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Cell Rep. 2019 Feb 5;26(6):1518-1532.e9. doi: 10.1016/j.celrep.2019.01.048.

Pre-existing Functional Heterogeneity of Tumorigenic Compartment as the Origin of Chemoresistance in Pancreatic Tumors.

Author information

1
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.
2
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.
3
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
4
Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
5
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
6
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
7
Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL, USA.
8
Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
9
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
10
Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: acarugo@mdanderson.org.
11
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: aviale@mdanderson.org.

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

PMID:
30726735
DOI:
10.1016/j.celrep.2019.01.048
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