@article{62e1cd021a494b6facbf513b0dbbb7d2,
title = "Pre-existing Functional Heterogeneity of Tumorigenic Compartment as the Origin of Chemoresistance in Pancreatic Tumors",
abstract = "Adaptive drug-resistance mechanisms allow human tumors to evade treatment through selection and expansion of treatment-resistant clones. Here, studying clonal evolution of tumor cells derived from human pancreatic tumors, we demonstrate that in vitro cultures and in vivo tumors are maintained by a common set of tumorigenic cells that can be used to establish clonal replica tumors (CRTs), large cohorts of animals bearing human tumors with identical clonal composition. Using CRTs to conduct quantitative assessments of adaptive responses to therapeutics, we uncovered a multitude of functionally heterogeneous subpopulations of cells with differential degrees of drug sensitivity. High-throughput isolation and deep characterization of unique clonal lineages showed genetic and transcriptomic diversity underlying functionally diverse subpopulations. Molecular annotation of gemcitabine-naive clonal lineages with distinct responses to treatment in the context of CRTs generated signatures that can predict the response to chemotherapy, representing a potential biomarker to stratify patients with pancreatic cancer.",
keywords = "clonal dynamics, clonal isolation, drug resistance, functional heterogeneity, lineage tracing, pancreatic cancer, prognostic stratification, subclonal gene signature, tumor heterogeneity",
author = "Sahil Seth and Li, {Chieh Yuan} and Ho, {I. Lin} and Denise Corti and Sara Loponte and Luigi Sapio and {Del Poggetto}, Edoardo and Yen, {Er Yen} and Robinson, {Frederick Scott} and Michael Peoples and Tatiana Karpinets and Deem, {Angela Kay} and Tapsi Kumar and Xingzhi Song and Shan Jiang and Ya'an Kang and Jason Fleming and Michael Kim and Jianhua Zhang and Anirban Maitra and Heffernan, {Timothy Paul} and Virginia Giuliani and Giannicola Genovese and Andrew Futreal and Draetta, {Giulio Francesco} and Alessandro Carugo and Andrea Viale",
note = "Funding Information: We thank A. Petrocchi, N. Feng, J. Gay, and R. Mullinox at the Institute for Applied Cancer Science at The MD Anderson Cancer Center (MDACC) for treatment advice; C. Bristow at the Institute for Applied Cancer Science for computational assistance; R. Nguyen in the Department of Genomic Medicine and T. Yuan at the Institute for Applied Cancer Science at MDACC for lab management; the MDACC Sequencing and Microarray Facility (SMF), funded by National Cancer Institute (NCI) grant CA016672 (SMF); the MDACC Science Park NGS Facility, funded by CPRIT Core Facility Support grants (RP120348 and RP170002); and the MDACC Flow Cytometry and Cellular Imaging Core Facility, supported by NCI grant P30CA16672. This study was supported by UT MD Anderson Cancer Center Start-Up Funds to A.V.; UT MD Anderson Cancer Center Pancreatic Cancer Moon Shot to G.F.D. and A.V.; and the Pancreatic Cancer Action Network (PanCAN) to G.F.D. and A.V.; National Cancer Institute (NCI) R01 CA218004 to A.M. Funding Information: We thank A. Petrocchi, N. Feng, J. Gay, and R. Mullinox at the Institute for Applied Cancer Science at The MD Anderson Cancer Center (MDACC) for treatment advice; C. Bristow at the Institute for Applied Cancer Science for computational assistance; R. Nguyen in the Department of Genomic Medicine and T. Yuan at the Institute for Applied Cancer Science at MDACC for lab management; the MDACC Sequencing and Microarray Facility (SMF), funded by National Cancer Institute (NCI) grant CA016672 (SMF); the MDACC Science Park NGS Facility, funded by CPRIT Core Facility Support grants ( RP120348 and RP170002 ); and the MDACC Flow Cytometry and Cellular Imaging Core Facility, supported by NCI grant P30CA16672 . This study was supported by UT MD Anderson Cancer Center Start-Up Funds to A.V.; UT MD Anderson Cancer Center Pancreatic Cancer Moon Shot to G.F.D. and A.V.; and the Pancreatic Cancer Action Network (PanCAN) to G.F.D. and A.V.; National Cancer Institute (NCI) R01 CA218004 to A.M. Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = feb,
day = "5",
doi = "10.1016/j.celrep.2019.01.048",
language = "English (US)",
volume = "26",
pages = "1518--1532.e9",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "6",
}