KRAS mutant rectal cancer cells interact with surrounding fibroblasts to deplete the extracellular matrix

Jin K. Kim, Michael R. Marco, Seo Hyun Choi, Xuan Qu, Chin Tung Chen, Moshe Elkabets, Lauren Fairchild, Oliver Chow, Francisco M. Barriga, Lukas E. Dow, Kevin O’Rourke, Bryan Szeglin, Dmitry Yarilin, Sho Fujisawa, Katia Manova-Todorova, Philip B. Paty, Jinru Shia, Christina Leslie, J. Joshua Smith, Scott LoweRaphael Pelossof, Francisco Sanchez-Vega, Julio Garcia-Aguilar

Research output: Contribution to journalArticlepeer-review

Abstract

Somatic mutations in the KRAS oncogene are associated with poor outcomes in locally advanced rectal cancer but the underlying biologic mechanisms are not fully understood. We profiled mRNA in 76 locally advanced rectal adenocarcinomas from patients that were enrolled in a prospective clinical trial and investigated differences in gene expression between KRAS mutant (KRAS-mt) and KRAS-wild-type (KRAS-wt) patients. We found that KRAS-mt tumors display lower expression of genes related to the tumor stroma and remodeling of the extracellular matrix. We validated our findings using samples from The Cancer Genome Atlas (TCGA) and also by performing immunohistochemistry (IHC) and immunofluorescence (IF) in orthogonal cohorts. Using in vitro and in vivo models, we show that oncogenic KRAS signaling within the epithelial cancer cells modulates the activity of the surrounding fibroblasts in the tumor microenvironment.

Original languageAmerican English
Pages (from-to)2766-2781
Number of pages16
JournalMolecular Oncology
Volume15
Issue number10
DOIs
StatePublished - 1 Oct 2021

Keywords

  • KRAS
  • cancer-associated fibroblast
  • extracellular matrix
  • rectal cancer
  • tumor response
  • tumor stroma

All Science Journal Classification (ASJC) codes

  • Genetics
  • Molecular Medicine
  • Oncology
  • Cancer Research

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