Abstract B098: Oncogenic KRAS relies on β1 integrin expression to drive pancreatic neoplasia and PDAC development

Abstract

Abstract Oncogenic Kras drives cancer progression through cooperation with multiple cellular factors, many of which are yet to be determined. The β1 integrins, a family of extracellular matrix receptors, are strong candidates; they are implicated in many aspects of cancer progression including cell growth and survival signaling, cell migration and metastasis. Additionally, multiple studies have identified β1 integrins within the interactome of oncogenic Kras. We are investigating the potential cooperation if β1 integrins in Kras-mediated oncogenesis using genetic perturbations within the tamoxifen-inducible and conditional Ptf1a-CreERTM; LSL- KrasG12D (p48-KCER) model of pancreatic cancer. Conditional deletion of the β1 integrins from the adult pancreas produced minimal tissue abnormalities; there were no obvious tissue defects at 6 months post induction, although there was some evidence of pancreatitis at 1 year post induction. However, deletion of the β1 integrins within the KCER model of pancreatic cancer (KCER-Δβ1) resulted in a profound suppression of pancreatic disease progression. There was no detectable neoplasias at 3 months post-induction and minimally detectable neoplasias at 6 months post-induction, compared to prominent neoplasia development and stromal expansion in the control KCER mice at these time-points. Moderate stromal expansion was observed in KCER-Δβ1 mice at 6 months post-induction despite the lack of neoplasia development. To investigate the mechanisms of this integrin-KRAS cooperation, we conditionally deleted the expression of two canonical integrin signaling molecules, the integrin-linked kinase (ILK) and the focal adhesion kinase (FAK). Neither the ILK knockout (KCER-ΔILK) nor the FAK knockout (KCER-ΔFAK) phenocopied the KCER-Δβ1 mice, as both developed neoplasias and stromal expansion at 3 months post-induction and beyond. To explore the role of integrin activation, we next deleted expression of the integrin-cytoskeleton linker molecule Talin-1 in the KCER model. Surprisingly, even though Talin-1 is key to integrin activation, the KCER-ΔTalin-1 mice also failed to phenocopy the KCER-Δβ1, showing ample neoplasia development at 3 and 6 months post-induction, and trending towards faster disease progression at later stages. These combined results demonstrate crucial cooperation between oncogenic Kras and β1 integrins to drive pancreatic cancer progression, and point to non-canonical β1 integrin functions in mediating this cooperation. Citation Format: John L. Muschler, Ge Huang, Alexander C. Smith, Rosalie C. Sears. Oncogenic KRAS relies on β1 integrin expression to drive pancreatic neoplasia and PDAC development [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B098.