267. IDENTIFYING CANCER-ASSOCIATED FIBROBLAST POPULATIONS DRIVING THERAPY RESISTANCE IN GASTROESOPHAGEAL ADENOCARCINOMA

Abstract Background Peri-operative docetaxel-based triplet chemotherapy is the standard-of-care treatment for advanced gastroesophageal adenocarcinoma (GEA). However, most patients recur due to innate or acquired resistance. Although distinct populations of cancer-associated fibroblasts (CAFs) within tumor microenvironment play important roles in conferring chemoresistance other cancer types, this paradigm has not been extensively studied GEA. We aim characterize CAF heterogeneity a well-annotated cohort GEA patients, identifying potential biomarkers and targets overcome chemoresistance. Methods Immunofluorescence flow cytometry assays were performed validate previously reported markers from literature primary patient fibroblasts. To identify specific GEA, an atlas was developed using single-cell RNA sequencing (scRNA-seq) data obtained 46 samples, including 28 with longitudinal samples over trajectory. Differential gene ontology analyses subpopulations dynamic across timepoints, while correlating in-patient response chemotherapy. In parallel, organoid-CAF co-cultures established subsequent vitro drug testing Results (VIM, FAP, PDPN, S100A4) found be differentially expressed isolated good poor pathological-response tumours. Analysis scRNA-seq reveals two main CAFs: myofibroblast CAFs (myCAFs) inflammatory (iCAFs). Two markers, CCL20 CHRDL1, identified as between pathological responders iCAFs, nine ISG20 C20orf27, clinical partial responders. Dynamic STAG2 HAT1, timepoints associated response. Conclusions demonstrate extensive comprise major subpopulations. Several chemotherapy, either chemonaïve setting context changes course therapy. These putative will further validated investigated, both additional co-culture settings, gain better understanding their relevance targeting potential.