bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Adaptive Upregulation of EGFR Limits Attenuation of Tumor Growth by Neutralizing IL6 Antibodies, with Implications for Combined Therapy in Ovarian Cancer
Authors: Milagre Carla S. , Gopinathan Ganga , Everitt Gemma , Thompson Richard G. , Kulbe Hagen , Zhong Haihong , Hollingsworth Robert E. , Grose Richard , Bowtell David D.L. , Hochhauser Daniel , Balkwill Frances R.
Published: April 2023

Abstract
Excess production of the proinflammatory IL6 has both local and systemic tumor-promoting activity in many cancers, including ovarian cancer. However, treatment of advanced ovarian cancer patients with a neutralizing IL6 antibody yielded little efficacy in a previous phase II clinical trial. Here, we report results that may explain this outcome, based on the finding that neutralizing antibodies to IL6 and STAT3 inhibition are sufficient to upregulate the EGFR pathway in high-grade serous and other ovarian cancer cells. Cell treatment with the EGFR inhibitor gefitinib abolished upregulation of the EGFR pathway. Combining neutralizing IL6 antibodies and gefitinib inhibited malignant cell growth in 2D and 3D culture. We found that ErbB-1 was localized predominantly in the nucleus of ovarian cancer cells examined, contrasting with plasma membrane localization in lung cancer cells. Treatment with anti-IL6, gefitinib, or their combination all led to partial restoration of ErbB-1 on the plasma membrane. In vivo experiments confirmed the effects of IL6 inhibition on the EGFR pathway and the enhanced activity of a combination of anti-IL6 antibodies and gefitinib on malignant cell growth. Taken together, our results offer a preclinical rationale to combine anti-IL6 and gefitinib to treat patients with advanced stage ovarian cancer. Cancer Res; 75(7); 1255–64. ©2015 AACR.
Data from Agr2 Mediates Paracrine Effects on Stromal Fibroblasts That Promote Invasion by Gastric Signet-Ring Carcinoma Cells
Authors: Tsuji Tadahiro , Satoyoshi Rika , Aiba Namiko , Kubo Takanori , Yanagihara Kazuyoshi , Maeda Daichi , Goto Akiteru , Ishikawa Kazuo , Yashiro Masakazu , Tanaka Masamitsu
Published: April 2023

Abstract
Agr2 is a disulfide isomerase residing in the endoplasmic reticulum (ER), which physiologically regulates protein folding and mediates resistance to ER stress. Agr2 is overexpressed in adenocarcinomas of various organs, where it participates in neoplastic transformation and metastasis, therefore acts as a pro-oncogenic protein. Besides its normal localization in the ER, Agr2 is also found in the serum and urine of cancer patients, although the physiological significance of extracellular Agr2 is poorly understood. In this study, we demonstrated that extracellular Agr2 can activate stromal fibroblasts and promote fibroblast-associated cancer invasion in gastric signet-ring cell carcinoma (SRCC), where Agr2 is highly expressed. Agr2 secreted from SRCC cells was incorporated by the surrounding gastric fibroblasts and promoted invasion by these cells. In turn, activated fibroblasts coordinated the invasive behavior of fibroblasts and cancer cells. Our findings suggested that Agr2 drives progression of gastric SRCC by exerting paracrine effects on fibroblasts in the tumor microenvironment, acting also to increase the growth and resistance of SRCC cells to oxidative and hypoxic stress as cell autonomous effects. Cancer Res; 75(2); 356–66. ©2014 AACR.
Data from Activation of Pim Kinases Is Sufficient to Promote Resistance to MET Small-Molecule Inhibitors
Authors: An Ningfei , Xiong Ying , LaRue Amanda C. , Kraft Andrew S. , Cen Bo
Published: April 2023

Abstract
Mesenchymal-epithelial transition (MET) blockade offers a new targeted therapy particularly in those cancers with MET amplification. However, the efficacy and the duration of the response to MET inhibitors are limited by the emergence of drug resistance. Here, we report that resistance to small-molecule inhibitors of MET can arise from increased expression of the prosurvival Pim protein kinases. This resistance mechanism was documented in non–small cell lung cancer and gastric cancer cells with MET amplification. Inhibition of Pim kinases enhanced cell death triggered by short-term treatment with MET inhibitors. Pim kinases control the translation of antiapoptotic protein Bcl-2 at an internal ribosome entry site and this mechanism was identified as the basis for Pim-mediated resistance to MET inhibitors. Protein synthesis was increased in drug-resistant cells, secondary to a Pim-mediated increase in cap-independent translation. In cells rendered drug resistant by chronic treatment with MET inhibitors, genetic or pharmacologic inhibition of Pim kinases was sufficient to restore sensitivity in vitro and in vivo. Taken together, our results rationalize Pim inhibition as a strategy to augment responses and blunt acquired resistance to MET inhibitors in cancer. Cancer Res; 75(24); 5318–28. ©2015 AACR.
Data from Epigenetic Silencing of miR-490-3p Reactivates the Chromatin Remodeler SMARCD1 to Promote Helicobacter pylori–Induced Gastric Carcinogenesis
Authors: Shen Jing , Xiao Zhangang , Wu William K.K. , Wang Maggie H. , To Ka F. , Chen Yangchao , Yang Weiqin , Li May S.M. , Shin Vivian Y. , Tong Joanna H. , Kang Wei , Zhang Lin , Li Minxing , Wang Lin , Lu Lan , Chan Ruby L.Y. , Wong Sunny H. , Yu Jun , Chan Matthew T.V. , Chan Francis K.L. , Sung Joseph J.Y. , Cheng Alfred S.L. , Cho Chi H.
Published: April 2023

Abstract
Chromatin remodeling has emerged as a hallmark of gastric cancer, but the regulation of chromatin regulators other than genetic change is unknown. Helicobacter pylori causes epigenetic dysregulation to promote gastric carcinogenesis, but the roles and functions of microRNAs (miRNA) in this multistage cascade are not fully explored. In this study, miRNA expression in preneoplastic and neoplastic lesions in murine stomachs induced by H. pylori and N-methyl-N-nitrosourea (MNU) was profiled by miRNA expression array. miR-490-3p exhibited progressive downregulation in gastritis, intestinal metaplasia, and adenocarcinoma during H. pylori and MNU-induced gastric carcinogenesis. Significant downregulation of miR-490-3p was confirmed in human gastric cancer tissues in which its regulatory region was found to be hypermethylated. miR-490-3p exerted growth- and metastasis-suppressive effects on gastric cancer cells through directly targeting SMARCD1, a SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex subunit. Knockdown of SMARCD1 significantly attenuated the protumorigenic effects of miR-490-3p inhibitor, whereas enforced expression of SMARCD1 promoted in vitro and in vivo oncogenic phenotypes of gastric cancer cells. SMARCD1 was markedly upregulated in gastric cancer in which its high expression was associated with shortened patients' survival independent of TNM staging. In conclusion, hypermethylation-mediated silencing of miR-490-3p reactivates SMARCD1 to confer malignant phenotypes, mechanistically linking H. pylori, chromatin remodeling, and gastric carcinogenesis. Cancer Res; 75(4); 754–65. ©2014 AACR.
Data from The CUL4B/AKT/β-Catenin Axis Restricts the Accumulation of Myeloid-Derived Suppressor Cells to Prohibit the Establishment of a Tumor-Permissive Microenvironment
Authors: Qian Yanyan , Yuan Jupeng , Hu Huili , Yang Qifeng , Li Jisheng , Zhang Shuqian , Jiang Baichun , Shao Changshun , Gong Yaoqin
Published: April 2023

Abstract
Cancer progression requires a permissive microenvironment that shields cancer from the host immunosurveillance. The presence of myeloid-derived suppressor cells (MDSC) is a key feature of a tumor-permissive microenvironment. Cullin 4B (CUL4B), a scaffold protein in the Cullin 4B-RING E3 ligase complex (CRL4B), represses tumor suppressors through diverse epigenetic mechanisms and is overexpressed in many malignancies. We report here that CUL4B unexpectedly functions as a negative regulator of MDSC functions in multiple tumor settings. Conditional ablation of CUL4B in the hematopoietic system, driven by Tek-Cre, resulted in significantly enhanced accumulation and activity of MDSCs. Mechanistically, we demonstrate that the aberrant abundance of MDSCs in the absence of CUL4B was mediated by the downregulation of the AKT/β-catenin pathway. Moreover, CUL4B repressed the phosphatases PP2A and PHLPP1/2 that dephosphorylate and inactivate AKT to sustain pathway activation. Importantly, the CUL4B/AKT/β-catenin axis was downregulated in MDSCs of healthy individuals and was further suppressed in tumor-bearing mice and cancer patients. Thus, our findings point to a pro- and antitumorigenic role for CUL4B in malignancy, in which its ability to impede the formation of a tumor-supportive microenvironment may be context-specific. Cancer Res; 75(23); 5070–83. ©2015 AACR.
Data from ABCG2 Transporter Expression Impacts Group 3 Medulloblastoma Response to Chemotherapy
Authors: Morfouace Marie , Cheepala Satish , Jackson Sadhana , Fukuda Yu , Patel Yogesh T. , Fatima Soghra , Kawauchi Daisuke , Shelat Anang A. , Stewart Clinton F. , Sorrentino Brian P. , Schuetz John D. , Roussel Martine F.
Published: April 2023

Abstract
While a small number of plasma membrane ABC transporters can export chemotherapeutic drugs and confer drug resistance, it is unknown whether these transporters are expressed or functional in less therapeutically tractable cancers such as Group 3 (G3) medulloblastoma. Herein we show that among this class of drug transporters, only ABCG2 was expressed at highly increased levels in human G3 medulloblastoma and a mouse model of this disease. In the mouse model, Abcg2 protein was expressed at the plasma membrane where it functioned as expected on the basis of export of prototypical substrates. By screening ABC substrates against mouse G3 medulloblastoma tumorspheres in vitro, we found that Abcg2 inhibition could potentiate responses to the clinically used drug topotecan, producing a more than 9-fold suppression of cell proliferation. Extended studies in vivo in this model confirmed that Abcg2 inhibition was sufficient to enhance antiproliferative responses to topotecan, producing a significant survival advantage compared with subjects treated with topotecan alone. Our findings offer a preclinical proof of concept for blockade of ABCG2 transporter activity as a strategy to empower chemotherapeutic responses in G3 medulloblastoma. Cancer Res; 75(18); 3879–89. ©2015 AACR.
Data from miR-124 and Androgen Receptor Signaling Inhibitors Repress Prostate Cancer Growth by Downregulating Androgen Receptor Splice Variants, EZH2, and Src
Authors: Shi Xu-Bao , Ma Ai-Hong , Xue Lingru , Li Meimei , Nguyen Hao G. , Yang Joy C. , Tepper Clifford G. , Gandour-Edwards Regina , Evans Christopher P. , Kung Hsing-Jien , deVere White Ralph W.
Published: April 2023

Abstract
miR-124 targets the androgen receptor (AR) transcript, acting as a tumor suppressor to broadly limit the growth of prostate cancer. In this study, we unraveled the mechanisms through which miR-124 acts in this setting. miR-124 inhibited proliferation of prostate cancer cells in vitro and sensitized them to inhibitors of androgen receptor signaling. Notably, miR-124 could restore the apoptotic response of cells resistant to enzalutamide, a drug approved for the treatment of castration-resistant prostate cancer. We used xenograft models to examine the effects of miR-124 in vivo when complexed with polyethylenimine-derived nanoparticles. Intravenous delivery of miR-124 was sufficient to inhibit tumor growth and to increase tumor cell apoptosis in combination with enzalutamide. Mechanistic investigations revealed that miR-124 directly downregulated AR splice variants AR-V4 and V7 along with EZH2 and Src, oncogenic targets that have been reported to contribute to prostate cancer progression and treatment resistance. Taken together, our results offer a preclinical rationale to evaluate miR-124 for cancer treatment. Cancer Res; 75(24); 5309–17. ©2015 AACR.
Data from Akt Inhibition Enhances Expansion of Potent Tumor-Specific Lymphocytes with Memory Cell Characteristics
Authors: Crompton Joseph G. , Sukumar Madhusudhanan , Roychoudhuri Rahul , Clever David , Gros Alena , Eil Robert L. , Tran Eric , Hanada Ken-ichi , Yu Zhiya , Palmer Douglas C. , Kerkar Sid P. , Michalek Ryan D. , Upham Trevor , Leonardi Anthony , Acquavella Nicolas , Wang Ena , Marincola Francesco M. , Gattinoni Luca , Muranski Pawel , Sundrud Mark S. , Klebanoff Christopher A. , Rosenberg Steven A. , Fearon Douglas T. , Restifo Nicholas P.
Published: April 2023

Abstract
Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) results in complete regression of advanced cancer in some patients, but the efficacy of this potentially curative therapy may be limited by poor persistence of TIL after adoptive transfer. Pharmacologic inhibition of the serine/threonine kinase Akt has recently been shown to promote immunologic memory in virus-specific murine models, but whether this approach enhances features of memory (e.g., long-term persistence) in TIL that are characteristically exhausted and senescent is not established. Here, we show that pharmacologic inhibition of Akt enables expansion of TIL with the transcriptional, metabolic, and functional properties characteristic of memory T cells. Consequently, Akt inhibition results in enhanced persistence of TIL after adoptive transfer into an immunodeficient animal model and augments antitumor immunity of CD8 T cells in a mouse model of cell-based immunotherapy. Pharmacologic inhibition of Akt represents a novel immunometabolomic approach to enhance the persistence of antitumor T cells and improve the efficacy of cell-based immunotherapy for metastatic cancer. Cancer Res; 75(2); 296–305. ©2014 AACR.
Data from In Vivo Radioimaging of Bradykinin Receptor B1, a Widely Overexpressed Molecule in Human Cancer
Authors: Lin Kuo-Shyan , Pan Jinhe , Amouroux Guillaume , Turashvili Gulisa , Mesak Felix , Hundal-Jabal Navjit , Pourghiasian Maral , Lau Joseph , Jenni Silvia , Aparicio Samuel , Bénard François
Published: April 2023

Abstract
The bradykinin receptor B1R is overexpressed in many human cancers where it might be used as a general target for cancer imaging. In this study, we evaluated the feasibility of using radiolabeled kallidin derivatives to visualize B1R expression in a preclinical model of B1R-positive tumors. Three synthetic derivatives were evaluated in vitro and in vivo for receptor binding and their ability to visualize tumors by PET. Enalaprilat and phosphoramidon were used to evaluate the impact of peptidases on tumor visualization. While we found that radiolabeled peptides based on the native kallidin sequence were ineffective at visualizing B1R-positive tumors, peptidase inhibition with phosphoramidon greatly enhanced B1R visualization in vivo. Two stabilized derivatives incorporating unnatural amino acids (68Ga-SH01078 and 68Ga-P03034) maintained receptor-binding affinities that were effective, allowing excellent tumor visualization, minimal accumulation in normal tissues, and rapid renal clearance. Tumor uptake was blocked in the presence of excess competitor, confirming that the specificity of tumor accumulation was receptor mediated. Our results offer a preclinical proof of concept for noninvasive B1R detection by PET imaging as a general tool to visualize many human cancers. Cancer Res; 75(2); 387–93. ©2014 AACR.
Data from Evaluating Patient-Derived Colorectal Cancer Xenografts as Preclinical Models by Comparison with Patient Clinical Data
Authors: Nunes Manoel , Vrignaud Patricia , Vacher Sophie , Richon Sophie , Lièvre Astrid , Cacheux Wulfran , Weiswald Louis-Bastien , Massonnet Gerald , Chateau-Joubert Sophie , Nicolas André , Dib Colette , Zhang Weidong , Watters James , Bergstrom Donald , Roman-Roman Sergio , Bièche Ivan , Dangles-Marie Virginie
Published: April 2023

Abstract
Development of targeted therapeutics required translationally relevant preclinical models with well-characterized cancer genome alterations. Here, by studying 52 colorectal patient-derived tumor xenografts (PDX), we examined key molecular alterations of the IGF2–PI3K and ERBB–RAS pathways and response to cetuximab. PDX molecular data were compared with that published for patient colorectal tumors in The Cancer Genome Atlas. We demonstrated a significant pattern of mutual exclusivity of genomic abnormalities in the IGF2–PI3K and ERBB–RAS pathways. The genomic anomaly frequencies observed in microsatellite stable PDX reproduce those detected in nonhypermutated patient tumors. We found frequent IGF2 upregulation (16%), which was mutually exclusive with IRS2, PIK3CA, PTEN, and INPP4B alterations, supporting IGF2 as a potential drug target. In addition to maintaining the genomic and histologic diversity, correct preclinical models need to reproduce drug response observed in patients. Responses of PDXs to cetuximab recapitulate also clinical data in patients, with partial or complete response in 15% (8 of 52) of PDXs and response strictly restricted to KRAS wild-type models. The response rate reaches 53% (8 of 15) when KRAS, BRAF, and NRAS mutations are concomitantly excluded, proving a functional cross-validation of predictive biomarkers obtained retrospectively in patients. Collectively, these results show that, because of their clinical relevance, colorectal PDXs are appropriate tools to identify both new targets, like IGF2, and predictive biomarkers of response/resistance to targeted therapies. Cancer Res; 75(8); 1560–6. ©2015 AACR.
Data from Eradication of Acute Myeloid Leukemia with FLT3 Ligand–Targeted miR-150 Nanoparticles
Authors: Jiang Xi , Bugno Jason , Hu Chao , Yang Yang , Herold Tobias , Qi Jun , Chen Ping , Gurbuxani Sandeep , Arnovitz Stephen , Strong Jennifer , Ferchen Kyle , Ulrich Bryan , Weng Hengyou , Wang Yungui , Huang Hao , Li Shenglai , Neilly Mary Beth , Larson Richard A. , Le Beau Michelle M. , Bohlander Stefan K. , Jin Jie , Li Zejuan , Bradner James E. , Hong Seungpyo , Chen Jianjun
Published: April 2023

Abstract
Acute myeloid leukemia (AML) is a common and fatal form of hematopoietic malignancy. Overexpression and/or mutations of FLT3 have been shown to occur in the majority of cases of AML. Our analysis of a large-scale AML patient cohort (N = 562) indicates that FLT3 is particularly highly expressed in some subtypes of AML, such as AML with t(11q23)/MLL-rearrangements or FLT3-ITD. Such AML subtypes are known to be associated with unfavorable prognosis. To treat FLT3-overexpressing AML, we developed a novel targeted nanoparticle system: FLT3 ligand (FLT3L)-conjugated G7 poly(amidoamine) (PAMAM) nanosized dendriplex encapsulating miR-150, a pivotal tumor suppressor and negative regulator of FLT3. We show that the FLT3L-guided miR-150 nanoparticles selectively and efficiently target FLT3-overexpressing AML cells and significantly inhibit viability/growth and promote apoptosis of the AML cells. Our proof-of-concept animal model studies demonstrate that the FLT3L-guided miR-150 nanoparticles tend to concentrate in bone marrow, and significantly inhibit progression of FLT3-overexpressing AML in vivo, while exhibiting no obvious side effects on normal hematopoiesis. Collectively, we have developed a novel targeted therapeutic strategy, using FLT3L-guided miR-150–based nanoparticles, to treat FLT3-overexpressing AML with high efficacy and minimal side effects. Cancer Res; 76(15); 4470–80. ©2016 AACR.
Data from EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer
Authors: Amato Katherine R. , Wang Shan , Tan Li , Hastings Andrew K. , Song Wenqiang , Lovly Christine M. , Meador Catherine B. , Ye Fei , Lu Pengcheng , Balko Justin M. , Colvin Daniel C. , Cates Justin M. , Pao William , Gray Nathanael S. , Chen Jin
Published: April 2023

Abstract
Despite the success of treating EGFR-mutant lung cancer patients with EGFR tyrosine kinase inhibitors (TKI), all patients eventually acquire resistance to these therapies. Although various resistance mechanisms have been described, there are currently no FDA-approved therapies that target alternative mechanisms to treat lung tumors with acquired resistance to first-line EGFR TKI agents. Here we found that EPHA2 is overexpressed in EGFR TKI-resistant tumor cells. Loss of EPHA2 reduced the viability of erlotinib-resistant tumor cells harboring EGFRT790M mutations in vitro and inhibited tumor growth and progression in an inducible EGFRL858R+T790M-mutant lung cancer model in vivo. Targeting EPHA2 in erlotinib-resistant cells decreased S6K1-mediated phosphorylation of cell death agonist BAD, resulting in reduced tumor cell proliferation and increased apoptosis. Furthermore, pharmacologic inhibition of EPHA2 by the small-molecule inhibitor ALW-II-41-27 decreased both survival and proliferation of erlotinib-resistant tumor cells and inhibited tumor growth in vivo. ALW-II-41-27 was also effective in decreasing viability of cells with acquired resistance to the third-generation EGFR TKI AZD9291. Collectively, these data define a role for EPHA2 in the maintenance of cell survival of TKI-resistant, EGFR-mutant lung cancer and indicate that EPHA2 may serve as a useful therapeutic target in TKI-resistant tumors. Cancer Res; 76(2); 305–18. ©2016 AACR.
Data from Genome-Wide Association Study of Bladder Cancer in a Chinese Cohort Reveals a New Susceptibility Locus at 5q12.3
Authors: Wang Meilin , Li Zhiqiang , Chu Haiyan , Lv Qiang , Ye Dingwei , Ding Qiang , Xu Chuanliang , Guo Jianming , Du Mulong , Chen Jianhua , Song Zhijian , Yin Changjun , Qin Chao , Gu Chengyuan , Zhu Yao , Xia Guowei , Liu Fang , Zhang Zhengsheng , Yuan Lin , Fu Guangbo , Hu Zhibin , Tong Na , Shen Jiawei , Liu Ke , Sun Jielin , Sun Yinghao , Li Jue , Li Xingwang , Shen Hongbing , Xu Jianfeng , Shi Yongyong , Zhang Zhengdong
Published: April 2023

Abstract
Genome-wide association studies (GWAS) of bladder cancer have identified a number of susceptibility loci in European populations but have yet to uncover the genetic determinants underlying bladder cancer incidence among other ethnicities. Therefore, we performed the first GWAS in a Chinese cohort comprising 3,406 cases of bladder cancer and 4,645 controls. We identified a new susceptibility locus for bladder cancer at 5q12.3, located in the intron of CWC27 (rs2042329), that was significantly associated with disease risk (OR = 1.40; P = 4.61 × 10−11). However, rs2042329 was not associated with bladder cancer risk in patients of European descent. The rs2042329 risk allele was also related to significantly increased expression levels of CWC27 mRNA and protein in bladder cancer tissues from Chinese patients. Additional functional analyses suggested that CWC27 played an oncogenic role in bladder cancer by inducing cell proliferation and suppressing apoptosis. In conclusion, the identification of a risk-associated locus at 5q12.3 provides new insights into the inherited susceptibility to bladder cancer in Chinese populations and may help to identify high-risk individuals. Cancer Res; 76(11); 3277–84. ©2016 AACR.
Data from Alox5 Blockade Eradicates JAK2V617F-Induced Polycythemia Vera in Mice
Authors: Chen Yaoyu , Shan Yi , Lu Min , DeSouza Ngoc , Guo Zhiru , Hoffman Ronald , Liang Aibin , Li Shaoguang
Published: April 2023

Abstract
Myeloproliferative neoplasms such as polycythemia vera (PV), which are associated with the JAK mutation V617F, remain incurable despite progress in the use of JAK2 inhibitors for treatment of some of these diseases. In this study, we employed mice that undergo JAK2V617F-induced PV as a tool to explore new candidate targets for therapy. Our investigations focused on the lipid metabolic enzyme arachidonate 5-lipoxygenase (Alox5), which we found to be strongly upregulated by JAK2V617F in hematopoietic cells in vitro and in vivo. Notably, genetic deletion of Alox5 or its inhibition in mice with a bioactive small-molecule inhibitor was sufficient to attenuate PV development. This therapeutic effect was associated with induction of a blockade in cell-cycle progression and also with apoptosis in PV cells. Genetic loss exerted an inhibitory effect on PV-initiating cells. Similarly, Alox5 inhibition was sufficient to suppress colony formation in human JAK2V617F-expressing CD34+ cells. Mechanistic investigations showed that Alox5 inhibition reduced AKT activation and decreased β-catenin expression in JAK2V617F-expressing cells. Together, our results define Alox5 as a key genetic effector of JAK2V617F in driving PV, and they identify this enzyme as a candidate therapeutic target to treat this refractory myeloproliferative neoplasm. Cancer Res; 77(1); 164–74. ©2016 AACR.
Data from Injury-Driven Stiffening of the Dermis Expedites Skin Carcinoma Progression
Authors: Mittapalli Venugopal R. , Madl Josef , Löffek Stefanie , Kiritsi Dimitra , Kern Johannes S. , Römer Winfried , Nyström Alexander , Bruckner-Tuderman Leena
Published: April 2023

Abstract
Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic skin fragility disorder characterized by injury-driven blister formation, progressive soft-tissue fibrosis, and a highly elevated risk of early-onset aggressive cutaneous squamous cell carcinoma (cSCC). However, the mechanisms underlying the unusually rapid progression of RDEB to cSCC are unknown. In this study, we investigated the contribution of injury-induced skin alterations to cSCC development by using a genetic model of RDEB and organotypic skin cultures. Analysis of RDEB patient samples suggested that premalignant changes to the dermal microenvironment drive tumor progression, which led us to subject a collagen VII hypomorphic mouse model of RDEB to chemical carcinogenesis. Carcinogen-treated RDEB mice developed invasive tumors phenocopying human RDEB-cSCC, whereas wild-type mice formed papillomas, indicating that the aggressiveness of RDEB-cSCC is mutation-independent. The inherent structural instability of the RDEB dermis, combined with repeated injury, increased the bioavailability of TGFβ, which promoted extracellular matrix production, cross-linking, thickening of dermal fibrils, and tissue stiffening. The biophysically altered dermis increased myofibroblast activity and integrin β1/pFAK/pAKT mechanosignaling in tumor cells, further demonstrating that cSCC progression is governed by pre-existing injury-driven changes in the RDEB tissue microenvironment. Treatment of three-dimensional organotypic RDEB skin cultures with inhibitors of TGFβ signaling, lysyl oxidase, or integrin β1–mediated mechanosignaling reduced or bypassed tissue stiffness and limited tumor cell invasion. Collectively, these findings provide a new mechanism by which RDEB tissue becomes malignant and offer new druggable therapeutic targets to prevent cSCC onset. Cancer Res; 76(4); 940–51. ©2015 AACR.
Data from Treatment of Triple-Negative Breast Cancer with TORC1/2 Inhibitors Sustains a Drug-Resistant and Notch-Dependent Cancer Stem Cell Population
Authors: Bhola Neil E. , Jansen Valerie M. , Koch James P. , Li Hua , Formisano Luigi , Williams Janice A. , Grandis Jennifer R. , Arteaga Carlos L.
Published: April 2023

Abstract
Approximately 30% of triple-negative breast cancers (TNBC) harbor molecular alterations in PI3K/mTOR signaling, but therapeutic inhibition of this pathway has not been effective. We hypothesized that intrinsic resistance to TORC1/2 inhibition is driven by cancer stem cell (CSC)-like populations that could be targeted to enhance the antitumor action of these drugs. Therefore, we investigated the molecular mechanisms by which PI3K/mTOR inhibitors affect the stem-like properties of TNBC cells. Treatment of established TNBC cell lines with a PI3K/mTOR inhibitor or a TORC1/2 inhibitor increased the expression of CSC markers and mammosphere formation. A CSC-specific PCR array revealed that inhibition of TORC1/2 increased FGF1 and Notch1 expression. Notch1 activity was also induced in TNBC cells treated with TORC1/2 inhibitors and associated with increased mitochondrial metabolism and FGFR1 signaling. Notably, genetic and pharmacologic blockade of Notch1 abrogated the increase in CSC markers, mammosphere formation, and in vivo tumor-initiating capacity induced by TORC1/2 inhibition. These results suggest that targeting the FGFR–mitochondrial metabolism–Notch1 axis prevents resistance to TORC1/2 inhibitors by eradicating drug-resistant CSCs in TNBC, and may thus represent an attractive therapeutic strategy to improve drug responsiveness and efficacy. Cancer Res; 76(2); 440–52. ©2015 AACR.
Data from Histone Deacetylase Inhibition in Prostate Cancer Triggers miR-320–Mediated Suppression of the Androgen Receptor
Authors: Sato Shinya , Katsushima Keisuke , Shinjo Keiko , Hatanaka Akira , Ohka Fumiharu , Suzuki Shugo , Naiki-Ito Aya , Soga Norihito , Takahashi Satoru , Kondo Yutaka
Published: April 2023

Abstract
Targeting androgen receptor (AR) by pharmacologic intervention is one of the effective approaches for treatment of malignant prostate cancers. Histone deacetylase (HDAC) alters the epigenetic status of tumor-associated genes, including those for miRNAs (miRNA), and affects the behavior of cancers. Here, we examined the molecular effects of a HDAC inhibitor, OBP-801, on AR expression and tumor cell growth in prostate cancers. Treatment with OBP-801 efficiently suppressed cell growth of three prostate cancer lines (22Rv1, VCaP, and LNCaP), together with AR downregulation, regardless of their hormone sensitivity. Intriguingly, this effect by OBP-801 was not due to decreased transcriptional activity of the AR gene, but due to posttranscriptional regulation, namely by miRNA-mediated suppression. Among the upregulated miRNAs after OBP-801 treatment in the three prostate cancer cell lines, miR-320a, whose expression was significantly correlated with prognosis of prostate cancers (P = 0.0185), was the most closely associated with AR expression. An miR-320a mimic suppressed AR protein expression together with growth suppression, while anti-miR-320a oligonucleotide significantly abrogated the growth suppression by OBP-801 treatment. FISH analysis revealed that miR-320a was highly expressed in human normal prostate luminal cells, but was rarely expressed in prostate cancer cells. In an AR-dependent prostate tumorigenic rat model, OBP-801 treatment profoundly increased miR-320a expression and repressed prostate tumorigenesis. Our data demonstrated that OBP-801 effectively suppressed AR activity via epigenetic upregulation of miR-320a, which resulted in tumor cell growth suppression of prostate cancers. OBP-801 may be a potent AR-targeting therapeutic reagent in AR-positive prostate cancer regardless of androgen dependency. Cancer Res; 76(14); 4192–204. ©2016 AACR.
Data from Distinct Subtypes of Gastric Cancer Defined by Molecular Characterization Include Novel Mutational Signatures with Prognostic Capability
Authors: Li Xiangchun , Wu William K.K. , Xing Rui , Wong Sunny H. , Liu Yuexin , Fang Xiaodong , Zhang Yanlin , Wang Mengyao , Wang Jiaqian , Li Lin , Zhou Yong , Tang Senwei , Peng Shaoliang , Qiu Kunlong , Chen Longyun , Chen Kexin , Yang Huanming , Zhang Wei , Chan Matthew T.V. , Lu Youyong , Sung Joseph J.Y. , Yu Jun
Published: April 2023

Abstract
Gastric cancer is not a single disease, and its subtype classification is still evolving. Next-generation sequencing studies have identified novel genetic drivers of gastric cancer, but their use as molecular classifiers or prognostic markers of disease outcome has yet to be established. In this study, we integrated somatic mutational profiles and clinicopathologic information from 544 gastric cancer patients from previous genomic studies to identify significantly mutated genes (SMG) with prognostic relevance. Gastric cancer patients were classified into regular (86.8%) and hypermutated (13.2%) subtypes based on mutation burden. Notably, TpCpW mutations occurred significantly more frequently in regular, but not hypermutated, gastric cancers, where they were associated with APOBEC expression. In the former group, six previously unreported (XIRP2, NBEA, COL14A1, CNBD1, ITGAV, and AKAP6) and 12 recurrent mutated genes exhibited high mutation prevalence (≥3.0%) and an unexpectedly higher incidence of nonsynonymous mutations. We also identified two molecular subtypes of regular-mutated gastric cancer that were associated with distinct prognostic outcomes, independently of disease staging, as confirmed in a distinct patient cohort by targeted capture sequencing. Finally, in diffuse-type gastric cancer, CDH1 mutation was found to be associated with shortened patient survival, independently of disease staging. Overall, our work identified previously unreported SMGs and a mutation signature predictive of patient survival in newly classified subtypes of gastric cancer, offering opportunities to stratify patients into optimal treatment plans based on molecular subtyping. Cancer Res; 76(7); 1724–32. ©2016 AACR.
Data from Novel Protein Disulfide Isomerase Inhibitor with Anticancer Activity in Multiple Myeloma
Authors: Vatolin Sergei , Phillips James G. , Jha Babal K. , Govindgari Shravya , Hu Jennifer , Grabowski Dale , Parker Yvonne , Lindner Daniel J. , Zhong Fei , Distelhorst Clark W. , Smith Mitchell R. , Cotta Claudiu , Xu Yan , Chilakala Sujatha , Kuang Rebecca R. , Tall Samantha , Reu Frederic J.
Published: April 2023

Abstract
Multiple myeloma cells secrete more disulfide bond–rich proteins than any other mammalian cell. Thus, inhibition of protein disulfide isomerases (PDI) required for protein folding in the endoplasmic reticulum (ER) should increase ER stress beyond repair in this incurable cancer. Here, we report the mechanistically unbiased discovery of a novel PDI-inhibiting compound with antimyeloma activity. We screened a 30,355 small-molecule library using a multilayered multiple myeloma cell–based cytotoxicity assay that modeled disease niche, normal liver, kidney, and bone marrow. CCF642, a bone marrow–sparing compound, exhibited a submicromolar IC50 in 10 of 10 multiple myeloma cell lines. An active biotinylated analog of CCF642 defined binding to the PDI isoenzymes A1, A3, and A4 in MM cells. In vitro, CCF642 inhibited PDI reductase activity about 100-fold more potently than the structurally distinct established inhibitors PACMA 31 and LOC14. Computational modeling suggested a novel covalent binding mode in active-site CGHCK motifs. Remarkably, without any further chemistry optimization, CCF642 displayed potent efficacy in an aggressive syngeneic mouse model of multiple myeloma and prolonged the lifespan of C57BL/KaLwRij mice engrafted with 5TGM1-luc myeloma, an effect comparable to the first-line multiple myeloma therapeutic bortezomib. Consistent with PDI inhibition, CCF642 caused acute ER stress in multiple myeloma cells accompanied by apoptosis-inducing calcium release. Overall, our results provide an illustration of the utility of simple in vivo simulations as part of a drug discovery effort, along with a sound preclinical rationale to develop a new small-molecule therapeutic to treat multiple myeloma. Cancer Res; 76(11); 3340–50. ©2016 AACR.
Data from HSP70 Inhibition Limits FAK-Dependent Invasion and Enhances the Response to Melanoma Treatment with BRAF Inhibitors
Authors: Budina-Kolomets Anna , Webster Marie R. , Leu Julia I-Ju , Jennis Matthew , Krepler Clemens , Guerrini Anastasia , Kossenkov Andrew V. , Xu Wei , Karakousis Giorgos , Schuchter Lynn , Amaravadi Ravi K. , Wu Hong , Yin Xiangfan , Liu Qin , Lu Yiling , Mills Gordon B. , Xu Xiaowei , George Donna L. , Weeraratna Ashani T. , Murphy Maureen E.
Published: April 2023

Abstract
The stress-inducible chaperone protein HSP70 (HSPA1) is implicated in melanoma development, and HSP70 inhibitors exert tumor-specific cytotoxic activity in cancer. In this study, we documented that a significant proportion of melanoma tumors express high levels of HSP70, particularly at advanced stages, and that phospho-FAK (PTK2) and BRAF are HSP70 client proteins. Treatment of melanoma cells with HSP70 inhibitors decreased levels of phospho-FAK along with impaired migration, invasion, and metastasis in vitro and in vivo. Moreover, the HSP70 inhibitor PET-16 reduced levels of mutant BRAF, synergized with the BRAF inhibitor PLX4032 in vitro, and enhanced the durability of response to BRAF inhibition in vivo. Collectively, these findings provide strong support for HSP70 inhibition as a therapeutic strategy in melanoma, especially as an adjuvant approach for overcoming the resistance to BRAF inhibitors frequently observed in melanoma patients. Cancer Res; 76(9); 2720–30. ©2016 AACR.
Data from Elucidation of the Roles of Tumor Integrin β1 in the Extravasation Stage of the Metastasis Cascade
Authors: Chen Michelle B. , Lamar John M. , Li Ran , Hynes Richard O. , Kamm Roger D.
Published: April 2023

Abstract
Tumor integrin β1 (ITGB1) contributes to primary tumor growth and metastasis, but its specific roles in extravasation have not yet been clearly elucidated. In this study, we engineered a three-dimensional microfluidic model of the human microvasculature to recapitulate the environment wherein extravasation takes place and assess the consequences of β1 depletion in cancer cells. Combined with confocal imaging, these tools allowed us to decipher the detailed morphology of transmigrating tumor cells and associated endothelial cells in vitro at high spatio-temporal resolution not easily achieved in conventional transmigration assays. Dynamic imaging revealed that β1-depleted cells lacked the ability to sustain protrusions into the subendothelial matrix in contrast with control cells. Specifically, adhesion via α3β1 and α6β1 to subendothelial laminin was a critical prerequisite for successful transmigration. β1 was required to invade past the endothelial basement membrane, whereas its attenuation in a syngeneic tumor model resulted in reduced metastatic colonization of the lung, an effect not observed upon depletion of other integrin alpha and beta subunits. Collectively, our findings in this novel model of the extravasation microenvironment revealed a critical requirement for β1 in several steps of extravasation, providing new insights into the mechanisms underlying metastasis. Cancer Res; 76(9); 2513–24. ©2016 AACR.
Data from Amphiregulin Is a Critical Downstream Effector of Estrogen Signaling in ERα-Positive Breast Cancer
Authors: Peterson Esther A. , Jenkins Edmund C. , Lofgren Kristopher A. , Chandiramani Natasha , Liu Hui , Aranda Evelyn , Barnett Maryia , Kenny Paraic A.
Published: April 2023

Abstract
Estrogen stimulation promotes epithelial cell proliferation in estrogen receptor (ERα)-positive breast cancer. Many ERα target genes have been enumerated, but the identities of the key effectors mediating the estrogen signal remain obscure. During mouse mammary gland development, the estrogen growth factor receptor (EGFR) ligand amphiregulin acts as an important stage-specific effector of estrogen signaling. In this study, we investigated the role of amphiregulin in breast cancer cell proliferation using human tissue samples and tumor xenografts in mice. Amphiregulin was enriched in ERα-positive human breast tumor cells and required for estrogen-dependent growth of MCF7 tumor xenografts. Furthermore, amphiregulin levels were suppressed in patients treated with endocrine therapy. Suppression of EGF receptor signaling appeared necessary for the therapeutic response in this setting. Our findings implicate amphiregulin as a critical mediator of the estrogen response in ERα-positive breast cancer, emphasizing the importance of EGF receptor signaling in breast tumor pathogenesis and therapeutic response. Cancer Res; 75(22); 4830–8. ©2015 AACR.
Supplementary Figure 5 from Collaborative Cancer Epidemiology in the 21st Century: The Model of Cancer Consortia
Authors: Burgio Michael R. , Ioannidis John P.A. , Kaminski Brett M. , DeRycke Eric , Rogers Scott , Khoury Muin J. , Seminara Daniela
Published: April 2023

PDF - 104KB, Ascertainment and review of CEC papers for this analysis.
Supplementary Figure 3 from Collaborative Cancer Epidemiology in the 21st Century: The Model of Cancer Consortia
Authors: Burgio Michael R. , Ioannidis John P.A. , Kaminski Brett M. , DeRycke Eric , Rogers Scott , Khoury Muin J. , Seminara Daniela
Published: April 2023

PDF - 138KB, Total number and total direct cost of all EGRP grants by year.
Supplementary tables 1a and 1b from Health Care Utilization, Lifestyle, and Emotional Factors and Mammography Practices in the Childhood Cancer Survivor Study
Authors: Rosenberg Shoshana M. , Moskowitz Chaya S. , Ford Jennifer S. , Henderson Tara O. , Frazier A. Lindsay , Diller Lisa R. , Hudson Melissa M. , Stanton Annette L. , Chou Joanne F. , Smith Stephanie , Leisenring Wendy M. , Mertens Ann C. , Cox Cheryl L. , Nathan Paul C. , Krull Kevin R. , Robison Leslie L. , Oeffinger Kevin C.
Published: April 2023

Supplementary Table 1a. Analysis of factors associated with having a screening mammogram within the prior two years in women age <40 (N=296) Supplementary Table 1b. Analysis of factors associated with having a screening mammogram within the prior two years in women age {greater than or equal to}40 (N=255)
CGH Results from Intermediate- and Low-Methylation Epigenotypes Do Not Correspond to CpG Island Methylator Phenotype (Low and -Zero) in Colorectal Cancer
Authors: Karpinski Pawel , Walter Michael , Szmida Elzbieta , Ramsey David , Misiak Blazej , Kozlowska Joanna , Bebenek Marek , Grzebieniak Zygmunt , Blin Nikolaus , Laczmanski Lukasz , Sasiadek Maria M.
Published: April 2023

XLS file -45KB, Clinical and molecular characteristics of 100 CRCs selected for CGH. This file contains detailed molecular characteristics of 100 CRCs selected for CGH. Data obtained by CGH is also included.
Supplementary Figure 3 from Metabolomics in Epidemiology: Sources of Variability in Metabolite Measurements and Implications
Authors: Sampson Joshua N. , Boca Simina M. , Shu Xiao Ou , Stolzenberg-Solomon Rachael Z. , Matthews Charles E. , Hsing Ann W. , Tan Yu Ting , Ji Bu-Tian , Chow Wong-Ho , Cai Qiuyin , Liu Da Ke , Yang Gong , Xiang Yong Bing , Zheng Wei , Sinha Rashmi , Cross Amanda J. , Moore Steven C.
Published: April 2023

PDF file - 13K, The plot illustrates the distributions of the technical CV's (metabolite levels on a log scale), a measure of laboratory variability. The x-axis represents the metabolite quantile ranking (e.g. 0.5 represents the median), the y-axis represents the actual CV, and the curves (black for SPA and dashed red for PLCO) show the CV for the specified metabolite quantile ranking.
Table S1 from Cellular Expression of PD-L1 in the Peripheral Blood of Lung Cancer Patients is Associated with Worse Survival
Authors: Boffa Daniel J. , Graf Ryon P. , Salazar Michelle C. , Hoag Jessica , Lu David , Krupa Rachel , Louw Jessica , Dugan Lyndsey , Wang Yipeng , Landers Mark , Suraneni Mahipal , Greene Stephanie B. , Magaña Marisa , Makani Samir , Bazhenova Lyudmila , Dittamore Ryan V. , Nieva Jorge
Published: April 2023

Cox Proportional Hazards Model of Patients With Confirmed Lung Cancer.
Supplementary Table 1 from Age-Specific Effectiveness of the Finnish Cervical Cancer Screening Programme
Authors: Lönnberg Stefan , Anttila Ahti , Luostarinen Tapio , Nieminen Pekka
Published: April 2023

XLS file, 19KB, ICD-O-3 morphology of cervical cancers diagnosed in Finland in 2000-2009 (Finnish Cancer Registry).
Figure S3 from Shifts in the Fecal Microbiota Associated with Adenomatous Polyps
Authors: Hale Vanessa L. , Chen Jun , Johnson Stephen , Harrington Sean C. , Yab Tracy C. , Smyrk Thomas C. , Nelson Heidi , Boardman Lisa A. , Druliner Brooke R. , Levin Theodore R. , Rex Douglas K. , Ahnen Dennis J. , Lance Peter , Ahlquist David A. , Chia Nicholas
Published: April 2023

Supplementary Figure 3. A receiver operating characteristic curve generated using the four significant taxa (Streptococcus, Veillonella, Mogibacterium, and Sutterella) identified by the random forests algorithm demonstrates a poor ability to predict adenoma status.
Supplementary Figure 25 from Sex Disparities in Cancer Mortality and Survival
Authors: Cook Michael B. , McGlynn Katherine A. , Devesa Susan S. , Freedman Neal D. , Anderson William F.
Published: April 2023

PDF file - 97K
Supplementary Table 1 from Risk of Colorectal Cancer in Patients with Acute Myocardial Infarction and Stroke: A Nationwide Cohort Study
Authors: Erichsen Rune , Sværke Claus , Sørensen Henrik T. , Sandler Robert S. , Baron John A.
Published: April 2023

PDF - 51KB, Shows diagnosis and procedure codes used in the Danish health registries.
Supplementary Figure 18 from Sex Disparities in Cancer Mortality and Survival
Authors: Cook Michael B. , McGlynn Katherine A. , Devesa Susan S. , Freedman Neal D. , Anderson William F.
Published: April 2023

PDF file - 102K
Supplemental Tables for Publication from Glycemic Index, Glycemic Load, and Lung Cancer Risk in Non-Hispanic Whites
Authors: Melkonian Stephanie C. , Daniel Carrie R. , Ye Yuanqing , Pierzynski Jeanne A. , Roth Jack A. , Wu Xifeng
Published: April 2023

This file contains supplemental material to the manuscript. Supplemental tables 1-3 replicate the data presented in the manuscript for the subset of the data matched for smoking status. Supplemental Table 4 shows the distribution of the host characteristics in the smokers versus non smokers in the controls only ( to show how individuals that smoke are also different based on other factors as well)
Supplementary Figure 14 from Sex Disparities in Cancer Mortality and Survival
Authors: Cook Michael B. , McGlynn Katherine A. , Devesa Susan S. , Freedman Neal D. , Anderson William F.
Published: April 2023

PDF file - 96K
Supplementary Figure 11 from Sex Disparities in Cancer Mortality and Survival
Authors: Cook Michael B. , McGlynn Katherine A. , Devesa Susan S. , Freedman Neal D. , Anderson William F.
Published: April 2023

PDF file - 96K
Supplementary Figure 1 from Sex Disparities in Cancer Mortality and Survival
Authors: Cook Michael B. , McGlynn Katherine A. , Devesa Susan S. , Freedman Neal D. , Anderson William F.
Published: April 2023

PDF file - 101K
Supplementary Table 2 from BRAF Mutation Status and Survival after Colorectal Cancer Diagnosis According to Patient and Tumor Characteristics
Authors: Phipps Amanda I. , Buchanan Daniel D. , Makar Karen W. , Burnett-Hartman Andrea N. , Coghill Anna E. , Passarelli Michael N. , Baron John A. , Ahnen Dennis J. , Win Aung Ko , Potter John D. , Newcomb Polly A.
Published: April 2023

PDF file, 60K, Joint BRAF / MSI status and survival after colorectal cancer diagnosis, excluding cases with unknown MSI status.
Supplementary Table 1 from Exposure to Infections and Risk of Leukemia in Young Children
Authors: Marcotte Erin L. , Ritz Beate , Cockburn Myles , Yu Fei , Heck Julia E.
Published: April 2023

PDF file - 43K, Analysis of Birth Month in a Study of Leukemia Risk Among California Children Diagnosed Between 1988 and 2007.
Supplementary Table 1 from The Natural History of Cervical Cancer in Chinese Women: Results from an 11-Year Follow-Up Study in China Using a Multistate Model
Authors: Zhang Shao-Kai , Kang Le-Ni , Chang Irene J. , Zhao Fang-Hui , Hu Shang-Ying , Chen Wen , Shi Ju-Fang , Zhang Xun , Pan Qin-Jing , Li Shu-Min , Qiao You-Lin
Published: April 2023

PDF - 70K, Transition Probability of The Adjusted Models Between States at 1, 3, 5 and 10 Years With 95% CI.
Supplementary Figure Legend from Age-Period-Cohort Analysis of Primary Bone Cancer Incidence Rates in the United States (1976–2005)
Authors: Anfinsen Kristin P. , Devesa Susan S. , Bray Freddie , Troisi Rebecca , Jonasdottir Thora J. , Bruland Oyvind S. , Grotmol Tom
Published: April 2023

Supplementary Figure Legend from Age-Period-Cohort Analysis of Primary Bone Cancer Incidence Rates in the United States (1976–2005)
Supplementary Table 5 from Germline Variants in DNA Repair Genes, Diagnostic Radiation, and Risk of Thyroid Cancer
Authors: Sandler Jason E. , Huang Huang , Zhao Nan , Wu Weiwei , Liu Fangfang , Ma Shuangge , Udelsman Robert , Zhang Yawei
Published: April 2023

Potential functional significance of selected SNPs on the binding of exonic splicing enhancers (ESEs).