for GBC (HR = 1.27; 95% CI, 1.19–1.36), IHBDC (HR = 1.32; 95% CI, 1.21–1.45), and EHBDC (HR = 1.13; 95% CI, 1.03–1.23), but not AVC (HR = 0.99; 95% CI, 0.88–1.11). Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. These results indicate that adult adiposity is associated with an increased risk of biliary tract cancer, particularly GBC and IHBDC. Moreover, they provide evidence for recommending weight maintenance programs to reduce the risk of developing these cancers.
Significance:
These findings identify a correlation between adiposity and biliary tract cancers, indicating that weight management programs may help minimize the risk of these diseases.
Data from The Deubiquitylase OTUB1 Mediates Ferroptosis via Stabilization of SLC7A11
Authors: Liu Tong , Jiang Le , Tavana Omid , Gu Wei
Published: March 2024

Abstract
Although cell-cycle arrest, senescence, and apoptosis are established mechanisms of tumor suppression, accumulating evidence reveals that ferroptosis, an iron-dependent, nonapoptotic form of cell death, represents a new regulatory pathway in suppressing tumor development. Ferroptosis is triggered by lipid peroxidation and is tightly regulated by SLC7A11, a key component of the cystine-glutamate antiporter. Although many studies demonstrate the importance of transcriptional regulation of SLC7A11 in ferroptotic responses, it remains largely unknown how the stability of SLC7A11 is controlled in human cancers. In this study, we utilized biochemial purification to identify the ubiquitin hydrolase OTUB1 as a key factor in modulating SLC7A11 stability. OTUB1 directly interacted with and stabilized SLC7A11; conversely, OTUB1 knockdown diminished SLC7A11 levels in cancer cells. OTUB1 was overexpressed in human cancers, and inactivation of OTUB1 destabilized SLC7A11 and led to growth suppression of tumor xenografts in mice, which was associated with reduced activation of ferroptosis. Notably, overexpression of the cancer stem cell marker CD44 enhanced the stability of SLC7A11 by promoting the interaction between SLC7A11 and OTUB1; depletion of CD44 partially abrogated this interaction. CD44 expression suppressed ferroptosis in cancer cells in an OTUB1-dependent manner. Together, these results show that OTUB1 plays an essential role in controlling the stability of SLC7A11 and the CD44-mediated effects on ferroptosis in human cancers.
Significance:
This study identifies OTUB1 as a key regulator of ferroptosis and implicates it as a potential target in cancer therapy.

See related commentary by Gan, p. 1749
Data from N6-Methyladenosine Modulates Nonsense-Mediated mRNA Decay in Human Glioblastoma
Authors: Li Fuxi , Yi Yang , Miao Yanyan , Long Wenyong , Long Teng , Chen Siyun , Cheng Weisheng , Zou Changye , Zheng Yueyuan , Wu Xingui , Ding Junjun , Zhu Kaiyu , Chen Delin , Xu Qiongcong , Wang Jinkai , Liu Qing , Zhi Feng , Ren Jian , Cao Qi , Zhao Wei
Published: March 2024

Abstract
The N6-methyladenosine (m6A) modification influences various mRNA metabolic events and tumorigenesis, however, its functions in nonsense-mediated mRNA decay (NMD) and whether NMD detects induced carcinogenesis pathways remain undefined. Here, we showed that the m6A methyltransferase METTL3 sustained its oncogenic role by modulating NMD of splicing factors and alternative splicing isoform switches in glioblastoma (GBM). Methylated RNA immunoprecipitation-seq (MeRIP-seq) analyses showed that m6A modification peaks were enriched at metabolic pathway–related transcripts in glioma stem cells (GSC) compared with neural progenitor cells. In addition, the clinical aggressiveness of malignant gliomas was associated with elevated expression of METTL3. Furthermore, silencing METTL3 or overexpressing dominant-negative mutant METTL3 suppressed the growth and self-renewal of GSCs. Integrated transcriptome and MeRIP-seq analyses revealed that downregulating the expression of METTL3 decreased m6A modification levels of serine- and arginine-rich splicing factors (SRSF), which led to YTHDC1-dependent NMD of SRSF transcripts and decreased SRSF protein expression. Reduced expression of SRSFs led to larger changes in alternative splicing isoform switches. Importantly, the phenotypes mediated by METTL3 deficiency could be rescued by downregulating BCL-X or NCOR2 isoforms. Overall, these results establish a novel function of m6A in modulating NMD and uncover the mechanism by which METTL3 promotes GBM tumor growth and progression.
Significance:
These findings establish the oncogenic role of m6A writer METTL3 in glioblastoma stem cells.
Data from Deletion of Atm in Tumor but not Endothelial Cells Improves Radiation Response in a Primary Mouse Model of Lung Adenocarcinoma
Authors: Torok Jordan A. , Oh Patrick , Castle Katherine D. , Reinsvold Michael , Ma Yan , Luo Lixia , Lee Chang-Lung , Kirsch David G.
Published: March 2024

Abstract
Stereotactic body radiotherapy is utilized to treat lung cancer. The mechanism of tumor response to high-dose radiotherapy (HDRT) is controversial, with competing hypotheses of increased direct tumor cell killing versus indirect effects on stroma including endothelial cells. Here we used dual recombinase technology in a primary murine lung cancer model to test whether tumor cells or endothelial cells are critical HDRT targets. Lenti-Cre deleted one or two copies of ataxia-telangiectasia mutated gene (Atm; KPAFL/+ or KPAFL/FL), whereas adeno-FlpO–infected mice expressed Cre in endothelial cells to delete one or both copies of Atm (KPVAFL/+ or KPVAFL/FL) to modify tumor cell or endothelial cell radiosensitivity, respectively. Deletion of Atm in either tumor cells or endothelial cells had no impact on tumor growth in the absence of radiation. Despite increased endothelial cell death in KPVAFL/FL mice following irradiation, tumor growth delay was not significantly increased. In contrast, a prolonged tumor growth delay was apparent in KPAFL/FL mice. Primary tumor cell lines lacking Atm expression also demonstrated enhanced radiosensitivity as determined via a clonogenic survival assay. These findings indicate that tumor cells, rather than endothelial cells, are critical targets of HDRT in primary murine lung cancer.
Significance:
These findings establish radiosensitizing tumor cells rather than endothelial cells as the primary mechanism of tumor response to high-dose radiotherapy, supporting efforts to maximize local control by radiosensitizing tumors cells.

See related commentary by Hallahan, p. 704
Data from Mesenchymal Stem Cell–Mediated Delivery of an Oncolytic Adenovirus Enhances Antitumor Efficacy in Hepatocellular Carcinoma
Authors: Yoon A-Rum , Hong JinWoo , Li Yan , Shin Ha Chul , Lee Hyunah , Kim Hyun Soo , Yun Chae-Ok
Published: March 2024

Abstract
Oncolytic virotherapy is a promising alternative to conventional treatment, yet systemic delivery of these viruses to tumors remains a major challenge. In this regard, mesenchymal stem cells (MSC) with well-established tumor-homing property could serve as a promising systemic delivery tool. We showed that MSCs could be effectively infected by hepatocellular carcinoma (HCC)-targeted oncolytic adenovirus (HCC-oAd) through modification of the virus' fiber domain and that the virus replicated efficiently in the cell carrier. HCC-targeting oAd loaded in MSCs (HCC-oAd/MSC) effectively lysed HCC cells in vitro under both normoxic and hypoxic conditions as a result of the hypoxia responsiveness of HCC-oAd. Importantly, systemically administered HCC-oAd/MSC, which were initially infected with a low viral dose, homed to HCC tumors and resulted in a high level of virion accumulation in the tumors, ultimately leading to potent tumor growth inhibition. Furthermore, viral dose reduction and tumor localization of HCC-oAd/MSC prevented the induction of hepatotoxicity by attenuating HCC-oAd hepatic accumulation. Taken together, these results demonstrate that MSC-mediated systemic delivery of oAd is a promising strategy for achieving synergistic antitumor efficacy with improved safety profiles.
Significance:
Mesenchymal stem cells enable delivery of an oncolytic adenovirus specifically to the tumor without posing any risk associated with systemic administration of naked virions to the host.
Data from Inactivation of the Prolyl Isomerase Pin1 Sensitizes BRCA1-Proficient Breast Cancer to PARP Inhibition
Authors: Luo Man-Li , Zheng Fang , Chen Wenying , Liang Zhi-Mei , Chandramouly Gurushankar , Tan Jianan , Willis Nicholas A. , Chen Chun-Hau , Taveira Mateus de Oliveira , Zhou Xiao Zhen , Lu Kun Ping , Scully Ralph , Wulf Gerburg M. , Hu Hai
Published: March 2024

Abstract
PARP inhibitor monotherapies are effective to treat patients with breast, ovary, prostate, and pancreatic cancer with BRCA1 mutations, but not to the much more frequent BRCA wild-type cancers. Searching for strategies that would extend the use of PARP inhibitors to BRCA1-proficient tumors, we found that the stability of BRCA1 protein following ionizing radiation (IR) is maintained by postphosphorylational prolyl-isomerization adjacent to Ser1191 of BRCA1, catalyzed by prolyl-isomerase Pin1. Extinction of Pin1 decreased homologous recombination (HR) to the level of BRCA1-deficient cells. Pin1 stabilizes BRCA1 by preventing ubiquitination of Lys1037 of BRCA1. Loss of Pin1, or introduction of a BRCA1-mutant refractory to Pin1 binding, decreased the ability of BRCA1 to localize to repair foci and augmented IR-induced DNA damage. In vitro growth of HR-proficient breast, prostate, and pancreatic cancer cells were modestly repressed by olaparib or Pin1 inhibition using all-trans retinoic acid (ATRA), while combination treatment resulted in near-complete block of cell proliferation. In MDA-MB-231 xenografts and triple-negative breast cancer patient-derived xenografts, either loss of Pin1 or ATRA treatment reduced BRCA1 expression and sensitized breast tumors to olaparib. Together, our study reveals that Pin1 inhibition, with clinical widely used ATRA, acts as an effective HR disrupter that sensitizes BRCA1-proficient tumors to PARP inhibition.
Significance:
PARP inhibitors have been limited to treat homologous recombination–deficient tumors. All-trans retinoic acid, by inhibiting Pin1 and destabilizing BRCA1, extends benefit of PARP inhibitors to patients with homologous recombination–proficient tumors.

See related commentary by Cai, p. 2977
Data from Sleeping Beauty Insertional Mutagenesis Reveals Important Genetic Drivers of Central Nervous System Embryonal Tumors
Authors: Beckmann Pauline J. , Larson Jon D. , Larsson Alex T. , Ostergaard Jason P. , Wagner Sandra , Rahrmann Eric P. , Shamsan Ghaidan A. , Otto George M. , Williams Rory L. , Wang Jun , Lee Catherine , Tschida Barbara R. , Das Paramita , Dubuc Adrian M. , Moriarity Branden S. , Picard Daniel , Wu Xiaochong , Rodriguez Fausto J. , Rosemarie Quincy , Krebs Ryan D. , Molan Amy M. , Demer Addison M. , Frees Michelle M. , Rizzardi Anthony E. , Schmechel Stephen C. , Eberhart Charles G. , Jenkins Robert B. , Wechsler-Reya Robert J. , Odde David J. , Huang Annie , Taylor Michael D. , Sarver Aaron L. , Largaespada David A.
Published: March 2024

Abstract
Medulloblastoma and central nervous system primitive neuroectodermal tumors (CNS-PNET) are aggressive, poorly differentiated brain tumors with limited effective therapies. Using Sleeping Beauty (SB) transposon mutagenesis, we identified novel genetic drivers of medulloblastoma and CNS-PNET. Cross-species gene expression analyses classified SB-driven tumors into distinct medulloblastoma and CNS-PNET subgroups, indicating they resemble human Sonic hedgehog and group 3 and 4 medulloblastoma and CNS neuroblastoma with FOXR2 activation. This represents the first genetically induced mouse model of CNS-PNET and a rare model of group 3 and 4 medulloblastoma. We identified several putative proto-oncogenes including Arhgap36, Megf10, and Foxr2. Genetic manipulation of these genes demonstrated a robust impact on tumorigenesis in vitro and in vivo. We also determined that FOXR2 interacts with N-MYC, increases C-MYC protein stability, and activates FAK/SRC signaling. Altogether, our study identified several promising therapeutic targets in medulloblastoma and CNS-PNET.
Significance:
A transposon-induced mouse model identifies several novel genetic drivers and potential therapeutic targets in medulloblastoma and CNS-PNET.
Data from Transcriptomics Associates Molecular Features with 18F-Fluorocholine PET/CT Imaging Phenotype and Its Potential Relationship to Survival in Hepatocellular Carcinoma
Authors: Kwee Sandi A. , Tiirikainen Maarit , Sato Miles M. , Acoba Jared D. , Wei Runmin , Jia Wei , Le Marchand Loic , Wong Linda L.
Published: March 2024

Abstract
Studies involving transcriptomics have revealed multiple molecular subtypes of hepatocellular carcinoma (HCC). Positron emission tomography/computed tomography (PET/CT) has also identified distinct molecular imaging subtypes, including those with increased and decreased choline metabolism as measured by the tissue uptake of the radiopharmaceutical 18F-fluorocholine. Gene signatures reflecting the molecular heterogeneity of HCC may identify the biological and clinical significance of these imaging subtypes. In this study, 41 patients underwent 18F-fluorocholine PET/CT, followed by tumor resection and gene expression profiling. Over- and underexpressed components of previously published gene signatures were evaluated for enrichment between tumors with high and low 18F-fluorocholine uptake using gene set analysis. Significant gene sets were enumerated by FDR based on phenotype permutation. Associations with overall survival were analyzed by univariate and multivariate proportional hazards regression. Ten gene sets related to HCC were significantly associated with high tumor 18F-fluorocholine uptake at FDR q < 0.05, including those from three different clinical molecular classification systems and two prognostic signatures for HCC that showed predictive value in the study cohort. Tumor avidity for 18F-fluorocholine was associated with favorable characteristics based on these signatures with lower mortality based on survival analysis (HR 0.36; 95% confidence interval, 0.14–0.95). Tumors demonstrating high 18F-fluorocholine uptake were also enriched for genes involved in oxidative phosphorylation, fatty acid metabolism, peroxisome, bile acid metabolism, xenobiotic metabolism, and adipogenesis. These results provide a pathobiological framework to further evaluate 18F-fluorocholine PET/CT as a molecular and prognostic classifier in HCC.
Significance:
A pathobiological framework for HCC brings together multiple prognostically relevant gene signatures via convergence with 18F-fluorocholine PET/CT imaging phenotype.
Data from Computational Staining of Pathology Images to Study the Tumor Microenvironment in Lung Cancer
Authors: Wang Shidan , Rong Ruichen , Yang Donghan M. , Fujimoto Junya , Yan Shirley , Cai Ling , Yang Lin , Luo Danni , Behrens Carmen , Parra Edwin R. , Yao Bo , Xu Lin , Wang Tao , Zhan Xiaowei , Wistuba Ignacio I. , Minna John , Xie Yang , Xiao Guanghua
Published: March 2024

Abstract
The spatial organization of different types of cells in tumor tissues reveals important information about the tumor microenvironment (TME). To facilitate the study of cellular spatial organization and interactions, we developed Histology-based Digital-Staining, a deep learning-based computation model, to segment the nuclei of tumor, stroma, lymphocyte, macrophage, karyorrhexis, and red blood cells from standard hematoxylin and eosin–stained pathology images in lung adenocarcinoma. Using this tool, we identified and classified cell nuclei and extracted 48 cell spatial organization-related features that characterize the TME. Using these features, we developed a prognostic model from the National Lung Screening Trial dataset, and independently validated the model in The Cancer Genome Atlas lung adenocarcinoma dataset, in which the predicted high-risk group showed significantly worse survival than the low-risk group (P = 0.001), with a HR of 2.23 (1.37–3.65) after adjusting for clinical variables. Furthermore, the image-derived TME features significantly correlated with the gene expression of biological pathways. For example, transcriptional activation of both the T-cell receptor and programmed cell death protein 1 pathways positively correlated with the density of detected lymphocytes in tumor tissues, while expression of the extracellular matrix organization pathway positively correlated with the density of stromal cells. In summary, we demonstrate that the spatial organization of different cell types is predictive of patient survival and associated with the gene expression of biological pathways.
Significance:
These findings present a deep learning-based analysis tool to study the TME in pathology images and demonstrate that the cell spatial organization is predictive of patient survival and is associated with gene expression.

See related commentary by Rodriguez-Antolin, p. 1912
Data from Overexpression of RUNX3 Represses RUNX1 to Drive Transformation of Myelodysplastic Syndrome
Authors: Yokomizo-Nakano Takako , Kubota Sho , Bai Jie , Hamashima Ai , Morii Mariko , Sun Yuqi , Katagiri Seiichiro , Iimori Mihoko , Kanai Akinori , Tanaka Daiki , Oshima Motohiko , Harada Yuka , Ohyashiki Kazuma , Iwama Atsushi , Harada Hironori , Osato Motomi , Sashida Goro
Published: March 2024

Abstract
RUNX3, a RUNX family transcription factor, regulates normal hematopoiesis and functions as a tumor suppressor in various tumors in humans and mice. However, emerging studies have documented increased expression of RUNX3 in hematopoietic stem/progenitor cells (HSPC) of a subset of patients with myelodysplastic syndrome (MDS) showing a worse outcome, suggesting an oncogenic function for RUNX3 in the pathogenesis of hematologic malignancies. To elucidate the oncogenic function of RUNX3 in the pathogenesis of MDS in vivo, we generated a RUNX3-expressing, Tet2-deficient mouse model with the pancytopenia and dysplastic blood cells characteristic of MDS in patients. RUNX3-expressing cells markedly suppressed the expression levels of Runx1, a critical regulator of hemaotpoiesis in normal and malignant cells, as well as its target genes, which included crucial tumor suppressors such as Cebpa and Csf1r. RUNX3 bound these genes and remodeled their Runx1-binding regions in Tet2-deficient cells. Overexpression of RUNX3 inhibited the transcriptional function of Runx1 and compromised hematopoiesis to facilitate the development of MDS in the absence of Tet2, indicating that RUNX3 is an oncogene. Furthermore, overexpression of RUNX3 activated the transcription of Myc target genes and rendered cells sensitive to inhibition of Myc-Max heterodimerization. Collectively, these results reveal the mechanism by which RUNX3 overexpression exerts oncogenic effects on the cellular function of and transcriptional program in Tet2-deficient stem cells to drive the transformation of MDS.
Significance:
This study defines the oncogenic effects of transcription factor RUNX3 in driving the transformation of myelodysplastic syndrome, highlighting RUNX3 as a potential target for therapeutic intervention.
Data from Consumption of the Fish Oil High-Fat Diet Uncouples Obesity and Mammary Tumor Growth through Induction of Reactive Oxygen Species in Protumor Macrophages
Authors: Liu Lianliang , Jin Rong , Hao Jiaqing , Zeng Jun , Yin Di , Yi Yanmei , Zhu Mingming , Mandal Anita , Hua Yuan , Ng Chin K. , Egilmez Nejat K. , Sauter Edward R. , Li Bing
Published: March 2024

Abstract
Obesity is associated with increased risk of many types of cancer and can be induced by various high-fat diets (HFD) from different fat sources. It remains unknown whether fatty acid composition in different HFD influences obesity-associated tumor development. Here we report that consumption of either a cocoa butter or fish oil HFD induced similar obesity in mouse models. While obesity induced by the cocoa butter HFD was associated with accelerated mammary tumor growth, consumption of the fish oil HFD uncoupled obesity from increased mammary tumor growth and exhibited a decrease in protumor macrophages. Compared with fatty acid (FA) components in both HFDs, n-3 FA rich in the fish oil HFD induced significant production of reactive oxygen species (ROS) and macrophage death. Moreover, A-FABP expression in the protumor macrophages facilitated intracellular transportation of n-3 FA and oxidation of mitochondrial FA. A-FABP deficiency diminished n-3 FA–mediated ROS production and macrophage death in vitro and in vivo. Together, our results demonstrate a novel mechanism by which n-3 FA induce ROS-mediated protumor macrophage death in an A-FABP–dependent manner.
Significance:
This study provides mechanistic insight into dietary supplementation with fish oil for breast cancer prevention and advances a new concept that not all HFDs leading to obesity are tumorigenic.
Data from YY1 Complex Promotes Quaking Expression via Super-Enhancer Binding during EMT of Hepatocellular Carcinoma
Authors: Han Jingxia , Meng Jing , Chen Shuang , Wang Xiaorui , Yin Shan , Zhang Qiang , Liu Huijuan , Qin Rong , Li Zhongwei , Zhong Weilong , Zhang Chao , Zhang Heng , Tang Yuanhao , Lin Tingting , Gao Wanfeng , Zhang Xiaoyun , Yang Lan , Liu Yanrong , Zhou Hong-gang , Sun Tao , Yang Cheng
Published: March 2024

Abstract
Quaking (QKI) is an alternative splicing factor that can regulate circRNA formation in the progression of epithelial–mesenchymal transition, but the mechanism remains unclear. High expression of QKI is correlated with short survival time, metastasis, and high clinical stage and pathology grade in hepatocellular carcinoma (HCC). Here we report that transcription of the QKI gene was activated by the Yin-Yang 1 (YY1)/p65/p300 complex, in which YY1 bound to the super-enhancer and promoter of QKI, p65 combined with the promoter, and p300 served as a mediator to maintain the stability of the complex. This YY1/p65/p300 complex increased QKI expression to promote the malignancy of HCC as well as an increased circRNA formation in vitro and in vivo. Hyperoside is one of several plant-derived flavonol glycoside compounds. Through virtual screening and antitumor activity analysis, we found that hyperoside inhibited QKI expression by targeting the YY1/p65/p300 complex. Overall, our study suggests that the regulatory mechanism of QKI depends on the YY1/p65/p300 complex and that it may serve as a potential target for treatment of HCC.
Significance:
These findings identify the YY1/p65/p300 complex as a regulator of QKI expression, identifying several potential therapeutic targets for the treatment of HCC.
Data from A miRNA Expression Signature in Breast Tumor Tissue Is Associated with Risk of Distant Metastasis
Authors: Rohan Thomas E. , Wang Tao , Weinmann Sheila , Wang Yihong , Lin Juan , Ginsberg Mindy , Loudig Olivier
Published: March 2024

Abstract
Dysregulation of miRNA expression may influence breast cancer progression, and experimental evidence suggests that miRNA silencing might suppress breast cancer metastasis. However, the relationship between miRNA and metastasis must be confirmed before this approach can be applied in the clinic. To this end, we conducted a two-stage study in a cohort of 3,760 patients with breast cancer to first identify and then validate the association between miRNA expression and risk of distant metastasis. The first stage (discovery) entailed miRNA sequencing of 126 case–control pairs; qPCR was used to validate the findings in a separate set of 80 case–control pairs. The 13 miRNAs most differentially expressed between cases and controls were combined into an miRNA score that was significantly associated with risk of distant metastasis in a logistic regression model that also included clinical variables (tumor size and number of positive lymph nodes) (ORper unit increase in score = 1.30; 95% confidence interval, 1.03–1.66). The results of this study suggest that in women with invasive breast cancer, a miRNA score that incorporates both clinical variables and miRNA expression levels in breast tumor tissue is moderately predictive of risk of subsequent distant metastasis.
Significance:
A novel predictive scoring system for patients with breast cancer includes clinical variables and the expression levels of 13 miRNAs and may help to identify those at increased risk of distant metastasis.
Data from Melphalan and Exportin 1 Inhibitors Exert Synergistic Antitumor Effects in Preclinical Models of Human Multiple Myeloma
Authors: Turner Joel G. , Cui Yan , Bauer Alexis A. , Dawson Jana L. , Gomez Juan A. , Kim Jongphil , Cubitt Christopher L. , Nishihori Taiga , Dalton William S. , Sullivan Daniel M.
Published: March 2024

Abstract
High-dose chemotherapy with melphalan followed by autologous transplantation is a first-line treatment for multiple myeloma. Here, we present preclinical evidence that this treatment may be significantly improved by the addition of exportin 1 inhibitors (XPO1i). The XPO1i selinexor, eltanexor, and KOS-2464 sensitized human multiple myeloma cells to melphalan. Human 8226 and U266 multiple myeloma cell lines and melphalan-resistant cell lines (8226-LR5 and U266-LR6) were highly sensitized to melphalan by XPO1i. Multiple myeloma cells from newly diagnosed and relapsed/refractory multiple myeloma patients were also sensitized by XPO1i to melphalan. In NOD/SCIDγ mice challenged with either parental 8226 or U266 multiple myeloma and melphalan-resistant multiple myeloma tumors, XPO1i/melphalan combination treatments demonstrated stronger synergistic antitumor effects than single-agent melphalan with minimal toxicity. Synergistic cell death resulted from increased XPO1i/melphalan-induced DNA damage in a dose-dependent manner and decreased DNA repair. In addition, repair of melphalan-induced DNA damage was inhibited by selinexor, which decreased melphalan-induced monoubiquitination of FANCD2 in multiple myeloma cells. Knockdown of FANCD2 was found to replicate the effect of selinexor when used with melphalan, increasing DNA damage (γH2AX) by inhibiting DNA repair. Thus, combination therapies that include selinexor or eltanexor with melphalan may have the potential to improve treatment outcomes of multiple myeloma in melphalan-resistant and newly diagnosed patients. The combination of selinexor and melphalan is currently being investigated in the context of high-dose chemotherapy and autologous transplant (NCT02780609).
Significance:
Inhibition of exportin 1 with selinexor synergistically sensitizes human multiple myeloma to melphalan by inhibiting Fanconi anemia pathway-mediated DNA repair.
Data from Loss of a Negative Feedback Loop between IRF8 and AR Promotes Prostate Cancer Growth and Enzalutamide Resistance
Authors: Wu Hongxi , You Linjun , Li Yan , Zhao Zhili , Shi Guangjiang , Chen Zhen , Wang Zhuo , Li Xianjing , Du Shijia , Ye Wanli , Gao Xiaofang , Duan Jingjing , Cheng Yan , Tao Weiyan , Bian Jinsong , Zhou Jin-Rong , Zhu Qingyi , Yang Yong
Published: March 2024

Abstract
In incurable castration-resistant prostate cancer (CRPC), resistance to the novel androgen receptor (AR) antagonist enzalutamide is driven mainly by AR overexpression. Here we report that the expression of interferon regulatory factor 8 (IRF8) is increased in primary prostate cancer but decreased in CRPC compared with normal prostate tissue. Decreased expression of IRF8 positively associated with CRPC progression and enzalutamide resistance. IRF8 interacted with AR and promoted its degradation via activation of the ubiquitin/proteasome systems. Epigenetic knockdown of IRF8 promoted AR-mediated prostate cancer progression and enzalutamide resistance in vitro and in vivo. Furthermore, IFNα increased expression of IRF8 and improved the efficacy of enzalutamide in CRPC by targeting the IRF8–AR axis. We also provide preliminary evidence for the efficacy of IFNα with hormonotherapy in a clinical study. Collectively, this study identifies IRF8 both as a tumor suppressor in prostate cancer pathogenesis and a potential alternative therapeutic option to overcome enzalutamide resistance.
Significance:
These findings identify IRF8-mediated AR degradation as a mechanism of resistance to AR-targeted therapy, highlighting the therapeutic potential of IFNα in targeting IRF8–AR axis in CRPC.
Data from Epigenetic SMAD3 Repression in Tumor-Associated Fibroblasts Impairs Fibrosis and Response to the Antifibrotic Drug Nintedanib in Lung Squamous Cell Carcinoma
Authors: Ikemori Rafael , Gabasa Marta , Duch Paula , Vizoso Miguel , Bragado Paloma , Arshakyan Marselina , Luis Iuliana-Cristiana , Marín Albert , Morán Sebastian , Castro Manuel , Fuster Gemma , Gea-Sorli Sabrina , Jauset Toni , Soucek Laura , Montuenga Luis M. , Esteller Manel , Monsó Eduard , Peinado Victor Ivo , Gascon Pere , Fillat Cristina , Hilberg Frank , Reguart Noemí , Alcaraz Jordi
Published: March 2024

Abstract
The tumor-promoting fibrotic stroma rich in tumor-associated fibroblasts (TAF) is drawing increased therapeutic attention. Intriguingly, a trial with the antifibrotic drug nintedanib in non–small cell lung cancer reported clinical benefits in adenocarcinoma (ADC) but not squamous cell carcinoma (SCC), even though the stroma is fibrotic in both histotypes. Likewise, we reported that nintedanib inhibited the tumor-promoting fibrotic phenotype of TAFs selectively in ADC. Here we show that tumor fibrosis is actually higher in ADC-TAFs than SCC-TAFs in vitro and patient samples. Mechanistically, the reduced fibrosis and nintedanib response of SCC-TAFs was associated with increased promoter methylation of the profibrotic TGFβ transcription factor SMAD3 compared with ADC-TAFs, which elicited a compensatory increase in TGFβ1/SMAD2 activation. Consistently, forcing global DNA demethylation of SCC-TAFs with 5-AZA rescued TGFβ1/SMAD3 activation, whereas genetic downregulation of SMAD3 in ADC-TAFs and control fibroblasts increased TGFβ1/SMAD2 activation, and reduced their fibrotic phenotype and antitumor responses to nintedanib in vitro and in vivo. Our results also support that smoking and/or the anatomic location of SCC in the proximal airways, which are more exposed to cigarette smoke particles, may prime SCC-TAFs to stronger SMAD3 epigenetic repression, because cigarette smoke condensate selectively increased SMAD3 promoter methylation. Our results unveil that the histotype-specific regulation of tumor fibrosis in lung cancer is mediated through differential SMAD3 promoter methylation in TAFs and provide new mechanistic insights on the selective poor response of SCC-TAFs to nintedanib. Moreover, our findings support that patients with ADC may be more responsive to antifibrotic drugs targeting their stromal TGFβ1/SMAD3 activation.
Significance:
This study implicates the selective epigenetic repression of SMAD3 in SCC-TAFs in the clinical failure of nintedanib in SCC and supports that patients with ADC may benefit from antifibrotic drugs targeting stromal TGFβ1/SMAD3.
Data from Replication Gaps Underlie BRCA Deficiency and Therapy Response
Authors: Panzarino Nicholas J. , Krais John J. , Cong Ke , Peng Min , Mosqueda Michelle , Nayak Sumeet U. , Bond Samuel M. , Calvo Jennifer A. , Doshi Mihir B. , Bere Matt , Ou Jianhong , Deng Bin , Zhu Lihua J. , Johnson Neil , Cantor Sharon B.
Published: March 2024

Abstract
Defects in DNA repair and the protection of stalled DNA replication forks are thought to underlie the chemosensitivity of tumors deficient in the hereditary breast cancer genes BRCA1 and BRCA2 (BRCA). Challenging this assumption are recent findings that indicate chemotherapies, such as cisplatin used to treat BRCA-deficient tumors, do not initially cause DNA double-strand breaks (DSB). Here, we show that ssDNA replication gaps underlie the hypersensitivity of BRCA-deficient cancer and that defects in homologous recombination (HR) or fork protection (FP) do not. In BRCA-deficient cells, ssDNA gaps developed because replication was not effectively restrained in response to stress. Gap suppression by either restoration of fork restraint or gap filling conferred therapy resistance in tissue culture and BRCA patient tumors. In contrast, restored FP and HR could be uncoupled from therapy resistance when gaps were present. Moreover, DSBs were not detected after therapy when apoptosis was inhibited, supporting a framework in which DSBs are not directly induced by genotoxic agents, but rather are induced from cell death nucleases and are not fundamental to the mechanism of action of genotoxic agents. Together, these data indicate that ssDNA replication gaps underlie the BRCA cancer phenotype, “BRCAness,” and we propose they are fundamental to the mechanism of action of genotoxic chemotherapies.
Significance:
This study suggests that ssDNA replication gaps are fundamental to the toxicity of genotoxic agents and underlie the BRCA-cancer phenotype “BRCAness,” yielding promising biomarkers, targets, and opportunities to resensitize refractory disease.

See related commentary by Canman, p. 1214