2. Academic Validation
  3. Oncogenic KRAS-dependent stromal interleukin-33 directs the pancreatic microenvironment to promote tumor growth

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

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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