Pre-existing Functional Heterogeneity of Tumorigenic Compartment as the Origin of Chemoresistance in Pancreatic Tumors
Sahil Seth,
Chieh-Yuan Li,
I-Lin Ho,
Denise Corti,
Sara Loponte,
Luigi Sapio,
Edoardo Del Poggetto,
Er-Yen Yen,
Frederick Scott Robinson,
Michael Peoples,
Tatiana Karpinets,
Angela Kay Deem,
Tapsi Kumar,
Xingzhi Song,
Shan Jiang,
Ya’an Kang,
Jason Fleming,
Michael Kim,
Jianhua Zhang,
Anirban Maitra,
Timothy Paul Heffernan,
Virginia Giuliani,
Giannicola Genovese,
Andrew Futreal,
Giulio Francesco Draetta,
Alessandro Carugo,
Andrea Viale
Affiliations
Sahil Seth
Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Chieh-Yuan Li
UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
I-Lin Ho
UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Denise Corti
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Sara Loponte
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Luigi Sapio
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Edoardo Del Poggetto
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Er-Yen Yen
UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Frederick Scott Robinson
Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Michael Peoples
Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Tatiana Karpinets
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Angela Kay Deem
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Tapsi Kumar
UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Xingzhi Song
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Shan Jiang
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Ya’an Kang
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Jason Fleming
Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL, USA
Michael Kim
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Jianhua Zhang
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Anirban Maitra
Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Timothy Paul Heffernan
Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Virginia Giuliani
Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Giannicola Genovese
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Andrew Futreal
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Giulio Francesco Draetta
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Alessandro Carugo
Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Corresponding author
Andrea Viale
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Corresponding author
Summary: 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. : High-complexity lineage tracing shows that tumors growing in different environments are maintained by a common set of tumorigenic cells that enables the generation of clonal replica tumors (CRTs). Applying CRTs, Seth et al. unmask functional heterogeneity in response to therapeutics and identify a signature that predicts chemoresistance in pancreatic cancer. Keywords: tumor heterogeneity, functional heterogeneity, lineage tracing, clonal dynamics, clonal isolation, pancreatic cancer, drug resistance, subclonal gene signature, prognostic stratification
