Oncogenic KRAS-dependent stromal interleukin-33 directs the pancreatic microenvironment to promote tumor growth

  • Cancer Discov. 2024 Jul 3. doi: 10.1158/2159-8290.CD-24-0100.
Katelyn L Donahue  1 ,  Hannah R Watkoske  2 ,  Padma Kadiyala  3 ,  Wenting Du  2 ,  Kristee Brown  4 ,  Michael K Scales  1 ,  Ahmed M Elhossiny  3 ,  Carlos E Espinoza  5 ,  Emily L Lasse Opsahl  5 ,  Brian D Griffith  6 ,  Yukang Wen  6 ,  Lei Sun  2 ,  Ashley Velez-Delgado  5 ,  Nur M Renollet  1 ,  Jacqueline Morales  5 ,  Nicholas M Nedzesky  6 ,  Rachael K Baliira  3 ,  Rosa E Menjivar  5 ,  Paola I Medina-Cabrera  1 ,  Arvind Rao  5 ,  Benjamin Allen  3 ,  Jiaqi Shi  3 ,  Timothy L Frankel  2 ,  Eileen S Carpenter  3 ,  Filip Bednar  1 ,  Yaqing Zhang  2 ,  Marina Pasca di Magliano  3
Affiliations
  • 1. University of Michigan-Ann Arbor, Ann Arbor, Michigan, United States.
  • 2. University of Michigan Medical School, Ann Arbor, MI, United States.
  • 3. University of Michigan-Ann Arbor, Ann Arbor, MI, United States.
  • 4. University of Michigan Medical Schooligan, United States.
  • 5. University of Michigan-Ann Arbor, Ann Arbor, United States.
  • 6. University of Michigan-Ann Arbor, United States.
PMID: 38958646 DOI: 10.1158/2159-8290.CD-24-0100
Abstract

Pancreatic Cancer is characterized by an extensive fibroinflammatory microenvironment. During carcinogenesis, normal stromal cells are converted to cytokine-high Cancer associated fibroblasts (CAFs). The mechanisms underlying this conversion, including regulation and function of fibroblast-derived cytokines, are poorly understood. Thus, efforts to target CAFs therapeutically have so far failed. Here, we show that signals from epithelial cells expressing oncogenic KRAS -a hallmark pancreatic Cancer mutation- activate fibroblast autocrine signaling, which drives expression of the cytokine interleukin-33 (IL-33). Stromal IL-33 expression remains high and dependent on epithelial KRAS throughout carcinogenesis; in turn, environmental stress induces IL-33 secretion. Using compartment-specific IL-33 knockout mice, we observed that lack of stromal IL-33 leads to profound reprogramming of multiple components of the pancreatic tumor microenvironment, including CAFs, myeloid cells and lymphocytes. Notably, loss of stromal IL-33 leads to an increase in CD8+ T cell infiltration and activation, and, ultimately, reduced tumor growth.

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