| First Author | Fonteneau G | Year | 2022 |
| Journal | Cancer Discov | Volume | 12 |
| Issue | 8 | Pages | 1984-2005 |
| PubMed ID | 35674408 | Mgi Jnum | J:351509 |
| Mgi Id | MGI:7328886 | Doi | 10.1158/2159-8290.CD-21-1672 |
| Citation | Fonteneau G, et al. (2022) Stress Granules Determine the Development of Obesity-Associated Pancreatic Cancer. Cancer Discov 12(8):1984-2005 |
| abstractText | 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. |
