Abstract 5368: Role of spatially distinct tumor fibroblast in erlotinib resistance

Abstract

Abstract Metabolic reprogramming toward the hexosamine biosynthesis pathway (HBP), an understudied glucose pathway leading to O-glycosylation, is associated with poor survival in the lung adenocarcinoma (LUAD). We found that this metabolic switch happens primarily in Cancer-Associated Fibroblasts (CAFs), an “activated” phenotype associated with bad outcomes in cancer. We show that spatially distinct CAFs harvested from the tumor edge (Tumor-Adjacent-Fibroblasts; TAFs) of LUAD specimens vs the tumor core (Tumor Core Fibroblasts; TCFs) successfully protect cancer cells from erlotinib treatment, as measured by proliferation (ki67), migration (podoplanin) and resistance (Multidrug Resistance 1; MDR1) markers. However, while TCFs increase O-GlcNAcylation in cancer cells, a type of dynamic O-glycosylation, TAFs decrease O-GlcNAcylation in a subpopulation of cells. Interestingly, this subpopulation of cancer cells shows an increase of partial EMT features, as well as proliferation. In addition, we find this population of cancer cells to overexpress the MDR1 transporter, known to actively export erlotinib outside the cell. These results were reproduced in a novel in vitro assembloid model using patient-derived organoids and primary fibroblast mixtures that allow us to characterize cancer and spatially distinct stromal cells in response to erlotinib treatment. Overall, our preliminary results show that TAFs from the invasive leading edge of lung tumors decrease O-GlcNAcylation in cancer cells, which promotes erlotinib resistance. In summary, O-GlcNAcylation represents a potential avenue to mitigate resistance induced by tumor-stroma crosstalk and improve cancer treatment. Citation Format: Gina Bouchard, Sylvia K. Plevritis. Role of spatially distinct tumor fibroblast in erlotinib resistance [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 5368.