Abstract 3195: Tumor inhibitory CAFs in CNS metastases

Abstract

Abstract The 2-year survival rate for patients with central nervous system (CNS) metastases (CMs) remains below 2%. With the aim to define new therapeutic options, researchers have investigated how interactions between CM cells and the surrounding tumor microenvironment (TME) support metastatic progression. As an important component of the TME, cancer associated fibroblasts (CAFs) have largely been reported as tumor supportive. But new evidence for the high heterogeneity of the CAF compartment, including in vivo studies from our lab, showed that certain CAF subpopulations could exhibit tumor inhibitory capabilities. Interestingly, recent reports revealed that CAFs showing high expression of Immunoglobulin Superfamily containing Leucin Rich Repeat (ISLR) could show tumor inhibitory capabilities in both pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC). Yet, despite the invaluable clinical potential of tumor inhibitory CAFs, the CAF compartment in the TME of CMs is still largely under described. Using CM patient tissue and CM patient-derived cell lines established in our lab, we performed single cell RNA sequencing (scRNA-seq) to define CAF subpopulations present in the TME of CMs. We identified distinct clusters characterized by differential expression of ISLR and tumor supportive CAF marker Actin Alpha 2, Smooth Muscle (ACTA2/α-SMA). CAF subpopulations were thus defined as follows: ISLRhigh/α-SMAlow, ISLRlow/α-SMAhigh, ISLRlow/α-SMAlow. Altogether, we hypothesized that ISLRhigh/α-SMAlow CAFs could act to restrain tumor progression in the TME of CMs, as opposed to potentially tumor supportive ISLRlow/α-SMAhighCAFs. ISLRhigh and ISLRlow CAFs were obtained through fluorescence-activated cell sorting (FACS) performed on one of our patient-derived CAF cell lines represented in all defined scRNA-seq clusters. ISLRhigh CAFs were validated to express lower levels of α-SMA (ISLRhigh/α-SMAlow CAFs) compared to ISLRlow cells (ISLRlow/α-SMAhigh CAFs). This mutually exclusive expression of ISLR and α-SMA in different CAF subpopulations is in accordance with recent data in PDAC and CRC and could indicate common underlying mechanisms driving the phenotype of each subpopulation. Further in vitro and in vivo experiments are currently underway in our lab to determine the tumor supportive capabilities of both ISLRhigh/α-SMAlow and ISLRlow/α-SMAhigh CAFs. Ultimately, we expect the current study to unravel the diverse and dynamic nature of CAFs in the TME of CMs, which is still largely unknown. Citation Format: Thomas Simon, David Buckley, Bodour Salhia. Tumor inhibitory CAFs in CNS metastases [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 3195.