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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Animals
  • Antimetabolites, Antineoplastic / pharmacology
  • Cells, Cultured
  • Clonal Evolution
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Drug Resistance, Neoplasm*
  • Genetic Heterogeneity*
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / pathology
  • Transcriptome*

Substances

  • Antimetabolites, Antineoplastic
  • Deoxycytidine
  • gemcitabine