Topi A Tervonen, Shishir M Pant, Denis Belitškin, Johanna I Englund, Katja Närhi, Caj Haglund, Panu E Kovanen, Emmy W Verschuren, Juha Klefström
Ras proteins play a causal role in human cancer by activating multiple pathways that promote cancer growth and invasion. However, little is known about how Ras induces the first diagnostic features of invasion in solid tumors, including loss of epithelial integrity and breaching of the basement membrane. In this study, we found that oncogenic Ras strongly promotes the activation of hepsin, a member of the hepsin/TMPRSS type II transmembrane serine protease family. Mechanistically, the Ras-dependent hepsin activation was mediated via Raf-MEK-ERK signaling, which controlled hepsin protein stability through the heat shock transcription factor-1 stress pathway...
January 18, 2021: Cancer Research
Stanley I Gutiontov, Sean P Pitroda, Phuoc T Tran, Ralph R Weichselbaum
Cancer metastasis is the leading cause of cancer-related mortality, and most patients with metastases from solid tumors have historically been considered incurable. Here we discuss the evolution of our understanding of the oligometastatic state with an emphasis on the view that cancer metastasis represents a spectrum of disease. We highlight several recently published prospective clinical trials demonstrating improvements in cancer-specific outcomes with the utilization of metastasis-directed local therapies...
January 15, 2021: Cancer Research
Fei Xing, Dan Zhao, Shin-Ying Wu, Abhishek Tyagi, Kerui Wu, Sambad Sharma, Yin Liu, Ravindra Deshpande, Yuezhu Wang, Jacob Cleary, Lance D Miller, Amar G Chittiboyina, Chinni Yalamanchili, Yin-Yuan Mo, Kounosuke Watabe
Ethnicity is considered to be one of the major risk factors in certain subtypes of breast cancer. However, the mechanism of this racial disparity remains poorly understood. Here we demonstrate that SOS1, a key regulator of Ras pathway, is highly expressed in African American (AA) breast cancer patients compared to Caucasian American (CA) patients. Because of the higher obesity rate in AA women, increased levels of SOS1 facilitated signal transduction of the c-Met pathway which was highly activated in AA breast cancer patients via HGF secreted from adipocytes...
January 14, 2021: Cancer Research
Anna Han, Timothy J Purwin, Andrew E Aplin
BRCA1-associated protein 1 (BAP1) is emerging as an intensively studied cancer-associated gene. Germline mutations in BAP1 lead to a cancer syndrome, and somatic loss is found in several cancer types. BAP1 encodes a deubiquitinase enzyme, which plays key roles in cell cycle regulation, cell death, and differentiation. Recent studies have demonstrated that BAP1 is also involved in several aspects of cellular metabolism, including metabolic homeostasis, glucose utilization, control of ferroptosis, and stress response...
January 14, 2021: Cancer Research
Gina M Ney, Kevin B Yang, Victor Ng, Lu Liu, Meiling Zhao, Wun Kuk, Lila Alaka, Leilani Sampang, Adam Ross, Morgan A Jones, Xi Jin, Laura M McKay, Hadie Evarts, Qing Li
Leukemic relapse is believed to be driven by transformed hematopoietic stem cells that harbor oncogenic mutations or have lost tumor suppressor function. Recent comprehensive sequencing studies have shown that mutations predicted to activate Ras signaling are highly prevalent in hematologic malignancies and, notably, in refractory and relapsed cases. To better understand what drives this clinical phenomenon, we expressed oncogenic NrasG12D within the hematopoietic system in mice and interrogated its effects on hematopoietic stem cell (HSC) survival...
January 13, 2021: Cancer Research
Raunak Shrestha, Marta Llaurado Fernandez, Amy Dawson, Joshua Hoenisch, Stanislav Volik, Yen-Yi Lin, Shawn Anderson, Hannah Kim, Anne M Haegert, Shane Colborne, Nelson K Y Wong, Brian McConeghy, Robert H Bell, Sonal Brahmbhatt, Cheng-Han Lee, Gabriel E DiMattia, Stephane Le Bihan, Gregg B Morin, Colin C Collins, Mark S Carey
Low-grade serous ovarian carcinoma (LGSOC) is a rare tumor subtype with high case fatality rates in patients with metastatic disease. There is a pressing need to develop effective treatments using newly available preclinical models for therapeutic discovery and drug evaluation. Here we use multiomics integration of whole exome sequencing, RNA sequencing, and mass spectrometry-based proteomics on fourteen LGSOC cell lines to elucidate novel biomarkers and therapeutic vulnerabilities. Comparison of LGSOC cell line data to LGSOC tumor data enabled predictive biomarker identification of MEK inhibitor (MEKi) efficacy, with KRAS mutations found exclusively in MEKi-sensitive cell lines and NRAS mutations found mostly in MEKi-resistant cell lines...
January 13, 2021: Cancer Research
Ana P Kutschat, Feda H Hamdan, Xin Wang, Alexander Q Wixom, Zeynab Najafova, Christine S Gibhardt, Waltraut Kopp, Jochen Gaedcke, Philipp Ströbel, Volker Ellenrieder, Ivan Bogeski, Elisabeth Hessmann, Steven A Johnsen
Pancreatic Ductal Adenocarcinoma (PDAC) displays a dismal prognosis due to late diagnosis and high chemoresistance incidence. For advanced disease stages or patients with comorbidities, treatment options are limited to gemcitabine alone or in combination with other drugs. While gemcitabine resistance has been widely attributed to the levels of one of its targets, RRM1, the molecular consequences of gemcitabine resistance in PDAC remain largely elusive. Here we sought to identify genomic, epigenomic, and transcriptomic events associated with gemcitabine resistance in PDAC and their potential clinical relevance...
January 12, 2021: Cancer Research
Xiwei Sun, Angli Xue, Ting Qi, Dan Chen, Dandan Shi, Yang Wu, Zhili Zheng, Jian Zeng, Jian Yang
Tumor mutational burden (TMB) is an emerging biomarker of response to immunotherapy in solid tumors. However, the extent to which variation in TMB between patients is attributable to germline genetic variation remains elusive. Here, using 7,004 unrelated patients of European descent across 33 cancer types from The Cancer Genome Atlas, we show that pan-cancer TMB is polygenic with ~13% of its variation explained by ~1.1 million common variants altogether. We identify germline variants that affect TMB in stomach adenocarcinoma through altering the expression levels of BAG5 and KLC1...
January 8, 2021: Cancer Research
Yingke Zhou, Xin Jin, Jian Ma, Dongling Ding, Zhenlin Huang, Haoyue Sheng, Yuqian Yan, Yunqian Pan, Ting Wei, Liguo Wang, Heshui Wu, Haojie Huang
The tumor suppressor protein RB acts as a transcription repressor via interaction of its pocket domain with an LXCXE motif in HDAC proteins such as HDAC1. Here we demonstrate that HDAC5 deficient for the LXCXE motif interacts with both RB-N (via an FXXXV motif) and RB-C segments, and such interactions are diminished by phosphorlyation of RB serine-249/threonine-252 and threonine-821. HDAC5 was frequently downregulated or deleted in human cancers such as prostate cancer. Loss of HDAC5 increased histone H3 lysine 27 acetylation (H3K27-ac) and circumvented RB-mediated repression of cell cycle-related pro-oncogenic genes...
January 8, 2021: Cancer Research
Shinji Iizuka, Manuela Quintavalle, Jose C Navarro, Kyle P Gribbin, Robert J Ardecky, Matthew M Abelman, Chen-Ting Ma, Eduard Sergienko, Fu-Yue Zeng, Ian Pass, George V Thomas, Shannon K McWeeney, Christian A Hassig, Anthony B Pinkerton, Sara A Courtneidge
Invadopodia are actin-based proteolytic membrane protrusions required for invasive behavior and tumor growth. In this study, we used our high-content screening assay to identify kinases whose activity impacts invadopodia formation. Among the top hits selected for further analysis was TAO3, a STE20-like kinase of the GCK subfamily. TAO3 was overexpressed in many human cancers and regulated invadopodia formation in melanoma, breast, and bladder cancers. Furthermore, TAO3 catalytic activity facilitated melanoma growth in 3-dimensional matrices and in vivo...
January 7, 2021: Cancer Research
Husheng Ding, Nicole D Vincelette, Cordelia D McGehee, Mira A Kohorst, Brian D Koh, Annapoorna Venkatachalam, X Wei Meng, Paula A Schneider, Karen S Flatten, Kevin L Peterson, Cristina Correia, Sun-Hee Lee, Mrinal Patnaik, Jonathan A Webster, Gabriel Ghiaur, B Douglas Smith, Judith E Karp, Keith W Pratz, Hu Li, Larry M Karnitz, Scott H Kaufmann
Although inhibitors of the kinases CHK1, ATR, and WEE1 are undergoing clinical testing, it remains unclear how these three classes of agents kill susceptible cells and whether they utilize the same cytotoxic mechanism. Here we observed that CHK1 inhibition induces apoptosis in a subset of acute leukemia cell lines in vitro, including TP53-null acute myeloid leukemia (AML) and BCR/ABL-positive acute lymphoid leukemia (ALL), and inhibits leukemic colony formation in clinical AML samples ex vivo. In further studies, downregulation or inhibition of CHK1 triggered signaling in sensitive human acute leukemia cell lines that involved CDK2 activation followed by AP1-dependent TNF transactivation, TNFa production, and engagement of a TNFR1- and BID-dependent apoptotic pathway...
January 7, 2021: Cancer Research
Francesco Tamiro, Andrew P Weng, Vincenzo Giambra
The concept that different leukemias are developmentally distinct and, like in normal hematopoiesis, generated by restricted populations of cells named leukemia-initiating cells (LIC), is becoming more established. These cancer stem-like cells have been assumed to have unique properties, including the capability of self-renewing and giving rise to "differentiated" or non-LIC that make up the whole tumor. Cell populations enriched with LIC-activity have been characterized in different hematopoietic malignancies, including human acute lymphoblastic leukemia (ALL)...
January 7, 2021: Cancer Research
Katelyn D Miller, Katherine Pniewski, Caroline E Perry, Sara B Papp, Joshua D Shaffer, Jesse N Velasco-Silva, Jessica C Casciano, Tomas M Aramburu, Yellamelli V V Srikanth, Joel Cassel, Emmanuel Skordalakes, Andrew V Kossenkov, Joseph M Salvino, Zachary T Schug
Acetyl-CoA is a vitally important and versatile metabolite used for many cellular processes including fatty acid synthesis, ATP production, and protein acetylation. Recent studies have shown that cancer cells upregulate acetyl-CoA synthetase 2 (ACSS2), an enzyme that converts acetate to acetyl-CoA, in response to stresses such as low nutrient availability and hypoxia. Stressed cancer cells use ACSS2 as a means to exploit acetate as an alternative nutrient source. Genetic depletion of ACSS2 in tumors inhibits the growth of a wide variety of cancers...
January 7, 2021: Cancer Research
Joseph O Humtsoe, Hyun-Su Kim, Brandon Leonard, Shizhang Ling, Bhumsuk Keam, Luigi Marchionni, Bahman Afsari, Michael Considine, Alexander V Favorov, Elana J Fertig, Hyunseok Kang, Patrick K Ha
Adenoid cystic carcinoma (ACC) is the second most common malignancy of the salivary gland. Although characterized as an indolent tumor, ACC often leads to incurable metastatic disease. Patients with ACC respond poorly to currently available therapeutic drugs, and factors contributing to the limited response remain unknown. Determining the role of molecular alterations frequently occurring in ACC may clarify ACC tumorigenesis and advance the development of effective treatment strategies. Applying Splice Expression Variant Analysis (SEVA) and outlier statistics on RNA-sequencing of primary ACC tumors and matched normal salivary gland tissues, we identified multiple alternative splicing events (ASE) of genes specific to ACC...
January 6, 2021: Cancer Research
Ömer Güllülü, Stephanie Hehlgans, Benjamin E Mayer, Ines Gößner, Chrysi Petraki, Melanie Hoffmann, Maximilian J Dombrowsky, Patrick Kunzmann, Kay Hamacher, Klaus Strebhardt, Emmanouil Fokas, Claus Rödel, Christian Münch, Franz Rödel
Substantial evidence has shown that overexpression of the inhibitor of apoptosis protein (IAP) Survivin in human tumors correlates significantly with treatment resistance and poor patient prognosis. Survivin serves as a radiation resistance factor that impacts the DNA damage response by interacting with DNA-dependent protein kinase (DNA-PKcs). However, the complexity, molecular determinants and functional consequences of this interrelationship remain largely unknown. By applying co-immunoprecipitation and flow cytometry-based Förster resonance energy transfer assays, we demonstrated a direct involvement of the Survivin baculovirus IAP repeat (BIR) domain in the regulation of radiation survival and DNA repair...
January 6, 2021: Cancer Research
Tiepeng Li, Lingdi Zhao, Yonghao Yang, Yao Wang, Yong Zhang, Jindong Guo, Guangyu Chen, Peng Qin, Benling Xu, Baozhen Ma, Fang Zhang, Yiman Shang, Qingjun Li, Kai Zhang, Dongfeng Yuan, Chaojie Feng, Yan Ma, Zhiyong Liu, Zhichao Tian, Hongle Li, Shengdian Wang, Quanli Gao
Both tumor-infiltrating lymphocytes (TIL) and PD-1+ peripheral blood lymphocytes (PBL) are enriched for tumor-reactive clones recognizing known and unknown tumor antigens. However, the relationship between the T-cell receptor (TCR)-β repertoires of the TIL and T cells expanded from paired PD-1+ PBL and whether T cells expanded from PD-1+ PBL can be used to treat patients with cancer as TIL substitutes remains unclear. Here we established a highly efficient protocol to prepare polyclonal T cells from PD-1+ PBL...
January 6, 2021: Cancer Research
Kazuhiko Yamada, Yusaku Hori, Satoshi Inoue, Yuji Yamamoto, Kentaro Iso, Hiroshi Kamiyama, Atsumi Yamaguchi, Takayuki Kimura, Mai Uesugi, Junichi Ito, Masahiro Matsuki, Kazutaka Nakamoto, Hitoshi Harada, Naoki Yoneda, Atsushi Takemura, Ikuo Kushida, Naomi Wakayama, Kenji Kubara, Yu Kato, Taro Semba, Akira Yokoi, Masayuki Matsukura, Takenao Odagami, Masao Iwata, Akihiko Tsuruoka, Toshimitsu Uenaka, Junji Matsui, Tomohiro Matsushima, Kenichi Nomoto, Hiroyuki Kouji, Takashi Owa, Yasuhiro Funahashi, Yoichi Ozawa
The Wnt/β-catenin signaling pathway plays crucial roles in embryonic development and the development of multiple types of cancer, and its aberrant activation provides cancer cells with escape mechanisms from immune checkpoint inhibitors. E7386, an orally active selective inhibitor of the interaction between β-catenin and CREB binding protein, which is part of the Wnt/β-catenin signaling pathway, disrupts the Wnt/β-catenin signal pathway in HEK-293 and APC (adenomatous polyposis coli)-mutated human gastric cancer ECC10 cells...
January 6, 2021: Cancer Research
Sai Ma, Bo Zhou, Qian Yang, Yunzhi Pan, Wei Yang, Stephen J Freedland, Ling-Wen Ding, Michael R Freeman, Joshua J Breunig, Neil A Bhowmick, Jian Pan, H Phillip Koeffler, De-Chen Lin
Although obesity is one of the strongest risk factors for esophageal adenocarcinoma (EAC), the molecular mechanisms underlying this association remain unclear. We recently identified 4 EAC-specific master regulator transcription factors (MRTF) ELF3, KLF5, GATA6, and EHF. In the present study, Gene Set Enrichment Analysis (GSEA) of both EAC patient samples and cell line models unbiasedly underscore fatty acid synthesis as the central pathway downstream of three MRTF (ELF3, KLF5, GATA6). Further characterizations unexpectedly identified a transcriptional feedback loop between MRTF and fatty acid synthesis, which mutually activated each other through the nuclear receptor PPARG...
January 5, 2021: Cancer Research
Zhaoji Liu, Linchong Sun, Yongping Cai, Shengqi Shen, Tong Zhang, Nana Wang, Gongwei Wu, Wenhao Ma, Shi-Ting Li, Caixia Suo, Yijie Hao, Wei-Dong Jia, Gregg L Semenza, Ping Gao, Huafeng Zhang
Metastasis is responsible for the majority of breast cancer (BrCa) deaths; however, the mechanisms underlying metastasis in this disease remain largely elusive. Here we report that under hypoxic conditions, alternative splicing of MBD2 is suppressed, favoring the production of MBD2a which facilitates BrCa metastasis. Specifically, MBD2a promoted, whereas its lesser known short form MBD2c suppressed metastasis. Activation of HIF-1 under hypoxia facilitated MBD2a production via repression of SRSF2-mediated alternative splicing...
January 5, 2021: Cancer Research
Jessica M Konen, B Leticia Rodriguez, Aparna Padhye, Joshua K Ochieng, Laura Gibson, Lixia Diao, Natalie W Fowlkes, Jared J Fradette, David H Peng, Robert Jg Cardnell, Jeffrey J Kovacs, Jing Wang, Lauren Averett Byers, Don L Gibbons
The epithelial-to-mesenchymal transition (EMT) is a dynamic epigenetic reprogramming event that occurs in a subset of tumor cells and is an initiating step towards invasion and distant metastasis. The process is reversible and gives plasticity to cancer cells to survive under variable conditions, with the acquisition of cancer stem cell-like characteristics and features such as drug resistance. Therefore, understanding survival dependencies of cells along the phenotypic spectrum of EMT will provide better strategies to target the spatial and temporal heterogeneity of tumors and prevent their ability to bypass single inhibitor treatment strategies...
January 5, 2021: Cancer Research
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