Stress Granules Determine the Development of Obesity-Associated Pancreatic Cancer

  • Cancer Discov. 2022 Aug 5;12(8):1984-2005. doi: 10.1158/2159-8290.CD-21-1672.
Guillaume Fonteneau  1 ,  Alexandra Redding   #  1 ,  Hannah Hoag-Lee   #  1 ,  Edward S Sim  1 ,  Stefan Heinrich  2 ,  Matthias M Gaida  3  4  5 ,  Elda Grabocka  1
Affiliations
  • 1. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
  • 2. Department of Surgery, University Medical Center Mainz, JGU-Mainz, Mainz, Germany.
  • 3. Institute of Pathology, University Medical Center Mainz, JGU-Mainz, Mainz, Germany.
  • 4. Research Center for Immunotherapy, University Medical Center Mainz, JGU-Mainz, Mainz, Germany.
  • 5. Joint Unit Immunopathology, Institute of Pathology, University Medical Center, JGU-Mainz and TRON, Translational Oncology at the University Medical Center, JGU-Mainz, Mainz, Germany.
  • # Contributed equally.
PMID: 35674408 DOI: 10.1158/2159-8290.CD-21-1672
Abstract

Obesity is a global epidemic and a major predisposing factor for Cancer. Increasing evidence shows that obesity-associated stress is a key driver of Cancer risk and progression. Previous work has identified the phase-separation organelles, stress granules (SG), as mutant KRAS-dependent mediators of stress adaptation. However, the dependence of tumorigenesis on these organelles is unknown. Here, we establish a causal link between SGs and pancreatic ductal adenocarcinoma (PDAC). Importantly, we uncover that dependence on SGs is drastically heightened in obesity-associated PDAC. Furthermore, we identify a previously unknown regulator and component of SGs, namely, the serine/arginine protein kinase 2 (SRPK2), as a specific determinant of SG formation in obesity-associated PDAC. We show that SRPK2-mediated SG formation in obesity-associated PDAC is driven by hyperactivation of the IGF1/PI3K/mTOR/S6K1 pathway and that S6K1 inhibition selectively attenuates SGs and impairs obesity-associated PDAC development.

Significance: : We show that stress adaptation via the phase-separation organelles SGs mediates PDAC development. Moreover, preexisting stress conditions such as obesity are a driving force behind tumor SG dependence, and enhanced SG levels are key determinants and a chemopreventive target for obesity-associated PDAC. This article is highlighted in the In This Issue feature, p. 1825.

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