2. Academic Validation
  3. Macropinocytosis controls metabolic stress-driven CAF subtype identity in pancreatic cancer

Macropinocytosis controls metabolic stress-driven CAF subtype identity in pancreatic cancer

  • bioRxiv. 2024 Dec 5:2024.11.29.625709. doi: 10.1101/2024.11.29.625709.
Yijuan Zhang 1,  Li Ling 1,  Swetha Maganti 1,  Jennifer L Hope 1,  Cheska Marie Galapate 1,  Florent Carrette 1,  Karen Duong-Polk 1,  Anindya Bagchi 2,  David A Scott 3,  Andrew M Lowy 4 5,  Linda M Bradley 1,  Cosimo Commisso 1
Affiliations

Affiliations

  • 1 Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • 2 Cancer Genome and Epigenetics Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • 3 Cancer Metabolism Core Resource, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • 4 Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
  • 5 Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA, USA.
PMID: 39677772 DOI: 10.1101/2024.11.29.625709
Abstract

Pancreatic ductal adenocarcinoma (PDAC) tumors are deficient in glutamine, an amino acid that tumor cells and CAFs use to sustain their fitness. In PDAC, both cell types stimulate macropinocytosis as an adaptive response to glutamine depletion. CAFs play a critical role in sculpting the tumor microenvironment, yet how adaptations to metabolic stress impact the stromal architecture remains elusive. In this study, we find that macropinocytosis functions to control CAF subtype identity when glutamine is limiting. Our data demonstrate that metabolic stress leads to an intrinsic inflammatory CAF (iCAF) program driven by MEK/ERK signaling. Utilizing in vivo models, we find that blocking macropinocytosis alters CAF subtypes and reorganizes the tumor stroma. Importantly, these changes in stromal architecture can be exploited to sensitize PDAC to immunotherapy and chemotherapy. Our findings demonstrate that metabolic stress plays a role in shaping the tumor microenvironment, and that this attribute can be harnessed for therapeutic impact.

Keywords

CAF heterogeneity; Metabolic stress; drug delivery; macropinocytosis; pancreatic cancer; stromal architecture; tumor microenvironment.

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