Synthetic vulnerabilities of mesenchymal subpopulations in pancreatic cancer

Nature. 2017 Feb 16;542(7641):362-366. doi: 10.1038/nature21064. Epub 2017 Feb 8.

Abstract

Malignant neoplasms evolve in response to changes in oncogenic signalling. Cancer cell plasticity in response to evolutionary pressures is fundamental to tumour progression and the development of therapeutic resistance. Here we determine the molecular and cellular mechanisms of cancer cell plasticity in a conditional oncogenic Kras mouse model of pancreatic ductal adenocarcinoma (PDAC), a malignancy that displays considerable phenotypic diversity and morphological heterogeneity. In this model, stochastic extinction of oncogenic Kras signalling and emergence of Kras-independent escaper populations (cells that acquire oncogenic properties) are associated with de-differentiation and aggressive biological behaviour. Transcriptomic and functional analyses of Kras-independent escapers reveal the presence of Smarcb1-Myc-network-driven mesenchymal reprogramming and independence from MAPK signalling. A somatic mosaic model of PDAC, which allows time-restricted perturbation of cell fate, shows that depletion of Smarcb1 activates the Myc network, driving an anabolic switch that increases protein metabolism and adaptive activation of endoplasmic-reticulum-stress-induced survival pathways. Increased protein turnover renders mesenchymal sub-populations highly susceptible to pharmacological and genetic perturbation of the cellular proteostatic machinery and the IRE1-α-MKK4 arm of the endoplasmic-reticulum-stress-response pathway. Specifically, combination regimens that impair the unfolded protein responses block the emergence of aggressive mesenchymal subpopulations in mouse and patient-derived PDAC models. These molecular and biological insights inform a potential therapeutic strategy for targeting aggressive mesenchymal features of PDAC.

Publication types

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

MeSH terms

  • Animals
  • Carcinoma, Pancreatic Ductal / drug therapy
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Deoxycytidine / therapeutic use
  • Endoplasmic Reticulum Stress / genetics
  • Female
  • Genes, myc
  • Genes, ras
  • Humans
  • MAP Kinase Kinase 4 / metabolism
  • MAP Kinase Signaling System
  • Male
  • Mesoderm / metabolism
  • Mesoderm / pathology*
  • Mice
  • Mosaicism
  • Oncogene Protein p55(v-myc) / metabolism
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Proteolysis
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • SMARCB1 Protein / deficiency
  • SMARCB1 Protein / metabolism
  • Transcriptome / genetics

Substances

  • Oncogene Protein p55(v-myc)
  • SMARCB1 Protein
  • Smarcb1 protein, mouse
  • Deoxycytidine
  • gemcitabine
  • MAP Kinase Kinase 4
  • MAP2K4 protein, human
  • Proto-Oncogene Proteins p21(ras)