Abstract 2974: A complex of tumor-suppressor NF1 and SPRED2 promotes pancreatic cancer tumorigenesis

Abstract

Listen

Translate article

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with poor prognosis due to late detection and lack of effective therapeutic options. >90% of PDAC tumors are driven by activating mutations in the KRAS oncogene, making it an appealing subject for further investigation into understanding PDAC biology and offering a potential genetic vulnerability to target in patients. Our laboratory has previously reported a mutant-KRAS-proximal complex at the plasma membrane that consists of tumor-suppressor Neurofibromatosis type 1 (NF1), Sprouty Related EVH1 Domain Containing 2 (SPRED2), and Ribosomal S6 Kinase 1 (RSK1). This complex mechanistically suppresses WT KRAS signaling via RSK1, a suppression which is then relieved upon mutant KRAS inhibition, ultimately promoting adaptive resistance for PDAC cells under these conditions. These data highlighted a potential paradoxical role for two canonical tumor-suppressors, NF1 and SPRED2, as promoters of PDAC tumorigenesis when mutant KRAS is inhibited. We find that knockout of NF1 in PDAC organoids induces a substantial growth defect in vivo, and our preliminary data indicates that SPRED2 knockout PDAC cells have reduced proliferation in vitro. Moreover, both SPRED2 and NF1 KO promotes a diminished migratory phenotype in vitro. Given NF1's well-established role as a tumor-suppressor, our observations of decreased tumorigenic properties upon NF1 deletion are unexpected. We hypothesize that NF1 and Spred2 promote tumorigenesis via recruitment of RSK1 to the plasma membrane, inducing the phosphorylation of putative substrates to stimulate a pro-migratory cellular behavior. Our work suggests the existence of a unique RSK1 program localized at the plasma membrane by mutant KRAS, providing a new facet of oncogenesis to investigate for fundamental understanding and potential therapeutic opportunities. Citation Format: Sunny Kim, Jonathan P. Kastan, Hsiu-Chi Ting, Youngkyu Park, Dave Tuveson. A complex of tumor-suppressor NF1 and SPRED2 promotes pancreatic cancer tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2974.