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Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation

Christopher J Tape1, Stephanie Ling2, Maria Dimitriadi2

  • 1The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Cell
|April 19, 2016
PubMed

Insights

Oncogenic KRAS (KRAS(G12D)) signaling in pancreatic cancer involves tumor and stromal cells. This reciprocal signaling expands oncogene effects, impacting tumor growth and metabolism.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling

Background:

  • Oncogenic mutations, like KRAS(G12D), drive cancer by altering cell signaling pathways.
  • Tumor cell signaling is traditionally viewed as cell-autonomous, neglecting interactions with the tumor microenvironment.
  • Understanding heterocellular signaling is crucial for a comprehensive view of oncogene function in cancer.

Purpose of the Study:

  • To investigate the role of oncogenic KRAS(G12D) in regulating tumor cell signaling through stromal cells.
  • To analyze the impact of reciprocal signaling on the tumor cell phosphoproteome and proteome.
  • To determine how heterocellular signaling influences tumor cell proliferation, apoptosis, and mitochondrial function.

Main Methods:

  • Utilized cell-specific proteome labeling combined with multivariate phosphoproteomics.
  • Analyzed heterocellular KRAS(G12D) signaling in pancreatic ductal adenocarcinoma (PDA) cells.
  • Investigated the engagement of fibroblasts and subsequent reciprocal signaling.

Main Results:

  • Tumor cell KRAS(G12D) engages fibroblasts, which then instigate reciprocal signaling in tumor cells.
  • Reciprocal signaling doubles the number of regulated signaling nodes compared to cell-autonomous KRAS(G12D).
  • Reciprocal signaling alters the tumor cell phosphoproteome and proteome, affecting proliferation, apoptosis, and mitochondrial capacity via an IGF1R/AXL-AKT axis.

Conclusions:

  • Oncogene signaling is a heterocellular process, not solely cell-autonomous.
  • The cell-autonomous perspective underrepresents the full extent of oncogene signaling in cancer.
  • Targeting heterocellular signaling pathways may offer new therapeutic strategies for pancreatic cancer.

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