bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Claudin-12 Deficiency Inhibits Tumor Growth by Impairing Transendothelial Migration of Myeloid-Derived Suppressor Cells
Authors: Cao Hong , Ni Chen , Han Le , Wang Ruoqi , Blasig Rosel , Haseloff Reiner , Qin Yue , Lan Jie , Lou Xiaohan , Ma Pan , Yao Xiaohan , Wang Linlin , Wang Fei , Zhu Linyu , Lei Ningjing , Blasig Ingolf E. , Qin Zhihai
Published: March 2023

Abstract
Migration of myeloid-derived suppressor cells (MDSC) out of the circulation, across vascular walls, and into tumor is crucial for their immunosuppressive activity. A deeper understanding of critical junctional molecules and the regulatory mechanisms that mediate the extravasation of MDSCs could identify approaches to overcome cancer immunosuppression. In this study, we used mice deficient in tight junction protein Claudin-12 (Cldn12) compared with wild-type mice and found that loss of host Cldn12 inhibited the growth of transplanted tumors, reduced intratumoral accumulation of MDSCs, increased antitumor immune responses, and decreased tumor vascular density. Further studies revealed that Cldn12 expression on the cell surface of both MDSCs and endothelial cells (EC) is required for MDSCs transit across tumor vascular ECs. Importantly, expression of Cldn12 in MDSCs was modulated by GM-CSF in an AKT-dependent manner. Therefore, our results indicate that Cldn12 could serve as a promising target for restoring the antitumor response by interfering with MDSCs transendothelial migration.
Significance:
Claudin-12–mediated homotypic interactions are critical for migration of myeloid-derived suppressor cells across vascular walls into tumor tissue, providing a potential therapeutic approach to overcome cancer immunosuppression.
Data from Inhibition of EGFR Overcomes Acquired Lenvatinib Resistance Driven by STAT3–ABCB1 Signaling in Hepatocellular Carcinoma
Authors: Hu Beiyuan , Zou Tiantian , Qin Wei , Shen Xiaotian , Su Yinghan , Li Jianhua , Chen Yang , Zhang Ze , Sun Haoting , Zheng Yan , Wang Chao-Qun , Wang Zhengxin , Li Tian-En , Wang Shun , Zhu Le , Wang Xufeng , Fu Yan , Ren Xudong , Dong Qiongzhu , Qin Lun-Xiu
Published: March 2023

Abstract
Lenvatinib is an inhibitor of multiple receptor tyrosine kinases that was recently authorized for first-line treatment of hepatocellular carcinoma (HCC). However, the clinical benefits derived from lenvatinib are limited, highlighting the urgent need to understand mechanisms of resistance. We report here that HCC cells develop resistance to lenvatinib by activating EGFR and stimulating the EGFR–STAT3–ABCB1 axis. Lenvatinib resistance was accompanied by aberrant cholesterol metabolism and lipid raft activation. ABCB1 was activated by EGFR in a lipid raft–dependent manner, which significantly enhanced the exocytosis of lenvatinib to mediate resistance. Furthermore, clinical specimens of HCC showed a correlation between the activation of the EGFR–STAT3–ABCB1 pathway and lenvatinib response. Erlotinib, an EGFR inhibitor that has also been shown to inhibit ABCB1, suppressed lenvatinib exocytosis, and combined treatment with lenvatinib and erlotinib demonstrated a significant synergistic effect on HCC both in vitro and in vivo. Taken together, these findings characterize a mechanism of resistance to a first-line treatment for HCC and offer a practical means to circumvent resistance and treat the disease.
Significance:
HCC cells acquire resistance to lenvatinib by activating the EGFR–STAT3–ABCB1 pathway, identifying combined treatment with erlotinib as a strategy to overcome acquired resistance and improve the clinical benefit of lenvatinib.
Data from Therapeutic Targeting of Macrophage Plasticity Remodels the Tumor-Immune Microenvironment
Authors: Jang Hee-Jin , Lee Hyun-Sung , Yu Wendong , Ramineni Maheshwari , Truong Cynthia Y. , Ramos Daniela , Splawn Taylor , Choi Jong Min , Jung Sung Yun , Lee Ju-Seog , Wang Daniel Y. , Sederstrom Joel M. , Pietropaolo Massimo , Kheradmand Farrah , Amos Christopher I. , Wheeler Thomas M. , Ripley R. Taylor , Burt Bryan M.
Published: March 2023

Abstract
Although the majority of patients with advanced lung adenocarcinoma (LUAD) are eligible to receive immune checkpoint blockade, approximately 80% of these tumors are resistant to this therapeutic approach. Insights at the single-cell level into mechanisms that drive LUAD tumorigenesis and the relationship of LUAD histologic heterogeneity to response to immune checkpoint blockade could help identify biomarkers and potential combinational approaches to improve immunotherapy efficacy. Here, we used a genetically engineered mouse model that replicates the development of human LUAD through a spectrum of preinvasive to invasive adenocarcinoma histologic subtypes. A systems onco-immunology approach of integrating the analytical power and unique, complementary capabilities of time-of-flight mass cytometry (CyTOF) and imaging mass cytometry was leveraged to identify cellular and spatial immune contextures in LUAD. Comprehensive investigation of mouse and human LUAD using these single-cell proteomics platforms showed that LUAD progression is associated with spatiotemporal evolution of tumor-associated macrophages in the tumor-immune microenvironment, which governs tumor response to immunotherapy. PD-1 was expressed in a highly plastic tumor-promoting subtype of tumor-associated macrophages that develops during tumor progression from preinvasive to invasive adenocarcinoma, controls the lymphocyte-depleted niche of invasive tumors, and protects tumor cells in the solid histologic components of the tumor. Longitudinal, multidimensional single-cell analyses of LUAD tumorigenesis revealed dynamic alteration of immunoregulatory PD-1–expressing tumor-associated macrophages that can be targeted to overcome resistance to checkpoint immunotherapy.
Significance:
Comprehensive single-cell proteomics analyses of lung adenocarcinoma progression reveal the role of tumor-associated macrophages in resistance to PD-1 blockade therapy.

See related commentary by Lee et al., p. 2515
Data from CHD1 Promotes Sensitivity to Aurora Kinase Inhibitors by Suppressing Interaction of AURKA with Its Coactivator TPX2
Authors: Li Haoyan , Wang Yin , Lin Kevin , Venkadakrishnan Varadha Balaji , Bakht Martin , Shi Wei , Meng Chenling , Zhang Jie , Tremble Kaitlyn , Liang Xin , Song Jian H. , Feng Xu , Van Vivien , Deng Pingna , Burks Jared K. , Aparicio Ana , Keyomarsi Khandan , Chen Junjie , Lu Yue , Beltran Himisha , Zhao Di
Published: March 2023

Abstract
Clinical studies have shown that subsets of patients with cancer achieve a significant benefit from Aurora kinase inhibitors, suggesting an urgent need to identify biomarkers for predicting drug response. Chromodomain helicase DNA binding protein 1 (CHD1) is involved in chromatin remodeling, DNA repair, and transcriptional plasticity. Prior studies have demonstrated that CHD1 has distinct expression patterns in cancers with different molecular features, but its impact on drug responsiveness remains understudied. Here, we show that CHD1 promotes the susceptibility of prostate cancer cells to inhibitors targeting Aurora kinases, while depletion of CHD1 impairs their efficacy in vitro and in vivo. Pan-cancer drug sensitivity analyses revealed that high expression of CHD1 was associated with increased sensitivity to Aurora kinase A (AURKA) inhibitors. Mechanistically, KPNA2 served as a direct target of CHD1 and suppressed the interaction of AURKA with the coactivator TPX2, thereby rendering cancer cells more vulnerable to AURKA inhibitors. Consistent with previous research reporting that loss of PTEN elevates CHD1 levels, studies in a genetically engineered mouse model, patient-derived organoids, and patient samples showed that PTEN defects are associated with a better response to AURKA inhibition in advanced prostate cancer. These observations demonstrate that CHD1 plays an important role in modulating Aurora kinases and drug sensitivities, providing new insights into biomarker-driven therapies targeting Aurora kinases for future clinical studies.
Significance:
CHD1 plays a critical role in controlling AURKA activation and promoting Aurora kinase inhibitor sensitivity, providing a potential clinical biomarker to guide cancer treatment.
Data from Asialoglycoprotein Receptor 1 Functions as a Tumor Suppressor in Liver Cancer via Inhibition of STAT3
Authors: Zhu Xingxin , Song Guangyuan , Zhang Shiyu , Chen Jun , Hu Xiaoyi , Zhu Hai , Jia Xing , Li Zequn , Song Wenfeng , Chen Jian , Jin Cheng , Zhou Mengqiao , Zhao Yongchao , Xie Haiyang , Zheng Shusen , Song Penghong
Published: March 2023

Abstract
Liver cancer is characterized by aggressive growth and high mortality. Asialoglycoprotein receptor 1 (ASGR1), which is expressed almost exclusively in liver cells, is reduced in liver cancer. However, the specific mechanism of ASGR1 function in liver cancer has not been fully elucidated. On the basis of database screening, we identified ASGR1 as a tumor suppressor regulated by DNA methylation. Expression of ASGR1 was downregulated in liver cancer and correlated with tumor size, grade, and survival. Functional gain and loss experiments showed that ASGR1 suppresses the progression of liver cancer in vivo and in vitro. RNA sequencing and mass spectrometry showed that ASGR1 inhibits tyrosine phosphorylation of STAT3 by interacting with Nemo-like kinase (NLK). NLK bound the SH2 domain of STAT3 in an ATP-dependent manner and competed with glycoprotein 130 (GP130), ultimately suppressing GP130/JAK1-mediated phosphorylation of STAT3. ASGR1 altered the binding strength of NLK and STAT3 by interacting with GP130. Furthermore, the domain region of NLK was crucial for binding STAT3 and curbing its phosphorylation. Collectively, these results confirm that ASGR1 suppresses the progression of liver cancer by promoting the binding of NLK to STAT3 and inhibiting STAT3 phosphorylation, suggesting that approaches to activate the ASGR1–NLK axis may be a potential therapeutic strategy in this disease.
Significance:
ASGR1 downregulation by DNA methylation facilitates liver tumorigenesis by increasing STAT3 phosphorylation.
Data from FOXR2 Is an Epigenetically Regulated Pan-Cancer Oncogene That Activates ETS Transcriptional Circuits
Authors: Tsai Jessica W. , Cejas Paloma , Wang Dayle K. , Patel Smruti , Wu David W. , Arounleut Phonepasong , Wei Xin , Zhou Ningxuan , Syamala Sudeepa , Dubois Frank P.B. , Crane Alexander , Pelton Kristine , Vogelzang Jayne , Sousa Cecilia , Baguette Audrey , Chen Xiaolong , Condurat Alexandra L. , Dixon-Clarke Sarah E. , Zhou Kevin N. , Lu Sophie D. , Gonzalez Elizabeth M. , Chacon Madison S. , Digiacomo Jeromy J. , Kumbhani Rushil , Novikov Dana , Hunter J'Ya , Tsoli Maria , Ziegler David S. , Dirksen Uta , Jager Natalie , Balasubramanian Gnana Prakash , Kramm Christof M. , Nathrath Michaela , Bielack Stefan , Baker Suzanne J. , Zhang Jinghui , McFarland James M. , Getz Gad , Aguet François , Jabado Nada , Witt Olaf , Pfister Stefan M. , Ligon Keith L. , Hovestadt Volker , Kleinman Claudia L. , Long Henry , Jones David T.W. , Bandopadhayay Pratiti , Phoenix Timothy N.
Published: March 2023

Abstract
Forkhead box R2 (FOXR2) is a forkhead transcription factor located on the X chromosome whose expression is normally restricted to the testis. In this study, we performed a pan-cancer analysis of FOXR2 activation across more than 10,000 adult and pediatric cancer samples and found FOXR2 to be aberrantly upregulated in 70% of all cancer types and 8% of all individual tumors. The majority of tumors (78%) aberrantly expressed FOXR2 through a previously undescribed epigenetic mechanism that involves hypomethylation of a novel promoter, which was functionally validated as necessary for FOXR2 expression and proliferation in FOXR2-expressing cancer cells. FOXR2 promoted tumor growth across multiple cancer lineages and co-opted ETS family transcription circuits across cancers. Taken together, this study identifies FOXR2 as a potent and ubiquitous oncogene that is epigenetically activated across the majority of human cancers. The identification of hijacking of ETS transcription circuits by FOXR2 extends the mechanisms known to active ETS transcription factors and highlights how transcription factor families cooperate to enhance tumorigenesis.
Significance:
This work identifies a novel promoter that drives aberrant FOXR2 expression and delineates FOXR2 as a pan-cancer oncogene that specifically activates ETS transcriptional circuits across human cancers.

See related commentary by Liu and Northcott, p. 2977
Data from DLGAP1-AS2–Mediated Phosphatidic Acid Synthesis Activates YAP Signaling and Confers Chemoresistance in Squamous Cell Carcinoma
Authors: Nan Yabing , Luo Qingyu , Wu Xiaowei , Liu Shi , Zhao Pengfei , Chang Wan , Zhou Aiping , Liu Zhihua
Published: March 2023

Abstract
Squamous cell carcinomas (SCC) constitute a group of human malignancies that originate from the squamous epithelium. Most patients with SCC experience treatment failure and relapse and have a poor prognosis due to de novo and acquired resistance to first-line chemotherapeutic agents. To identify chemoresistance mechanisms and to explore novel targets for chemosensitization, we performed whole-transcriptome sequencing of paired resistant and parental SCC cells. We identified DLGAP1 antisense RNA 2 (D-AS2) as a crucial noncoding RNA that contributes to chemoresistance in SCC. Mechanistically, D-AS2 affected chromatin accessibility around the histone mark H3K27ac of FAM3 metabolism regulating signaling molecule D (FAM3D), reducing FAM3D mRNA transcription and extracellular protein secretion. FAM3D interacted with the Gαi-coupled G protein–coupled receptors formyl peptide receptor 1 (FPR1) and FPR2 to suppress phospholipase D (PLD) activity, and reduced FAM3D increased PLD signaling. Moreover, activated PLD promoted phosphatidic acid (PA) production and subsequent nuclear translocation of yes-associated protein (YAP). Accordingly, in vivo administration of a D-AS2–targeting antisense oligonucleotide sensitized SCC to cisplatin treatment. In summary, this study shows that D-AS2/FAM3D-mediated PLD/PA lipid signaling is essential for SCC chemoresistance, suggesting D-AS2 can be targeted to sensitize SCC to cytotoxic chemotherapeutic agents.
Significance:
This study identifies D-AS2 as a targetable lipid-related long noncoding RNA that increases phospholipase D activity to promote YAP signaling, triggering chemoresistance in SCC.
Data from High-Resolution Profiling of Lung Adenocarcinoma Identifies Expression Subtypes with Specific Biomarkers and Clinically Relevant Vulnerabilities
Authors: Roh Whijae , Geffen Yifat , Cha Hongui , Miller Mendy , Anand Shankara , Kim Jaegil , Heiman David I. , Gainor Justin F. , Laird Peter W. , Cherniack Andrew D. , Ock Chan-Young , Lee Se-Hoon , Getz Gad
Published: March 2023

Abstract
Lung adenocarcinoma (LUAD) is one of the most common cancer types and has various treatment options. Better biomarkers to predict therapeutic response are needed to guide choice of treatment modality and to improve precision medicine. Here, we used a consensus hierarchical clustering approach on 509 LUAD cases from The Cancer Genome Atlas to identify five robust LUAD expression subtypes. Genomic and proteomic data from patient samples and cell lines was then integrated to help define biomarkers of response to targeted therapies and immunotherapies. This approach defined subtypes with unique proteogenomic and dependency profiles. Subtype 4 (S4)–associated cell lines exhibited specific vulnerability to loss of CDK6 and CDK6-cyclin D3 complex gene (CCND3). Subtype 3 (S3) was characterized by dependency on CDK4, immune-related expression patterns, and altered MET signaling. Experimental validation showed that S3-associated cell lines responded to MET inhibitors, leading to increased expression of programmed death-ligand 1 (PD-L1). In an independent real-world patient dataset, patients with S3 tumors were enriched with responders to immune checkpoint blockade. Genomic features in S3 and S4 were further identified as biomarkers for enabling clinical diagnosis of these subtypes. Overall, our consensus hierarchical clustering approach identified robust tumor expression subtypes, and our subsequent integrative analysis of genomics, proteomics, and CRISPR screening data revealed subtype-specific biology and vulnerabilities. These LUAD expression subtypes and their biomarkers could help identify patients likely to respond to CDK4/6, MET, or PD-L1 inhibitors, potentially improving patient outcome.
Significance:
Integrative analysis of multiomic and drug dependency data uncovers robust lung adenocarcinoma expression subtypes with unique therapeutic vulnerabilities and subtype-specific biomarkers of response.
Data from A Probody T Cell–Engaging Bispecific Antibody Targeting EGFR and CD3 Inhibits Colon Cancer Growth with Limited Toxicity
Authors: Boustany Leila M. , LaPorte Sherry L. , Wong Laurie , White Clayton , Vinod Veena , Shen Joel , Yu Wendy , Koditek David , Winter Michael B. , Moore Stephen J. , Mei Li , Diep Linnea , Huang Yuanhui , Liu Shouchun , Vasiljeva Olga , West Jim , Richardson Jennifer , Irving Bryan , Belvin Marcia , Kavanaugh W. Michael
Published: March 2023

Abstract
T cell–engaging bispecific antibodies (TCB) are highly potent therapeutics that can recruit and activate cytotoxic T cells to stimulate an antitumor immune response. However, the development of TCBs against solid tumors has been limited by significant on-target toxicity to normal tissues. Probody therapeutics have been developed as a novel class of recombinant, protease-activated antibody prodrugs that are “masked” to reduce antigen binding in healthy tissues but can become conditionally unmasked by proteases that are preferentially active in the tumor microenvironment (TME). Here, we describe the preclinical efficacy and safety of CI107, a Probody TCB targeting EGFR and CD3. In vitro, the protease-activated, unmasked CI107 effectively bound EGFR and CD3 expressed on the surface of cells and induced T-cell activation, cytokine release, and cytotoxicity toward tumor cells. In contrast, dually masked CI107 displayed a >500-fold reduction in antigen binding and >15,000-fold reduction in cytotoxic activity. In vivo, CI107 potently induced dose-dependent tumor regression of established colon cancer xenografts in mice engrafted with human peripheral blood mononuclear cells. Furthermore, the MTD of CI107 in cynomolgus monkeys was more than 60-fold higher than that of the unmasked TCB, and much lower levels of toxicity were observed in animals receiving CI107. Therefore, by localizing activity to the TME and thus limiting toxicity to normal tissues, this Probody TCB demonstrates the potential to expand clinical opportunities for TCBs as effective anticancer therapies for solid tumor indications.
Significance:
A conditionally active EGFR-CD3 T cell–engaging Probody therapeutic expands the safety window of bispecific antibodies while maintaining efficacy in preclinical solid tumor settings.
Data from Potent and Selective PTDSS1 Inhibitors Induce Collateral Lethality in Cancers with PTDSS2 Deletion
Authors: Yoshihama Yohei , Namiki Hidenori , Kato Taiga , Shimazaki Naomi , Takaishi Sachiko , Kadoshima-Yamaoka Kumiko , Yukinaga Hideo , Maeda Naoyuki , Shibutani Tomoko , Fujimoto Kazunori , Hirasawa Makoto , Goto Hiroki , Wada Naoya , Tsutsumi Shinji , Hirota Yasuhide , Ishikawa Tomoki , Yamamoto Shoji
Published: March 2023

Abstract
Targeting collateral deletion of housekeeping genes caused by the loss of tumor suppressor genes is a potential strategy to identify context-specific, molecular-targeted therapies in cancer. In mammals, phosphatidylserine (PS) synthesis depends on two redundant PS synthetases, PTDSS1 and PTDSS2, and PTDSS2 is located at a tumor-suppressive locus, 11p15.5. Here, we sought to determine whether PTDSS2 loss would confer vulnerability to disruption of PTDSS1 function. PTDSS2 was lost in a wide range of cancer types, and PTDSS1 depletion specifically suppressed growth in PTDSS2-deficient cancer cell lines. Potent and selective PTDSS1 inhibitors were developed whose activity phenocopied the effect of PTDSS1 depletion, and in vivo treatment of PTDSS2-deleted tumors with these inhibitors led to tumor regression. Whole-transcriptome analysis revealed that inhibition of PTDSS1 in PTDSS2-depleted cells activated the endoplasmic reticulum (ER) stress response downstream of PS depletion. ER stress-mediated cell death induced by PTDSS1 inhibitors activated tumor immunity through the secretion of HMGB1 protein followed by activation of bone marrow-derived dendritic cells. PTDSS2 loss showed intratumoral heterogeneity in clinical samples, raising concerns about resistance to PTDSS1 inhibition. However, the PTDSS1 inhibitor effectively suppressed the growth of tumor containing both PTDSS2 wild-type and knockout cells in immunocompetent mice, showing potency for overcoming tumor heterogeneity by modulating the tumor immune microenvironment. Thus, these newly developed PTDSS1 inhibitors provide a therapeutic option for treating cancer with PTDSS2 loss, harnessing the synthetic lethality of PTDSS1/2.
Significance:
This study identifies a specific dependency on PTDSS1 for phosphatidylserine synthesis following PTDSS2 deletion and introduces novel PTDSS1 inhibitors as a therapeutic option to induce collateral lethality in cancer with PTDSS2 loss.
Data from MEX3C-Mediated Decay of SOCS3 mRNA Promotes JAK2/STAT3 Signaling to Facilitate Metastasis in Hepatocellular Carcinoma
Authors: Xiao Yunyun , Li Yue , Shi Dongni , Wang Xiaoqing , Dai Shuqin , Yang Muwen , Kong Lingzhi , Chen Boyu , Huang Xinjian , Lin Chuyong , Liao Wenting , Xu Benke , Chen Xin , Wang Lishuai , Chen Xiangfu , Ouyang Ying , Liu Guozhen , Li Heping , Song Libing
Published: March 2023

Abstract
Tumor metastasis is one of the major causes of high mortality in patients with hepatocellular carcinoma (HCC). Sustained activation of STAT3 signaling plays a critical role in HCC metastasis. RNA binding protein (RBP)–mediated posttranscriptional regulation is involved in the precise control of signal transduction, including STAT3 signaling. In this study, we investigated whether RBPs are important regulators of HCC metastasis. The RBP MEX3C was found to be significantly upregulated in highly metastatic HCC and correlated with poor prognosis in HCC. Mechanistically, MEX3C increased JAK2/STAT3 pathway activity by downregulating SOCS3, a major negative regulator of JAK2/STAT3 signaling. MEX3C interacted with the 3′UTR of SOCS3 and recruited CNOT7 to ubiquitinate and accelerate decay of SOCS3 mRNA. Treatment with MEX3C-specific antisense oligonucleotide significantly inhibited JAK2/STAT3 pathway activation, suppressing HCC migration in vitro and metastasis in vivo. These findings highlight a novel mRNA decay-mediated mechanism for the disruption of SOCS3-driven negative regulation of JAK2/STAT3 signaling, suggesting MEX3C may be a potential prognostic biomarker and promising therapeutic target in HCC.
Significance:
This study reveals that RNA-binding protein MEX3C induces SOCS3 mRNA decay to promote JAK2/STAT3 activation and tumor metastasis in hepatocellular carcinoma, identifying MEX3C targeting as a potential approach for treating metastatic disease.
Data from HDAC5 Loss Enhances Phospholipid-Derived Arachidonic Acid Generation and Confers Sensitivity to cPLA2 Inhibition in Pancreatic Cancer
Authors: Pan Penglin , Qin Gengdu , Wang Bo , Yu Haixin , Chen Jie , Liu Jiaying , Bing Kaijian , Shen Jian , Ren Dianyun , Zhao Yuhan , Xia Wentao , Li Hui , Wu Heshui , Zhou Yingke
Published: March 2023

Abstract
HDAC5 is a class IIa histone deacetylase member that is downregulated in multiple solid tumors, including pancreatic cancer, and loss of HDAC5 is associated with unfavorable prognosis. In this study, assessment of The Cancer Genome Atlas pancreatic adenocarcinoma dataset revealed that expression of HDAC5 correlates negatively with arachidonic acid (AA) metabolism, which has been implicated in inflammatory responses and cancer progression. Nontargeted metabolomics analysis revealed that HDAC5 knockdown resulted in a significant increase in AA and its downstream metabolites, such as eicosanoids and prostaglandins. HDAC5 negatively regulated the expression of the gene encoding calcium-dependent phospholipase A2 (cPLA2), the key enzyme in the production of AA from phospholipids. Mechanistically, HDAC5 repressed cPLA2 expression via deacetylation of GATA1. HDAC5 knockdown in cancer cells enhanced sensitivity to genetic or pharmacologic inhibition of cPLA2 in vitro and in vivo. Fatty acid supplementation in the diet reversed the sensitivity of HDAC5-deficient tumors to cPLA2 inhibition. These data indicate that HDAC5 loss in pancreatic cancer results in the hyperacetylation of GATA1, enabling the upregulation of cPLA2, which contributes to overproduction of AA. Dietary management plus cPLA2-targeted therapy could serve as a viable strategy for treating HDAC5-deficient pancreatic cancer patients.
Significance:
The HDAC5-GATA1-cPLA2-AA signaling axis regulates sensitivity to fat restriction plus cPLA2 inhibition in pancreatic ductal adenocarcinoma, proposing dietary management as a feasible strategy for treating a subset of patients with pancreatic cancer.
Data from Endometriosis-Associated Mesenchymal Stem Cells Support Ovarian Clear Cell Carcinoma through Iron Regulation
Authors: Atiya Huda I. , Frisbie Leonard , Goldfeld Ester , Orellana Taylor , Donnellan Nicole , Modugno Francesmary , Calderon Michael , Watkins Simon , Zhang Rugang , Elishaev Esther , Soong Thing Rinda , Vlad Anda , Coffman Lan
Published: March 2023

Abstract
Ovarian clear cell carcinoma (OCCC) is a deadly and treatment-resistant cancer, which arises within the unique microenvironment of endometriosis. In this study, we identified a subset of endometriosis-derived mesenchymal stem cells (enMSC) characterized by loss of CD10 expression that specifically support OCCC growth. RNA sequencing identified alterations in iron export in CD10-negative enMSCs and reciprocal changes in metal transport in cocultured OCCC cells. CD10-negative enMSCs exhibited elevated expression of iron export proteins hephaestin and ferroportin and donate iron to associated OCCCs, functionally increasing the levels of labile intracellular iron. Iron is necessary for OCCC growth, and CD10-negative enMSCs prevented the growth inhibitory effects of iron chelation. In addition, enMSC-mediated increases in OCCC iron resulted in a unique sensitivity to ferroptosis. In vitro and in vivo, treatment with the ferroptosis inducer erastin resulted in significant death of cancer cells grown with CD10-negative enMSCs. Collectively, this work describes a novel mechanism of stromal-mediated tumor support via iron donation. This work also defines an important role of endometriosis-associated MSCs in supporting OCCC growth and identifies a critical therapeutic vulnerability of OCCC to ferroptosis based on stromal phenotype.
Significance:
Endometriosis-derived mesenchymal stem cells support ovarian clear cell carcinoma via iron donation necessary for cancer growth, which also confers sensitivity to ferroptosis-inducing therapy.
Data from Loss of LOXL2 Promotes Uterine Hypertrophy and Tumor Progression by Enhancing H3K36ac-Dependent Gene Expression
Authors: Lu Xufeng , Xin Dazhuan E. , Du Juanjuan K. , Zou Quanli C. , Wu Qian , Zhang Yanan S. , Deng Wenhai , Yue Jicheng , Fan Xing S. , Zeng Yuanyuan , Cheng Xiaju , Li Xue , Hou Zhaoyuan , Mohan Man , Zhao Ting C. , Lu Xiaomei , Chang Zhijie , Xu Liyan , Sun Yu , Zu Xiongbing , Zhang Yu , Chinn Y. Eugene
Published: March 2023

Abstract
Lysyl oxidase-like 2 (LOXL2) is a member of the scavenger receptor cysteine-rich (SRCR) repeat carrying LOX family. Although LOXL2 is suspected to be involved in histone association and chromatin modification, the role of LOXL2 in epigenetic regulation during tumorigenesis and cancer progression remains unclear. Here, we report that nuclear LOXL2 associates with histone H3 and catalyzes H3K36ac deacetylation and deacetylimination. Both the N-terminal SRCR repeats and the C-terminal catalytic domain of LOXL2 carry redundant deacetylase catalytic activity. Overexpression of LOXL2 markedly reduced H3K36 acetylation and blocked H3K36ac-dependent transcription of genes, including c-MYC, CCND1, HIF1A, and CD44. Consequently, LOXL2 overexpression reduced cancer cell proliferation in vitro and inhibited xenograft tumor growth in vivo. In contrast, LOXL2 deficiency resulted in increased H3K36 acetylation and aberrant expression of H3K36ac-dependent genes involved in multiple oncogenic signaling pathways. Female LOXL2-deficient mice spontaneously developed uterine hypertrophy and uterine carcinoma. Moreover, silencing LOXL2 in cancer cells enhanced tumor progression and reduced the efficacy of cisplatin and anti-programmed cell death 1 (PD-1) combination therapy. Clinically, low nuclear LOXL2 expression and high H3K36ac levels corresponded to poor prognosis in uterine endometrial carcinoma patients. These results suggest that nuclear LOXL2 restricts cancer development in the female reproductive system via the regulation of H3K36ac deacetylation.
Significance:
LOXL2 loss reprograms the epigenetic landscape to promote uterine cancer initiation and progression and repress the efficacy of anti–PD-1 immunotherapy, indicating that LOXL2 is a tumor suppressor.
Data from An Exercise-Induced Metabolic Shield in Distant Organs Blocks Cancer Progression and Metastatic Dissemination
Authors: Sheinboim Danna , Parikh Shivang , Manich Paulee , Markus Irit , Dahan Sapir , Parikh Roma , Stubbs Elisa , Cohen Gali , Zemser-Werner Valentina , Bell Rachel E. , Ruiz Sara Arciniegas , Percik Ruth , Brenner Ronen , Leibou Stav , Vaknine Hananya , Arad Gali , Gerber Yariv , Keinan-Boker Lital , Shimony Tal , Bikovski Lior , Goldstein Nir , Constantini Keren , Labes Sapir , Mordechai Shimonov , Doron Hila , Lonescu Ariel , Ziv Tamar , Nizri Eran , Choshen Guy , Eldar-Finkelman Hagit , Tabach Yuval , Helman Aharon , Ben-Eliyahu Shamgar , Erez Neta , Perlson Eran , Geiger Tamar , Ben-Zvi Danny , Khaled Mehdi , Gepner Yftach , Levy Carmit
Published: March 2023

Abstract
Exercise prevents cancer incidence and recurrence, yet the underlying mechanism behind this relationship remains mostly unknown. Here we report that exercise induces the metabolic reprogramming of internal organs that increases nutrient demand and protects against metastatic colonization by limiting nutrient availability to the tumor, generating an exercise-induced metabolic shield. Proteomic and ex vivo metabolic capacity analyses of murine internal organs revealed that exercise induces catabolic processes, glucose uptake, mitochondrial activity, and GLUT expression. Proteomic analysis of routinely active human subject plasma demonstrated increased carbohydrate utilization following exercise. Epidemiologic data from a 20-year prospective study of a large human cohort of initially cancer-free participants revealed that exercise prior to cancer initiation had a modest impact on cancer incidence in low metastatic stages but significantly reduced the likelihood of highly metastatic cancer. In three models of melanoma in mice, exercise prior to cancer injection significantly protected against metastases in distant organs. The protective effects of exercise were dependent on mTOR activity, and inhibition of the mTOR pathway with rapamycin treatment ex vivo reversed the exercise-induced metabolic shield. Under limited glucose conditions, active stroma consumed significantly more glucose at the expense of the tumor. Collectively, these data suggest a clash between the metabolic plasticity of cancer and exercise-induced metabolic reprogramming of the stroma, raising an opportunity to block metastasis by challenging the metabolic needs of the tumor.
Significance:
Exercise protects against cancer progression and metastasis by inducing a high nutrient demand in internal organs, indicating that reducing nutrient availability to tumor cells represents a potential strategy to prevent metastasis.

See related commentary by Zerhouni and Piskounova, p. 4124
Data from Doxorubicin-Loaded Polymeric Meshes Prevent Local Recurrence after Sarcoma Resection While Avoiding Cardiotoxicity
Authors: Bressler Eric M. , Chu Ngoc-Quynh , Sabatelle Robert C. , Mahvi David A. , Korunes-Miller Jenny T. , Nagashima Fumiaki , Ichinose Fumito , Liu Rong , Grinstaff Mark W. , Colson Yolonda L. , Raut Chandrajit P.
Published: March 2023

Abstract
Surgery is the only potentially curative treatment for localized soft-tissue sarcomas. However, for sarcomas arising in the retroperitoneum, locoregional recurrence rates are 35% to 59% despite resection. Doxorubicin (DOX) is the standard first-line systemic chemotherapy for advanced soft-tissue sarcoma, yet its intravenous administration yields limited clinical efficacy and results in dose-limiting cardiotoxicity. We report the fabrication and optimization of a novel electrospun poly(caprolactone) (PCL) surgical mesh coated with layers of a hydrophobic polymer (poly(glycerol monostearate-co-caprolactone), PGC-C18), which delivers DOX directly to the operative bed following sarcoma resection. In xenograft models of liposarcoma and chondrosarcoma, DOX-loaded meshes (DoM) increased overall survival 4-fold compared with systemically administered DOX and prevented local recurrence in all but one animal. Importantly, mice implanted with DoMs exhibited preserved cardiac function, whereas mice receiving an equivalent dose systemically displayed a 23% decrease from baseline in both cardiac output and ejection fraction 20 days after administration. Collectively, this work demonstrates a feasible therapeutic approach to simultaneously prevent post-surgical tumor recurrence and minimize cardiotoxicity in soft-tissue sarcoma.
Significance:
A proof-of-principle study in animal models shows that a novel local drug delivery approach can prevent tumor recurrence as well as drug-related adverse events following surgical resection of soft-tissue sarcomas.
Data from Immunotherapeutic Targeting and PET Imaging of DLL3 in Small-Cell Neuroendocrine Prostate Cancer
Authors: Chou Jonathan , Egusa Emily A. , Wang Sinan , Badura Michelle L. , Lee Fei , Bidkar Anil P. , Zhu Jun , Shenoy Tanushree , Trepka Kai , Robinson Troy M. , Steri Veronica , Huang Jiaoti , Wang Yuzhuo , Small Eric J. , Chan Emily , Stohr Bradley A. , Ashworth Alan , Delafontaine Brant , Rottey Sylvie , Cooke Keegan S. , Hashemi Sadraei Nooshin , Yu Brian , Salvati Mark , Bailis Julie M. , Feng Felix Y. , Flavell Robert R. , Aggarwal Rahul
Published: March 2023

Abstract
Effective treatments for de novo and treatment-emergent small-cell/neuroendocrine (t-SCNC) prostate cancer represent an unmet need for this disease. Using metastatic biopsies from patients with advanced cancer, we demonstrate that delta-like ligand 3 (DLL3) is expressed in de novo and t-SCNC and is associated with reduced survival. We develop a PET agent, [89Zr]-DFO-DLL3-scFv, that detects DLL3 levels in mouse SCNC models. In multiple patient-derived xenograft models, AMG 757 (tarlatamab), a half-life–extended bispecific T-cell engager (BiTE) immunotherapy that redirects CD3-positive T cells to kill DLL3-expressing cells, exhibited potent and durable antitumor activity. Late relapsing tumors after AMG 757 treatment exhibited lower DLL3 levels, suggesting antigen loss as a resistance mechanism, particularly in tumors with heterogeneous DLL3 expression. These findings have been translated into an ongoing clinical trial of AMG 757 in de novo and t-SCNC, with a confirmed objective partial response in a patient with histologically confirmed SCNC. Overall, these results identify DLL3 as a therapeutic target in SCNC and demonstrate that DLL3-targeted BiTE immunotherapy has significant antitumor activity in this aggressive prostate cancer subtype.
Significance:
The preclinical and clinical evaluation of DLL3-directed immunotherapy, AMG 757, and development of a PET radiotracer for noninvasive DLL3 detection demonstrate the potential of targeting DLL3 in SCNC prostate cancer.
Data from A Genetically Encoded Magnetic Resonance Imaging Reporter Enables Sensitive Detection and Tracking of Spontaneous Metastases in Deep Tissues
Authors: Nyström Nivin N. , McRae Sean W. , Martinez Francisco M. , Kelly John J. , Scholl Timothy J. , Ronald John A.
Published: March 2023

Abstract
Metastasis is the leading cause of cancer-related death. However, it remains a poorly understood aspect of cancer biology, and most preclinical cancer studies do not examine metastasis, focusing solely on the primary tumor. One major factor contributing to this paradox is a gap in available tools for accurate spatiotemporal measurements of metastatic spread in vivo. Here, our objective was to develop an imaging reporter system that offers sensitive three-dimensional (3D) detection of cancer cells at high resolutions in live mice. An organic anion-transporting polypeptide 1b3 (oatp1b3) was used as an MRI reporter gene, and its sensitivity was systematically optimized for in vivo tracking of viable cancer cells in a spontaneous metastasis model. Metastases with oatp1b3-MRI could be observed at the single lymph node level and tracked over time as cancer cells spread to multiple lymph nodes and different organ systems in individual animals. While initial single lesions were successfully imaged in parallel via bioluminescence, later metastases were largely obscured by light scatter from the initial node. Importantly, MRI could detect micrometastases in lung tissue comprised on the order of 1,000 cancer cells. In summary, oatp1b3-MRI enables longitudinal tracking of cancer cells with combined high resolution and high sensitivity that provides 3D spatial information and the surrounding anatomical context.
Significance:
An MRI reporter gene system optimized for tracking metastasis in deep tissues at high resolutions and able to detect spontaneous micrometastases in lungs of mice provides a useful tool for metastasis research.
Supplementary Figure 2 from Identification of a Novel Biomarker, SEMA5A, for Non–Small Cell Lung Carcinoma in Nonsmoking Women
Authors: Lu Tzu-Pin , Tsai Mong-Hsun , Lee Jang-Ming , Hsu Chung-Ping , Chen Pei-Chun , Lin Chung-Wu , Shih Jin-Yuan , Yang Pan-Chyr , Hsiao Chuhsing Kate , Lai Liang-Chuan , Chuang Eric Y.
Published: March 2023

Supplementary Figure 2 from Identification of a Novel Biomarker, SEMA5A, for Non–Small Cell Lung Carcinoma in Nonsmoking Women
Supplementary Table 1 from Elevated Systemic Levels of Inflammatory Cytokines in Older Women with Persistent Cervical Human Papillomavirus Infection
Authors: Kemp Troy J. , Hildesheim Allan , García-Piñeres Alfonso , Williams Marcus C. , Shearer Gene M. , Rodriguez Ana Cecilia , Schiffman Mark , Burk Robert , Freer Enrique , Bonilla Jose , Herrero Rolando , Pinto Ligia A.
Published: March 2023

Supplementary Table 1 from Elevated Systemic Levels of Inflammatory Cytokines in Older Women with Persistent Cervical Human Papillomavirus Infection
Supplementary Figures 1 and 2 from Evaluation of Multiplexed Cytokine and Inflammation Marker Measurements: a Methodologic Study
Authors: Chaturvedi Anil K. , Kemp Troy J. , Pfeiffer Ruth M. , Biancotto Angelique , Williams Marcus , Munuo Stella , Purdue Mark P. , Hsing Ann W. , Pinto Ligia , McCoy J. Philip , Hildesheim Allan
Published: March 2023

Supplementary Figures 1 and 2 from Evaluation of Multiplexed Cytokine and Inflammation Marker Measurements: a Methodologic Study
Supplementary Appendix 1 from Screening for Colorectal Cancer in a Safety-Net Health Care System: Access to Care Is Critical and Has Implications for Screening Policy
Authors: Gupta Samir , Tong Liyue , Allison James E. , Carter Elizabeth , Koch Mark , Rockey Don C. , Anderson Paula , Ahn Chul , Argenbright Keith , Skinner Celette Sugg
Published: March 2023

Supplementary Appendix 1 from Screening for Colorectal Cancer in a Safety-Net Health Care System: Access to Care Is Critical and Has Implications for Screening Policy
Supplementary Table 1C from State Disparities in Colorectal Cancer Mortality Patterns in the United States
Authors: Naishadham Deepa , Lansdorp-Vogelaar Iris , Siegel Rebecca , Cokkinides Vilma , Jemal Ahmedin
Published: March 2023

PDF file - 83K, Mortality rates and trends in Colorectal Cancer, by State, US, 1990-2007, Hispanics
Supplemental Table 1 from Lung Cancer Incidence Trends by Histology Type among Asian American, Native Hawaiian, and Pacific Islander Populations in the United States, 1990–2010
Authors: Cheng Iona , Le Gem M. , Noone Anne-Michelle , Gali Kathleen , Patel Manali , Haile Robert W. , Wakelee Heather A. , Gomez Scarlett L.
Published: March 2023

Supplemental Table 1. Geographic areas included in cancer incidence rates for each Asian American, Native Hawaiian, Pacific Islander ethnic group, 1990-2008.
Supplementary Tables 1-3 from Epigenetic Deregulation Across Chromosome 2q14.2 Differentiates Normal from Prostate Cancer and Provides a Regional Panel of Novel DNA Methylation Cancer Biomarkers
Authors: Devaney James , Stirzaker Clare , Qu Wenjia , Song Jenny Z. , Statham Aaron L. , Patterson Kate I. , Horvath Lisa G. , Tabor Bruce , Coolen Marcel W. , Hulf Toby , Kench James G. , Henshall Susan M. , Pe Benito Ruth , Haynes Anne-Maree , Mayor Regina , Peinado Miguel A. , Sutherland Robert L. , Clark Susan J.
Published: March 2023

Supplementary Tables 1-3 from Epigenetic Deregulation Across Chromosome 2q14.2 Differentiates Normal from Prostate Cancer and Provides a Regional Panel of Novel DNA Methylation Cancer Biomarkers
Supplementary Table 2 from Polymorphisms in MicroRNAs Are Associated with Survival in Non–Small Cell Lung Cancer
Authors: Zhao Yang , Wei Qingyi , Hu Lingming , Chen Feng , Hu Zhibin , Heist Rebecca S. , Su Li , Amos Christopher I. , Shen Hongbing , Christiani David C.
Published: March 2023

Supplementary Table 2: This table provides the results from the replication cohorts.
Supplementary Figure 4 from Polymorphisms in MicroRNAs Are Associated with Survival in Non–Small Cell Lung Cancer
Authors: Zhao Yang , Wei Qingyi , Hu Lingming , Chen Feng , Hu Zhibin , Heist Rebecca S. , Su Li , Amos Christopher I. , Shen Hongbing , Christiani David C.
Published: March 2023

Supplementary Figure 4. A: Rs2042253 is located in adjacent region of miR-5197-5p. Rs7522956 is located in loop sequences of mir-4742 gene. B: the Top 10 enriched KEGG pathways of relevant miRNAs
Data Supplement from Gene–Environment Interaction Involving Recently Identified Colorectal Cancer Susceptibility Loci
Authors: Kantor Elizabeth D. , Hutter Carolyn M. , Minnier Jessica , Berndt Sonja I. , Brenner Hermann , Caan Bette J. , Campbell Peter T. , Carlson Christopher S. , Casey Graham , Chan Andrew T. , Chang-Claude Jenny , Chanock Stephen J. , Cotterchio Michelle , Du Mengmeng , Duggan David , Fuchs Charles S. , Giovannucci Edward L. , Gong Jian , Harrison Tabitha A. , Hayes Richard B. , Henderson Brian E. , Hoffmeister Michael , Hopper John L. , Jenkins Mark A. , Jiao Shuo , Kolonel Laurence N. , Le Marchand Loic , Lemire Mathieu , Ma Jing , Newcomb Polly A. , Ochs-Balcom Heather M. , Pflugeisen Bethann M. , Potter John D. , Rudolph Anja , Schoen Robert E. , Seminara Daniela , Slattery Martha L. , Stelling Deanna L. , Thomas Fridtjof , Thornquist Mark , Ulrich Cornelia M. , Warnick Greg S. , Zanke Brent W. , Peters Ulrike , Hsu Li , White Emily
Published: March 2023

Supplemental Table 2. All GxE interactions
Supplementary Tables 1-2 from Relationship of Extreme Chromosomal Instability with Long-term Survival in a Retrospective Analysis of Primary Breast Cancer
Authors: Roylance Rebecca , Endesfelder David , Gorman Patricia , Burrell Rebecca A. , Sander Jil , Tomlinson Ian , Hanby Andrew M. , Speirs Valerie , Richardson Andrea L. , Birkbak Nicolai J. , Eklund Aron C. , Downward Julian , Kschischo Maik , Szallasi Zoltan , Swanton Charles
Published: March 2023

PDF file - 106K
Supplementary Figure 3 from Relationship of Extreme Chromosomal Instability with Long-term Survival in a Retrospective Analysis of Primary Breast Cancer
Authors: Roylance Rebecca , Endesfelder David , Gorman Patricia , Burrell Rebecca A. , Sander Jil , Tomlinson Ian , Hanby Andrew M. , Speirs Valerie , Richardson Andrea L. , Birkbak Nicolai J. , Eklund Aron C. , Downward Julian , Kschischo Maik , Szallasi Zoltan , Swanton Charles
Published: March 2023

PDF file - 106K, Association of Mean Centromeric Deviation Cohort with Breast cancer death for patients treated with chemotherapy: Kaplan-Meier survival analysis of extreme aneuploid (MCD4) ER negative breast cancer patients treated with chemotherapy compared to all other MCD groups together.
Supplementary Figure 2A from Relationship of Extreme Chromosomal Instability with Long-term Survival in a Retrospective Analysis of Primary Breast Cancer
Authors: Roylance Rebecca , Endesfelder David , Gorman Patricia , Burrell Rebecca A. , Sander Jil , Tomlinson Ian , Hanby Andrew M. , Speirs Valerie , Richardson Andrea L. , Birkbak Nicolai J. , Eklund Aron C. , Downward Julian , Kschischo Maik , Szallasi Zoltan , Swanton Charles
Published: March 2023

PDF file - 202K, Distribution of centromere signals for MCD1 and MCD4 ER-negative breast cancer patients: Histograms of centromere numbers for chromosome 2.
Supplementary Table 2 from Smoking and Passive Smoking in Cervical Cancer Risk: Pooled Analysis of Couples from the IARC Multicentric Case–Control Studies
Authors: Louie Karly S. , Castellsague Xavier , de Sanjose Silvia , Herrero Rolando , Meijer Chris J. , Shah Keerti , Munoz Nubia , Bosch F. Xavier
Published: March 2023

Supplementary Table 2 from Smoking and Passive Smoking in Cervical Cancer Risk: Pooled Analysis of Couples from the IARC Multicentric Case–Control Studies
Supplementary Table 3 from Childhood Exposure to Secondhand Smoke and Functional Mannose Binding Lectin Polymorphisms Are Associated with Increased Lung Cancer Risk
Authors: Olivo-Marston Susan E. , Yang Ping , Mechanic Leah E. , Bowman Elise D. , Pine Sharon R. , Loffredo Christopher A. , Alberg Anthony J. , Caporaso Neil , Shields Peter G. , Chanock Stephen , Wu Yanhong , Jiang Ruoxiang , Cunningham Julie , Jen Jin , Harris Curtis C.
Published: March 2023

Supplementary Table 3 from Childhood Exposure to Secondhand Smoke and Functional Mannose Binding Lectin Polymorphisms Are Associated with Increased Lung Cancer Risk