bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Renalase Expression by Melanoma and Tumor-Associated Macrophages Promotes Tumor Growth through a STAT3-Mediated Mechanism
Authors: Hollander Lindsay , Guo Xiaojia , Velazquez Heino , Chang John , Safirstein Robert , Kluger Harriet , Cha Charles , Desir Gary V.
Published: April 2023

Abstract
To sustain their proliferation, cancer cells overcome negative-acting signals that restrain their growth and promote senescence and cell death. Renalase (RNLS) is a secreted flavoprotein that functions as a survival factor after ischemic and toxic injury, signaling through the plasma calcium channel PMCA4b to activate the PI3K/AKT and MAPK pathways. We show that RNLS expression is increased markedly in primary melanomas and CD163+ tumor-associated macrophages (TAM). In clinical specimens, RNLS expression in the tumor correlated inversely with disease-specific survival, suggesting a pathogenic role for RNLS. Attenuation of RNLS by RNAi, blocking antibodies, or an RNLS-derived inhibitory peptide decreased melanoma cell survival, and anti-RNLS therapy blocked tumor growth in vivo in murine xenograft assays. Mechanistic investigations showed that increased apoptosis in tumor cells was temporally related to p38 MAPK-mediated Bax activation and that increased cell growth arrest was associated with elevated expression of the cell-cycle inhibitor p21. Overall, our results established a role for the secreted flavoprotein RNLS in promoting melanoma cell growth and CD163+ TAM in the tumor microenvironment, with potential therapeutic implications for the management of melanoma. Cancer Res; 76(13); 3884–94. ©2016 AACR.
Data from FOXD1–ALDH1A3 Signaling Is a Determinant for the Self-Renewal and Tumorigenicity of Mesenchymal Glioma Stem Cells
Authors: Cheng Peng , Wang Jia , Waghmare Indrayani , Sartini Stefania , Coviello Vito , Zhang Zhuo , Kim Sung-Hak , Mohyeldin Ahmed , Pavlyukov Marat S. , Minata Mutsuko , Valentim Claudia L.L. , Chhipa Rishi Raj , Bhat Krishna P.L. , Dasgupta Biplab , La Motta Concettina , Kango-Singh Madhuri , Nakano Ichiro
Published: April 2023

Abstract
Glioma stem–like cells (GSC) with tumor-initiating activity orchestrate the cellular hierarchy in glioblastoma and engender therapeutic resistance. Recent work has divided GSC into two subtypes with a mesenchymal (MES) GSC population as the more malignant subtype. In this study, we identify the FOXD1–ALDH1A3 signaling axis as a determinant of the MES GSC phenotype. The transcription factor FOXD1 is expressed predominantly in patient-derived cultures enriched with MES, but not with the proneural GSC subtype. shRNA-mediated attenuation of FOXD1 in MES GSC ablates their clonogenicity in vitro and in vivo. Mechanistically, FOXD1 regulates the transcriptional activity of ALDH1A3, an established functional marker for MES GSC. Indeed, the functional roles of FOXD1 and ALDH1A3 are likely evolutionally conserved, insofar as RNAi-mediated attenuation of their orthologous genes in Drosophila blocks formation of brain tumors engineered in that species. In clinical specimens of high-grade glioma, the levels of expression of both FOXD1 and ALDH1A3 are inversely correlated with patient prognosis. Finally, a novel small-molecule inhibitor of ALDH we developed, termed GA11, displays potent in vivo efficacy when administered systemically in a murine GSC-derived xenograft model of glioblastoma. Collectively, our findings define a FOXD1–ALDH1A3 pathway in controling the clonogenic and tumorigenic potential of MES GSC in glioblastoma tumors. Cancer Res; 76(24); 7219–30. ©2016 AACR.
Data from p120 Catenin Suppresses Basal Epithelial Cell Extrusion in Invasive Pancreatic Neoplasia
Authors: Hendley Audrey M. , Wang Yue J. , Polireddy Kishore , Alsina Janivette , Ahmed Ishrat , Lafaro Kelly J. , Zhang Hao , Roy Nilotpal , Savidge Samuel G. , Cao Yanna , Hebrok Matthias , Maitra Anirban , Reynolds Albert B. , Goggins Michael , Younes Mamoun , Iacobuzio-Donahue Christine A. , Leach Steven D. , Bailey Jennifer M.
Published: April 2023

Abstract
Aberrant regulation of cellular extrusion can promote invasion and metastasis. Here, we identify molecular requirements for early cellular invasion using a premalignant mouse model of pancreatic cancer with conditional knockout of p120 catenin (Ctnnd1). Mice with biallelic loss of p120 catenin progressively develop high-grade pancreatic intraepithelial neoplasia (PanIN) lesions and neoplasia accompanied by prominent acute and chronic inflammatory processes, which is mediated, in part, through NF-κB signaling. Loss of p120 catenin in the context of oncogenic Kras also promotes remarkable apical and basal epithelial cell extrusion. Abundant single epithelial cells exit PanIN epithelium basally, retain epithelial morphology, survive, and display features of malignancy. Similar extrusion defects are observed following p120 catenin knockdown in vitro, and these effects are completely abrogated by the activation of S1P/S1pr2 signaling. In the context of oncogenic Kras, p120 catenin loss significantly reduces expression of genes mediating S1P/S1pr2 signaling in vivo and in vitro, and this effect is mediated at least, in part, through activation of NF-κB. These results provide insight into mechanisms controlling early events in the metastatic process and suggest that p120 catenin and S1P/S1pr2 signaling enhance cancer progression by regulating epithelial cell invasion. Cancer Res; 76(11); 3351–63. ©2016 AACR.
Data from Penfluridol: An Antipsychotic Agent Suppresses Metastatic Tumor Growth in Triple-Negative Breast Cancer by Inhibiting Integrin Signaling Axis
Authors: Ranjan Alok , Gupta Parul , Srivastava Sanjay K.
Published: April 2023

Abstract
Metastasis of breast cancer, especially to the brain, is the major cause of mortality. The inability of anticancer agents to cross the blood-brain-barrier represents a critical challenge for successful treatment. In the current study, we investigated the antimetastatic potential of penfluridol, an antipsychotic drug frequently prescribed for schizophrenia with anticancer activity. We show that penfluridol induced apoptosis and reduced the survival of several metastatic triple-negative breast cancer (TNBC) cell lines. In addition, penfluridol treatment significantly reduced the expression of integrin α6, integrin β4, Fak, paxillin, Rac1/2/3, and ROCK1 in vitro. We further evaluated the efficacy of penfluridol in three different in vivo tumor models. We demonstrate that penfluridol administration to an orthotopic model of breast cancer suppressed tumor growth by 49%. On the other hand, penfluridol treatment inhibited the growth of metastatic brain tumors introduced by intracardiac or intracranial injection of breast cancer cells by 90% and 72%, respectively. Penfluridol-treated tumors from all three models exhibited reduced integrin β4 and increased apoptosis. Moreover, chronic administration of penfluridol failed to elicit significant toxic or behavioral side effects in mice. Taken together, our results indicate that penfluridol effectively reduces the growth of primary TNBC tumors and especially metastatic growth in the brain by inhibiting integrin signaling, and prompt further preclinical investigation into repurposing penfluridol for the treatment of metastatic TNBC. Cancer Res; 76(4); 877–90. ©2015 AACR.
Data from Tumor Cell Invasion Can Be Blocked by Modulators of Collagen Fibril Alignment That Control Assembly of the Extracellular Matrix
Authors: Grossman Moran , Ben-Chetrit Nir , Zhuravlev Alina , Afik Ran , Bassat Elad , Solomonov Inna , Yarden Yosef , Sagi Irit
Published: April 2023

Abstract
Abnormal architectures of collagen fibers in the extracellular matrix (ECM) are hallmarks of many invasive diseases, including cancer. Targeting specific stages of collagen assembly in vivo presents a great challenge due to the involvement of various crosslinking enzymes in the multistep, hierarchical process of ECM build-up. Using advanced microscopic tools, we monitored stages of fibrillary collagen assembly in a native fibroblast-derived 3D matrix system and identified anti-lysyl oxidase-like 2 (LOXL2) antibodies that alter the natural alignment and width of endogenic fibrillary collagens without affecting ECM composition. The disrupted collagen morphologies interfered with the adhesion and invasion properties of human breast cancer cells. Treatment of mice bearing breast cancer xenografts with the inhibitory antibodies resulted in disruption of the tumorigenic collagen superstructure and in reduction of primary tumor growth. Our approach could serve as a general methodology to identify novel therapeutics targeting fibrillary protein organization to treat ECM-associated pathologies. Cancer Res; 76(14); 4249–58. ©2016 AACR.
Data from Cancer Stem-like Cells Act via Distinct Signaling Pathways in Promoting Late Stages of Malignant Progression
Authors: da Silva-Diz Victoria , Simón-Extremera Pilar , Bernat-Peguera Adrià , de Sostoa Jana , Urpí Maria , Penín Rosa M. , Sidelnikova Diana Pérez , Bermejo Oriol , Viñals Joan Maria , Rodolosse Annie , González-Suárez Eva , Moruno Antonio Gómez , Pujana Miguel Ángel , Esteller Manel , Villanueva Alberto , Viñals Francesc , Muñoz Purificación
Published: April 2023

Abstract
Cancer stem-like cells (CSC) play key roles in long-term tumor propagation and metastasis, but their dynamics during disease progression are not understood. Tumor relapse in patients with initially excised skin squamous cell carcinomas (SCC) is characterized by increased metastatic potential, and SCC progression is associated with an expansion of CSC. Here, we used genetically and chemically-induced mouse models of skin SCC to investigate the signaling pathways contributing to CSC function during disease progression. We found that CSC regulatory mechanisms change in advanced SCC, correlating with aggressive tumor growth and enhanced metastasis. β-Catenin and EGFR signaling, induced in early SCC CSC, were downregulated in advanced SCC. Instead, autocrine FGFR1 and PDGFRα signaling, which have not been previously associated with skin SCC CSC, were upregulated in late CSC and promoted tumor growth and metastasis, respectively. Finally, high-grade and recurrent human skin SCC recapitulated the signaling changes observed in advanced mouse SCC. Collectively, our findings suggest a stage-specific switch in CSC regulation during disease progression that could be therapeutically exploited by targeting the PDGFR and FGFR1 pathways to block relapse and metastasis of advanced human skin SCC.Cancer Res; 76(5); 1245–59. ©2015 AACR.
Data from Ubiquitin-Specific Protease 4-Mediated Deubiquitination and Stabilization of PRL-3 Is Required for Potentiating Colorectal Oncogenesis
Authors: Xing Cheng , Lu Xing-Xing , Guo Peng-Da , Shen Tong , Zhang Shen , He Xiao-Shun , Gan Wen-Juan , Li Xiu-Ming , Wang Jing-Ru , Zhao Yuan-Yuan , Wu Hua , Li Jian-Ming
Published: April 2023

Abstract
Ubiquitin specific protease 4 (USP4) is a deubiquitinating enzyme with key roles in the regulation of p53 and TGFβ signaling, suggesting its importance in tumorigenesis. However, the mechanisms and regulatory roles of USP4 in cancer, including colorectal cancer, remain largely elusive. Here, we present the first evidence that USP4 regulates the growth, invasion, and metastasis of colorectal cancer. USP4 expression was significantly elevated in colorectal cancer tissues and was significantly associated with tumor size, differentiation, distant metastasis, and poor survival. Knockdown of USP4 diminished colorectal cancer cell growth, colony formation, migration, and invasion in vitro and metastasis in vivo. Importantly, we found that phosphatase of regenerating liver-3 (PRL-3) is indispensable for USP4-mediated oncogenic activity in colorectal cancer. Mechanistically, we observed that USP4 interacted with and stabilized PRL-3 via deubiquitination. This resulted in activation of Akt and reduction of E-cadherin, critical regulators of cancer cell growth and metastasis. Examination of clinical samples confirmed that USP4 expression positively correlates with PRL-3 protein expression, but not mRNA transcript levels. Taken together, our results demonstrate that aberrant expression of USP4 contributes to the development and progression of colorectal cancer and reveal a critical mechanism underlying USP4-mediated oncogenic activity. These observations suggest that the potential of harnessing proteolytic degradation processes for therapeutic manipulation may offer a much-needed new approach for improving colorectal cancer treatment strategies. Cancer Res; 76(1); 83–95. ©2015 AACR.
Data from Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types
Authors: Chartier Cecile , Raval Janak , Axelrod Fumiko , Bond Chris , Cain Jennifer , Dee-Hoskins Cristina , Ma Shirley , Fischer Marcus M. , Shah Jalpa , Wei Jie , Ji May , Lam Andrew , Stroud Michelle , Yen Wan-Ching , Yeung Pete , Cancilla Belinda , O'Young Gilbert , Wang Min , Kapoun Ann M. , Lewicki John , Hoey Timothy , Gurney Austin
Published: April 2023

Abstract
Deregulation of the β-catenin signaling has long been associated with cancer. Intracellular components of this pathway, including axin, APC, and β-catenin, are frequently mutated in a range of human tumors, but the contribution of specific extracellular ligands that promote cancer development through this signaling axis remains unclear. We conducted a reporter-based screen in a panel of human tumors to identify secreted factors that stimulate β-catenin signaling. Through this screen and further molecular characterization, we found that R-spondin (RSPO) proteins collaborate with Wnt proteins to activate β-catenin. RSPO family members were expressed in several human tumors representing multiple malignancies, including ovarian, pancreatic, colon, breast, and lung cancer. We generated specific monoclonal antibody antagonists of RSPO family members and found that anti-RSPO treatment markedly inhibited tumor growth in human patient-derived tumor xenograft models, either as single agents or in combination with chemotherapy. Furthermore, blocking RSPO signaling reduced the tumorigenicity of cancer cells based on serial transplantation studies. Moreover, gene-expression analyses revealed that anti-RSPO treatment in responsive tumors strongly inhibited β-catenin target genes known to be associated with cancer and normal stem cells. Collectively, our results suggest that the RSPO family is an important stimulator of β-catenin activity in many human tumors and highlight a new effective approach for therapeutically modulating this fundamental signaling axis. Cancer Res; 76(3); 713–23. ©2015 AACR.
Data from AKT1 Inhibits Epithelial-to-Mesenchymal Transition in Breast Cancer through Phosphorylation-Dependent Twist1 Degradation
Authors: Li Chia-Wei , Xia Weiya , Lim Seung-Oe , Hsu Jennifer L. , Huo Longfei , Wu Yun , Li Long-Yuan , Lai Chien-Chen , Chang Shih-Shin , Hsu Yi-Hsin , Sun Hui-Lung , Kim Jongchan , Yamaguchi Hirohito , Lee Dung-Fang , Wang Hongmei , Wang Yan , Chou Chao-Kai , Hsu Jung-Mao , Lai Yun-Ju , LaBaff Adam M. , Ding Qingqing , Ko How-Wen , Tsai Fuu-Jen , Tsai Chang-Hai , Hortobagyi Gabriel N. , Hung Mien-Chie
Published: April 2023

Abstract
Epithelial-to-mesenchymal transition (EMT) is an essential physiologic process that promotes cancer cell migration, invasion, and metastasis. Several lines of evidence from both cellular and genetic studies suggest that AKT1/PKBα, but not AKT2 or AKT3, serves as a negative regulator of EMT and breast cancer metastasis. However, the underlying mechanism by which AKT1 suppresses EMT remains poorly defined. Here, we demonstrate that phosphorylation of Twist1 by AKT1 is required for β-TrCP–mediated Twist1 ubiquitination and degradation. The clinically used AKT inhibitor MK-2206, which possesses higher specificity toward AKT1, stabilized Twist1 and enhanced EMT in breast cancer cells. However, we discovered that resveratrol, a naturally occurring compound, induced β-TrCP–mediated Twist1 degradation to attenuate MK-2206–induced EMT in breast cancer cells. Taken together, our findings demonstrate that resveratrol counteracts the unexpected metastatic potential induced by anti-AKT therapy and therefore suggest that the addition of resveratrol to an anti-AKT therapeutic regimen may provide extra support for limiting EMT. Cancer Res; 76(6); 1451–62. ©2016 AACR.
Data from Endothelial Side Population Cells Contribute to Tumor Angiogenesis and Antiangiogenic Drug Resistance
Authors: Naito Hisamichi , Wakabayashi Taku , Kidoya Hiroyasu , Muramatsu Fumitaka , Takara Kazuhiro , Eino Daisuke , Yamane Keitaro , Iba Tomohiro , Takakura Nobuyuki
Published: April 2023

Abstract
Angiogenesis plays a crucial role in tumor growth, with an undisputed contribution of resident endothelial cells (EC) to new blood vessels in the tumor. Here, we report the definition of a small population of vascular-resident stem/progenitor–like EC that contributes predominantly to new blood vessel formation in the tumor. Although the surface markers of this population are similar to other ECs, those from the lung vasculature possess colony-forming ability in vitro and contribute to angiogenesis in vivo. These specific ECs actively proliferate in lung tumors, and the percentage of this population significantly increases in the tumor vasculature relative to normal lung tissue. Using genetic recombination and bone marrow transplant models, we show that these cells are phenotypically true ECs and do not originate from hematopoietic cells. After treatment of tumors with antiangiogenic drugs, these specific ECs selectively survived and remained in the tumor. Together, our results established that ECs in the peripheral vasculature are heterogeneous and that stem/progenitor–like ECs play an indispensable role in tumor angiogenesis as EC-supplying cells. The lack of susceptibility of these ECs to antiangiogenic drugs may account for resistance of the tumor to this drug type. Thus, inhibiting these ECs might provide a promising strategy to overcome antiangiogenic drug resistance. Cancer Res; 76(11); 3200–10. ©2016 AACR.
Data from The Small Molecule IMR-1 Inhibits the Notch Transcriptional Activation Complex to Suppress Tumorigenesis
Authors: Astudillo Luisana , Da Silva Thiago G. , Wang Zhiqiang , Han Xiaoqing , Jin Ke , VanWye Jeffrey , Zhu Xiaoxia , Weaver Kelly , Oashi Taiji , Lopes Pedro E.M. , Orton Darren , Neitzel Leif R. , Lee Ethan , Landgraf Ralf , Robbins David J. , MacKerell Alexander D. , Capobianco Anthony J.
Published: April 2023

Abstract
In many cancers, aberrant Notch activity has been demonstrated to play a role in the initiation and maintenance of the neoplastic phenotype and in cancer stem cells, which may allude to its additional involvement in metastasis and resistance to therapy. Therefore, Notch is an exceedingly attractive therapeutic target in cancer, but the full range of potential targets within the pathway has been underexplored. To date, there are no small-molecule inhibitors that directly target the intracellular Notch pathway or the assembly of the transcriptional activation complex. Here, we describe an in vitro assay that quantitatively measures the assembly of the Notch transcriptional complex on DNA. Integrating this approach with computer-aided drug design, we explored potential ligand-binding sites and screened for compounds that could disrupt the assembly of the Notch transcriptional activation complex. We identified a small-molecule inhibitor, termed Inhibitor of Mastermind Recruitment-1 (IMR-1), that disrupted the recruitment of Mastermind-like 1 to the Notch transcriptional activation complex on chromatin, thereby attenuating Notch target gene transcription. Furthermore, IMR-1 inhibited the growth of Notch-dependent cell lines and significantly abrogated the growth of patient-derived tumor xenografts. Taken together, our findings suggest that a novel class of Notch inhibitors targeting the transcriptional activation complex may represent a new paradigm for Notch-based anticancer therapeutics, warranting further preclinical characterization. Cancer Res; 76(12); 3593–603. ©2016 AACR.
Data from PINK1 Is a Negative Regulator of Growth and the Warburg Effect in Glioblastoma
Authors: Agnihotri Sameer , Golbourn Brian , Huang Xi , Remke Marc , Younger Susan , Cairns Rob A. , Chalil Alan , Smith Christian A. , Krumholtz Stacey-Lynn , Mackenzie Danielle , Rakopoulos Patricia , Ramaswamy Vijay , Taccone Michael S. , Mischel Paul S. , Fuller Gregory N. , Hawkins Cynthia , Stanford William L. , Taylor Michael D. , Zadeh Gelareh , Rutka James T.
Published: April 2023

Abstract
Proliferating cancer cells are characterized by high rates of glycolysis, lactate production, and altered mitochondrial metabolism. This metabolic reprogramming provides important metabolites for proliferation of tumor cells, including glioblastoma. These biological processes, however, generate oxidative stress that must be balanced through detoxification of reactive oxygen species (ROS). Using an unbiased retroviral loss-of-function screen in nontransformed human astrocytes, we demonstrate that mitochondrial PTEN-induced kinase 1 (PINK1) is a regulator of the Warburg effect and negative regulator of glioblastoma growth. We report that loss of PINK1 contributes to the Warburg effect through ROS-dependent stabilization of hypoxia-inducible factor-1A and reduced pyruvate kinase muscle isozyme 2 activity, both key regulators of aerobic glycolysis. Mechanistically, PINK1 suppresses ROS and tumor growth through FOXO3a, a master regulator of oxidative stress and superoxide dismutase 2. These findings highlight the importance of PINK1 and ROS balance in normal and tumor cells. PINK1 loss was observed in a significant number of human brain tumors including glioblastoma (n > 900) and correlated with poor patient survival. PINK1 overexpression attenuates in vivo glioblastoma growth in orthotopic mouse xenograft models and a transgenic glioblastoma model in Drosophila. Cancer Res; 76(16); 4708–19. ©2016 AACR.
Data from MCAM and LAMA4 Are Highly Enriched in Tumor Blood Vessels of Renal Cell Carcinoma and Predict Patient Outcome
Authors: Wragg Joseph W. , Finnity Jonathan P. , Anderson Jane A. , Ferguson Henry J.M. , Porfiri Emilio , Bhatt Rupesh I. , Murray Paul G. , Heath Victoria L. , Bicknell Roy
Published: April 2023

Abstract
The structure and molecular signature of tumor-associated vasculature are distinct from those of the host tissue, offering an opportunity to selectively target the tumor blood vessels. To identify tumor-specific endothelial markers, we performed a microarray on tumor-associated and nonmalignant endothelium collected from patients with renal cell carcinoma (RCC), colorectal carcinoma, or colorectal liver metastasis. We identified a panel of genes consistently upregulated by tumor blood vessels, of which melanoma cell adhesion molecule (MCAM) and its extracellular matrix interaction partner laminin alpha 4 (LAMA4) emerged as the most consistently expressed genes. This result was subsequently confirmed by immunohistochemical analysis of MCAM and LAMA4 expression in RCC and colorectal carcinoma blood vessels. Strong MCAM and LAMA4 expression was also shown to predict poor survival in RCC, but not in colorectal carcinoma. Notably, MCAM and LAMA4 were enhanced in locally advanced tumors as well as both the primary tumor and secondary metastases. Expression analysis in 18 different cancers and matched healthy tissues revealed vascular MCAM as highly specific in RCC, where it was induced strongly by VEGF, which is highly abundant in this disease. Lastly, MCAM monoclonal antibodies specifically localized to vessels in a murine model of RCC, offering an opportunity for endothelial-specific targeting of anticancer agents. Overall, our findings highlight MCAM and LAMA4 as prime candidates for RCC prognosis and therapeutic targeting. Cancer Res; 76(8); 2314–26. ©2016 AACR.
Data from A Myc Activity Signature Predicts Poor Clinical Outcomes in Myc-Associated Cancers
Authors: Jung MoonSun , Russell Amanda J. , Liu Bing , George Joshy , Liu Pei Yan , Liu Tao , DeFazio Anna , Bowtell David D.L. , Oberthuer André , London Wendy B. , Fletcher Jamie I. , Haber Michelle , Norris Murray D. , Henderson Michelle J.
Published: April 2023

Abstract
Myc transcriptional activity is frequently deregulated in human cancers, but a Myc-driven gene signature with prognostic ability across multiple tumor types remains lacking. Here, we selected 18 Myc-regulated genes from published studies of Myc family targets in epithelial ovarian cancer (EOC) and neuroblastoma. A Myc family activity score derived from the 18 genes was correlated to MYC/MYCN/MYCL1 expression in a panel of 35 cancer cell lines. The prognostic ability of this signature was evaluated in neuroblastoma, medulloblastoma, diffuse large B-cell lymphoma (DLBCL), and EOC microarray gene expression datasets using Kaplan–Meier and multivariate Cox regression analyses and was further validated in 42 primary neuroblastomas using qPCR. Cell lines with high MYC, MYCN, and/or MYCL1 gene expression exhibited elevated expression of the signature genes. Survival analysis showed that the signature was associated with poor outcome independently of well-defined prognostic factors in neuroblastoma, breast cancer, DLBCL, and medulloblastoma. In EOC, the 18-gene Myc activity signature was capable of identifying a group of patients with poor prognosis in a "high-MYCN" molecular subtype but not in the overall cohort. The predictive ability of this signature was reproduced using qPCR analysis of an independent cohort of neuroblastomas, including a subset of tumors without MYCN amplification. These data reveal an 18-gene Myc activity signature that is highly predictive of poor prognosis in diverse Myc-associated malignancies and suggest its potential clinical application in the identification of Myc-driven tumors that might respond to Myc-targeted therapies. Cancer Res; 77(4); 971–81. ©2016 AACR.
Data from A Three-Dimensional Organoid Culture System Derived from Human Glioblastomas Recapitulates the Hypoxic Gradients and Cancer Stem Cell Heterogeneity of Tumors Found In Vivo
Authors: Hubert Christopher G. , Rivera Maricruz , Spangler Lisa C. , Wu Qiulian , Mack Stephen C. , Prager Briana C. , Couce Marta , McLendon Roger E. , Sloan Andrew E. , Rich Jeremy N.
Published: April 2023

Abstract
Many cancers feature cellular hierarchies that are driven by tumor-initiating cancer stem cells (CSC) and rely on complex interactions with the tumor microenvironment. Standard cell culture conditions fail to recapitulate the original tumor architecture or microenvironmental gradients and are not designed to retain the cellular heterogeneity of parental tumors. Here, we describe a three-dimensional culture system that supports the long-term growth and expansion of tumor organoids derived directly from glioblastoma specimens, including patient-derived primary cultures, xenografts, genetically engineered glioma models, or patient samples. Organoids derived from multiple regions of patient tumors retain selective tumorigenic potential. Furthermore, organoids could be established directly from brain metastases not typically amenable to in vitro culture. Once formed, tumor organoids grew for months and displayed regional heterogeneity with a rapidly dividing outer region of SOX2+, OLIG2+, and TLX+ cells surrounding a hypoxic core of primarily non-stem senescent cells and diffuse, quiescent CSCs. Notably, non-stem cells within organoids were sensitive to radiotherapy, whereas adjacent CSCs were radioresistant. Orthotopic transplantation of patient-derived organoids resulted in tumors displaying histologic features, including single-cell invasiveness, that were more representative of the parental tumor compared with those formed from patient-derived sphere cultures. In conclusion, we present a new ex vivo model in which phenotypically diverse stem and non-stem glioblastoma cell populations can be simultaneously cultured to explore new facets of microenvironmental influences and CSC biology. Cancer Res; 76(8); 2465–77. ©2016 AACR.
Data from Increased Expression of miR-23a Mediates a Loss of Expression in the RAF Kinase Inhibitor Protein RKIP
Authors: Hatzl Stefan , Geiger Olivia , Kuepper Maja Kim , Caraffini Veronica , Seime Till , Furlan Tobias , Nussbaumer Erika , Wieser Rotraud , Pichler Martin , Scheideler Marcel , Nowek Katarzyna , Jongen-Lavrencic Mojca , Quehenberger Franz , Wölfler Albert , Troppmair Jakob , Sill Heinz , Zebisch Armin
Published: April 2023

Abstract
RAF kinase inhibitor protein (RKIP) is a seminal regulator of intracellular signaling and exhibits both antimetastatic and antitumorigenic properties. Decreased expression of RKIP has been described in several human malignancies, including acute myelogenous leukemia (AML). As the mechanisms leading to RKIP loss in AML are still unclear, we aimed to analyze the potential involvement of miRNAs within this study. miRNA microarray and qPCR data of more than 400 AML patient specimens revealed correlation between decreased expression of RKIP and increased expression of miR-23a, a member of the miR-23a/27a/24-2 cluster. In functional experiments, overexpression of miR-23a decreased RKIP mRNA and protein expression, whereas miR-23a inhibition caused the opposite effect. By using an RKIP 3′-untranslated region luciferase reporter construct with and without mutation or deletion of the putative miR-23a–binding site, we could show that RKIP modulation by miR-23a is mediated via direct binding to this region. Importantly, miR-23a overexpression induced a significant increase of proliferation in hematopoietic cells. Simultaneous transfection of an RKIP expression construct lacking the miR-23a–binding sites reversed this phenotype, indicating that this effect is truly mediated via downregulation of RKIP. Finally, by analyzing more than 4,300 primary patient specimens via database retrieval from The Cancer Genome Atlas, we could highlight the importance of the miR-23a/RKIP axis in a broad range of human cancer entities. In conclusion, we have identified miR-23a as a negative regulator of RKIP expression in AML and have provided data that suggest the importance of our observation beyond this tumor entity. Cancer Res; 76(12); 3644–54. ©2016 AACR.
Data from Targeting HER2 Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib
Authors: Han Han , Li Shuai , Chen Ting , Fitzgerald Michael , Liu Shengwu , Peng Chengwei , Tang Kwan Ho , Cao Shougen , Chouitar Johara , Wu Jiansheng , Peng David , Deng Jiehui , Gao Zhendong , Baker Theresa E. , Li Fei , Zhang Hua , Pan Yuanwang , Ding Hailin , Hu Hai , Pyon Val , Thakurdin Cassandra , Papadopoulos Eleni , Tang Sittinon , Gonzalvez Francois , Chen Haiquan , Rivera Victor M. , Brake Rachael , Vincent Sylvie , Wong Kwok-Kin
Published: April 2023

Abstract
No targeted treatments are currently approved for HER2 exon 20 insertion–mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion–mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion–mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody–drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion–mutant lung adenocarcinoma patients.
Significance:
This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion–mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation.
Figure 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

Assessment of PD-L1 Assay Sensitivity and Specificity.
Supplementary Figure 3 from Adult Stature and Risk of Cancer at Different Anatomic Sites in a Cohort of Postmenopausal Women
Authors: Kabat Geoffrey C. , Anderson Matthew L. , Heo Moonseong , Hosgood H. Dean , Kamensky Victor , Bea Jennifer W. , Hou Lifang , Lane Dorothy S. , Wactawski-Wende Jean , Manson JoAnn E. , Rohan Thomas E.
Published: April 2023

PDF - 69KB, Association of height with risk of melanoma cancer by level of potential effect modifiers. HR4s are adjusted for covariates in footnote 6 in Table 3.
Supplementary Table 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 - 89K
Supplementary Figure 21 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 - 105K
Supplementary tables 1-6 from A Newly Identified Susceptibility Locus near FOXP1 Modifies the Association of Gastroesophageal Reflux with Barrett's Esophagus
Authors: Dai James Y. , de Dieu Tapsoba Jean , Buas Matthew F. , Onstad Lynn E. , Levine David M. , Risch Harvey A. , Chow Wong-Ho , Bernstein Leslie , Ye Weimin , Lagergren Jesper , Bird Nigel C. , Corley Douglas A. , Shaheen Nicholas J. , Wu Anna H. , Reid Brian J. , Hardie Laura J. , Whiteman David C. , Vaughan Thomas L.
Published: April 2023

Supplementary Table 1. Missing rates for three risk factors by study site in BEAGESS Supplementary Table 2. Genome-wide significant single nucleotide polymorphisms (SNPs) selected for GxE analysis. Supplementary Table 3. Odds ratios (95% confidence intervals) for risk factors in the BEACON study according to the number of minor alleles (rs2687201 or rs10419226), using a combined BE/EA case group. Inverse probability weighting techniques were used to account for the missing risk factor data in the GXE interaction analysis. The weights were computed based on a logistic regression model fit to the indicator variable of the risk factor being observed, adjusting for case control status, region (Australia, Europe, North America), age, sex, SNP genotype, and four principal components. Supplementary Table 4. Odds ratios (95% confidence intervals) for risk factors in the BEACON study according to the number of minor alleles (rs2687201 or rs10419226), using a combined BE/EA case group. Supplementary Table 5. Thirteen imputed SNPs found to interact with GERD more significantly than rs2687201 in relation to risk of Barrett's esophagus (BE). Supplementary Table 6.1 Annotations for top SNPs identified in GxE analysis (ordered by interaction P value). Supplementary Table 6.2 Genotype-Tissue Expression (GTEx) eQTL analysis of top 14 SNPs identified.
Supplementary Table 1 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

DNA repair genes with chromosomal location and number of SNPs analyzed.
Supplemental Tables 1-5 and Legend to Supplemental Figure 1 from A Cross-Cancer Genetic Association Analysis of the DNA Repair and DNA Damage Signaling Pathways for Lung, Ovary, Prostate, Breast, and Colorectal Cancer
Authors: Scarbrough Peter M. , Weber Rachel Palmieri , Iversen Edwin S. , Brhane Yonathan , Amos Christopher I. , Kraft Peter , Hung Rayjean J. , Sellers Thomas A. , Witte John S. , Pharoah Paul , Henderson Brian E. , Gruber Stephen B. , Hunter David J. , Garber Judy E. , Joshi Amit D. , McDonnell Kevin , Easton Doug F. , Eeles Ros , Kote-Jarai Zsofia , Muir Kenneth , Doherty Jennifer A. , Schildkraut Joellen M.
Published: April 2023

Supplemental Table 1: Detailed characteristics of studies included in the ASSET meta-analysis of DNA damage repair and signaling genes. Supplemental Table 2: DNA repair gene, region, and final SNP selection data, using human reference genome assembly, GRCh38. Supplemental Table 3: List of all DNA repair genes and DNA repair pathways included in this study. Supplemental Table 4: Statistical associations (p-values) for cancer risk versus genetic variation within DNA repair pathways. Sensitivity analysis of Table 3, with RAD51B, MSH5, and BRCA2 gene removed from analysis. Statistically significant values are in bold (p < 0.05). Supplemental Table 5: Statistical associations (p-values) for cancer risk versus genetic variation within DNA repair pathways. Sensitivity analysis of Table 3, with 6 genes removed from the analysis -- all genes containing loci with individual SNP associations of p < 1 x 10-4. Statistically significant values are in bold (p < 0.05).
Supplementary Materials and Methods from Body Mass Index, Physical Activity, and Serum Markers of Inflammation, Immunity, and Insulin Resistance
Authors: Kitahara Cari M. , Trabert Britton , Katki Hormuzd A. , Chaturvedi Anil K. , Kemp Troy J. , Pinto Ligia A. , Moore Steven C. , Purdue Mark P. , Wentzensen Nicolas , Hildesheim Allan , Shiels Meredith S.
Published: April 2023

Supplementary Materials and Methods: Details on development of sampling weights and their use in analysis.
Table S4. QC results of 61 BS-converted samples for viral methylation analysis from Targeted, Deep Sequencing Reveals Full Methylation Profiles of Multiple HPV Types and Potential Biomarkers for Cervical Cancer Progression
Authors: Liu Pengyuan , Iden Marissa , Fye Samantha , Huang Yi-Wen , Hopp Elizabeth , Chu Chen , Lu Yan , Rader Janet S.
Published: April 2023

Quality measurements for BS-converted samples including yield, read number, mean quality score, percentage of reads mapped to both reference genomes (human and HPV), number of reads mapped to HPV, and BS-conversion rates.
Supplementary Figure S5. Distinct HPV methylation in CpG sites between CIN and ICC and CIN3 and SCC from Targeted, Deep Sequencing Reveals Full Methylation Profiles of Multiple HPV Types and Potential Biomarkers for Cervical Cancer Progression
Authors: Liu Pengyuan , Iden Marissa , Fye Samantha , Huang Yi-Wen , Hopp Elizabeth , Chu Chen , Lu Yan , Rader Janet S.
Published: April 2023

Methylation differences among CpG sites in HPV 16 between (A) CIN and ICC or (B) CIN3 and SCC. Methylation difference (%) was calculated by subtracting the mean methylation rate of CIN or CIN3 from the mean methylation rate of ICC or SCC at a specific CpG site. Dashed lines imply p values = 0.05.
Supplementary Figure 2 from Biomarker Discovery for Heterogeneous Diseases
Authors: Wallstrom Garrick , Anderson Karen S. , LaBaer Joshua
Published: April 2023

PDF file - 5384K, Figure S2. Estimated power for single stage design using t3 samples for a (a) homogeneous disease and a (b) heterogeneous disease.
Supplementary Table 1 and Table 2 and Table 3 from Work Loss Duration and Predictors Following Rectal Cancer Treatment among Patients with and without Prediagnostic Work Loss
Authors: Chen Lingjing , Glimelius Ingrid , Neovius Martin , Ekberg Sara , Martling Anna , Eloranta Sandra , Smedby Karin E.
Published: April 2023

Supplementary Table S1. Numbers of patients at risk and mean days of work loss for clinical subgroups among relapse-free patients without pre-diagnostic work loss between 2 years before diagnosis and 5 years after diagnosis. Supplementary Table S2. Incidence rate ratio of work loss related to demographic covariates following diagnosis among relapse-free rectal cancer patients stratified by pre-diagnostic work loss Supplementary Table S3. Incidence rate ratio (IRR) of work loss following rectal cancer diagnosis associated with clinical covariates among relapse-free rectal cancer patients with pre-diagnostic sick leave (SL) only or disability pension (DP).
Supplementary Table S3 from Expanding Epigenomics to Archived FFPE Tissues: An Evaluation of DNA Repair Methodologies
Authors: Siegel Erin M. , Berglund Anders E. , Riggs Bridget M. , Eschrich Steven A. , Putney Ryan M. , Ajidahun Abidemi O. , Coppola Domenico , Shibata David
Published: April 2023

Supplementary Table S3. Mean Î”Î² for each experimental condition and patient sample, by normalization: (A) DASEN, (B) minfi-Illumina, (C) SWAN and (D) raw Î²-values.
Supplementary Figure Legend and Tables 1 - 3 from Fine-Mapping of IL16 Gene and Prostate Cancer Risk in African Americans
Authors: Batai Ken , Shah Ebony , Murphy Adam B. , Newsome Jennifer , Ruden Maria , Ahaghotu Chiledum , Kittles Rick A.
Published: April 2023

PDF file, 98K, Fine-mapping of IL16 gene and prostate cancer risk in African Americans.
Supplementary Figure S1 from Expanding Epigenomics to Archived FFPE Tissues: An Evaluation of DNA Repair Methodologies
Authors: Siegel Erin M. , Berglund Anders E. , Riggs Bridget M. , Eschrich Steven A. , Putney Ryan M. , Ajidahun Abidemi O. , Coppola Domenico , Shibata David
Published: April 2023

Supplementary Figure S1. Representative density correlation plot between FF-FFPE pairs using the minfi-Illumina normalization. Plots shown for (a) Restore (RES1 vs. FF) and (b) REPLI-g Ligase (LIG3 vs. FF) across patient samples processed using the minfi-Illumina normalization method.
Supplementary Figure 3 from Fine-Mapping of IL16 Gene and Prostate Cancer Risk in African Americans
Authors: Batai Ken , Shah Ebony , Murphy Adam B. , Newsome Jennifer , Ruden Maria , Ahaghotu Chiledum , Kittles Rick A.
Published: April 2023

PDF file, 204K, LD plot of the top 30 genotyped and imputed SNPs generated with 1000 Genomes YRI genotype data.
Data from Characterizing Genetic Susceptibility to Breast Cancer in Women of African Ancestry
Authors: Feng Ye , Rhie Suhn Kyong , Huo Dezheng , Ruiz-Narvaez Edward A. , Haddad Stephen A. , Ambrosone Christine B. , John Esther M. , Bernstein Leslie , Zheng Wei , Hu Jennifer J. , Ziegler Regina G. , Nyante Sarah , Bandera Elisa V. , Ingles Sue A. , Press Michael F. , Deming Sandra L. , Rodriguez-Gil Jorge L. , Zheng Yonglan , Yao Song , Han Yoo-Jeong , Ogundiran Temidayo O. , Rebbeck Timothy R. , Adebamowo Clement , Ojengbede Oladosu , Falusi Adeyinka G. , Hennis Anselm , Nemesure Barbara , Ambs Stefan , Blot William , Cai Qiuyin , Signorello Lisa , Nathanson Katherine L. , Lunetta Kathryn L. , Sucheston-Campbell Lara E. , Bensen Jeannette T. , Chanock Stephen J. , Marchand Loic Le , Olshan Andrew F. , Kolonel Laurence N. , Conti David V. , Coetzee Gerhard A. , Stram Daniel O. , Olopade Olufunmilayo I. , Palmer Julie R. , Haiman Christopher A.
Published: April 2023

Abstract
Background: Genome-wide association studies have identified approximately 100 common genetic variants associated with breast cancer risk, the majority of which were discovered in women of European ancestry. Because of different patterns of linkage disequilibrium, many of these genetic markers may not represent signals in populations of African ancestry.

Methods: We tested 74 breast cancer risk variants and conducted fine-mapping of these susceptibility regions in 6,522 breast cancer cases and 7,643 controls of African ancestry from three genetic consortia (AABC, AMBER, and ROOT).

Results: Fifty-four of the 74 variants (73%) were found to have ORs that were directionally consistent with those previously reported, of which 12 were nominally statistically significant (P < 0.05). Through fine-mapping, in six regions (3p24, 12p11, 14q13, 16q12/FTO, 16q23, 19p13), we observed seven markers that better represent the underlying risk variant for overall breast cancer or breast cancer subtypes, whereas in another two regions (11q13, 16q12/TOX3), we identified suggestive evidence of signals that are independent of the reported index variant. Overlapping chromatin features and regulatory elements suggest that many of the risk alleles lie in regions with biological functionality.

Conclusions: Through fine-mapping of known susceptibility regions, we have revealed alleles that better characterize breast cancer risk in women of African ancestry.

Impact: The risk alleles identified represent genetic markers for modeling and stratifying breast cancer risk in women of African ancestry. Cancer Epidemiol Biomarkers Prev; 26(7); 1016–26. ©2017 AACR.
Data from Association of AMP-Activated Protein Kinase with Risk and Progression of Non–Hodgkin Lymphoma
Authors: Hoffman Aaron E. , Demanelis Kathryn , Fu Alan , Zheng Tongzhang , Zhu Yong
Published: April 2023

Abstract
Background: Metabolic dysregulation has been identified as an “emerging hallmark” of cancer. The heterotrimeric AMP-activated protein kinase (AMPK) complex is a central regulator of the metabolic system and an important component of the mTOR pathway and the p53 axis, making it uniquely positioned to influence carcinogenesis through its canonical functions in the metabolic arena, as well as through more traditional mechanisms such as regulation of apoptosis and angiogenesis.

Methods: We conducted a population-based genetic association study to examine the impact of mutations in AMPK subunit genes on risk of non–Hodgkin lymphoma (NHL). We also analyzed public microarray data to determine the expression of AMPK in NHL cells and to assess the influence of AMPK expression on overall survival in patients with NHL.

Results: We identified an AMPK subunit haplotype, which was significantly associated with NHL [OR, 5.44, 95% confidence interval (CI), 2.15–13.75] in women with no family history of cancer. Haplotypes in two subunits, PRKAA2 and PRKAG3, were nominally associated with the follicular and diffuse large B-cell lymphoma histologic subtypes, respectively, although these associations did not retain statistical significance after correction for multiple comparisons. Further, both of these subunits were differentially expressed (P < 0.05) in one or more lymphoma cell type, and higher expression of two versions of the AMPK-β subunit was significantly associated with increased 5-year survival among patients with NHL (P = 0.001 and P = 0.021).

Conclusion: These results provide evidence for AMPK involvement in the pathogenesis and progression of NHL.

Impact: These findings may lead to a novel area of research into NHL treatment and chemoprevention. Cancer Epidemiol Biomarkers Prev; 22(4); 736–44. ©2013 AACR.