@article{2e73ae1041db43da865717e7f99a8a74,
title = "Single-cell RNA-seq analysis reveals the platinum resistance gene COX7B and the surrogate marker CD63",
abstract = "Cancers acquire resistance to systemic treatment with platinum-based chemotherapy (eg, cisplatin [CDDP]) as a result of a dynamic intratumoral heterogeneity (ITH) and clonal repopulation. However, little is known about the influence of chemotherapy on ITH at the single-cell level. Here, mapping the transcriptome of cancers treated with CDDP by scRNA-seq, we uncovered a novel gene, COX7B, associated with platinum-resistance, and surrogate marker, CD63. Knockdown of COX7B in cancer cells decreased the sensitivity of CDDP whereas overexpression recovered the sensitivity of CDDP. Low COX7B levels correlated with higher mortality rates in patients with various types of cancer and were significantly associated with poor response to chemotherapy in urinary bladder cancer. Tumor samples from patients, who underwent CDDP therapy, showed decreased COX7B protein levels after the treatment. Analyzing scRNA-seq data from platinum-na{\"i}ve cancer cells demonstrated a low-COX7B subclone that could be sorted out from bulk cancer cells by assaying CD63. This low-COX7B subclone behaved as cells with acquired platinum-resistance when challenged to CDDP. Our results offer a new transcriptome landscape of platinum-resistance that provides valuable insights into chemosensitivity and drug resistance in cancers, and we identify a novel platinum resistance gene, COX7B, and a surrogate marker, CD63.",
keywords = "CD63, COX7B, platinum resistance, single-cell RNA-seq, tumor heterogeneity",
author = "Nobuyuki Tanaka and Shintaro Katayama and Aparna Reddy and Kaneyasu Nishimura and Naoya Niwa and Hiroshi Hongo and Koichiro Ogihara and Takeo Kosaka and Ryuichi Mizuno and Eiji Kikuchi and Shuji Mikami and Ayako Miyakawa and Ernest Arenas and Juha Kere and Mototsugu Oya and Per Uhl{\'e}n",
note = "Funding Information: Swedish Cancer Society (grant CAN 2013‐802, CAN 2016‐801 to P.U. and CAN 2016‐572 to E.A.), and the Olle Engkvist Foundation (P.U.), J.K. is a recipient of The Royal Society Wolfson Research Excellence Award. The computations were performed on resources provided by SNIC through the Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project b2016089. Single‐cell RNA‐seq services were provided by the Eukaryotic Single‐ cell Genomics facility and the National Genomics Infrastructure at Science for Life Laboratory. The authors acknowledge support from Science for Life Laboratory, the Knut and Alice Wallenberg Foundation, the National Genomics Infrastructure funded by the Swedish Research Council, and UPPMAX for assistance with massively parallel sequencing (alternatively genotyping) and access to the UPPMAX computational infrastructure. Funding Information: This study was supported in part through Grants‐in‐Aid for Scientific Research (#26462429 to N.T. and #15H04977 to M.O.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, the YASUDA Medical Foundation, Japan (N.T.), the Takeda Science Foundation, Japan (N.T.), the Uehara Memorial Foundation, Japan (N.T.), the David and Astrid Hagel{\'e}n Foundation, Sweden (N.T.), the Karolinska Institutet Research Foundation (N.T. and S.K.), the EU Seventh Framework Programme FP7‐PEOPLE‐2012‐IAPP grant SARM (#324509 to J.K.), the Knut and Alice Wallenberg Foundation (J.K.), the Swedish Research Council (grants 2009‐3364, 2013‐3189, and 2017‐00815 to P.U.), the Funding Information: Funding information This study was supported in part through Grants-in-Aid for Scientific Research (#26462429 to N.T. and #15H04977 to M.O.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, the YASUDA Medical Foundation, Japan (N.T.), the Takeda Science Foundation, Japan (N.T.), the Uehara Memorial Foundation, Japan (N.T.), the David and Astrid Hagel?n Foundation, Sweden (N.T.), the Karolinska Institutet Research Foundation (N.T. and S.K.), the EU Seventh Framework Programme FP7-PEOPLE-2012-IAPP grant SARM (#324509 to J.K.), the Knut and Alice Wallenberg Foundation (J.K.), the Swedish Research Council (grants 2009-3364, 2013-3189, and 2017-00815 to P.U.), the Swedish Cancer Society (grant CAN 2013-802, CAN 2016-801 to P.U. and CAN 2016-572 to E.A.), and the Olle Engkvist Foundation (P.U.), J.K. is a recipient of The Royal Society Wolfson Research Excellence Award. The computations were performed on resources provided by SNIC through the Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project b2016089. Single-cell RNA-seq services were provided by the Eukaryotic Single-cell Genomics facility and the National Genomics Infrastructure at Science for Life Laboratory. The authors acknowledge support from Science for Life Laboratory, the Knut and Alice Wallenberg Foundation, the National Genomics Infrastructure funded by the Swedish Research Council, and UPPMAX for assistance with massively parallel sequencing (alternatively genotyping) and access to the UPPMAX computational infrastructure. The authors wish to thank Dr. Bertrand Joseph and Dr. Lauri Louhivuori of the Karolinska Institutet for their helpful discussions. Publisher Copyright: {\textcopyright} 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.",
year = "2018",
month = dec,
doi = "10.1002/cam4.1828",
language = "English",
volume = "7",
pages = "6193--6204",
journal = "Cancer medicine",
issn = "2045-7634",
publisher = "John Wiley and Sons Ltd",
number = "12",
}
