Abstract 3644: Schwann cells reshape tumor cells and cancer associated fibroblasts in pancreatic ductal adenocarcinoma microenvironment

Abstract

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by high degree of innervation and desmoplasia in its tumor microenvironment (TME). Nerves and cancer associated fibroblast (CAFs) represent two key components of TME. Schwann cells (SCs), the most prevalent cell type in peripheral nerves, have been reported to support neurons and facilitate neuronal guidance during repair, but their role and mechanism in PDAC development remain largely unknown. Cancer-associated fibroblasts (CAFs) are believed to be mainly responsible for desmoplasia in PDAC TME, but whether they are also involved in the regulation of SCs functions in PDAC is yet to be explored. Here, we aimed to illustrate the function and underlying mechanism of SCs in PDAC TME and verified its clinical relevance. Methods: We performed tissue microarray to evaluate the enrichment of SCs in tumors of different stages, as well as in adjacent normal tissues. Single cell RNA-sequencing (scRNA-seq) and microarray-based spatial transcriptomics (ST) were used to determine the interactions among SCs, tumor cells, and CAFs. We utilized co-culture and conditioned medium (CM) model to evaluate the role of SCs in reshaping TME. We employed intrasplenic injection model and patient-derived xenograft (PDX) mouse models to determine the role of SCs in tumor progression. To evaluate the differentiation of CAFs after SCs CM treatment, immunohistochemistry (IHC), immunofluorescence (IF), Western blot, enzyme-linked immunosorbent assay (ELISA), qPCR and bulk-RNA seq were performed. Mass spectrometry (MS), ELISA, and IF assays were also performed to identify the key regulators of SCs. Results: Significant neural hypertrophy and SCs infiltration were observed in tumor tissues and were associated with worse prognosis in PDAC patients. More cancer cells and CAFs could also be seen in proximity to SCs. scRNA-seq of PDAC samples demonstrated high degree of heterogeneity in both cancer cells and CAFs. We found a basal-like subgroup of cancer cells with more malignant behavior, and a pro-inflammatory subpopulation of CAFs (iCAFs) that promotes tumor progression. ST further showed that both basal-like cancer cells and iCAFs were located immediately adjacent to SCs in human PDAC tissues. The malignant phenotypes of cancer cells including migration, invasion, and proliferation were significantly promoted by SCs CM treatment. Furthermore, SCs CM treatment promotes iCAFs formation and PDAC progression in vitro and in vivo. Lastly, IL-1α was identified as a SCs-secreted ligand that generate iCAFs. Conclusion: Collectively, we find that SCs play an oncogenic role in PDAC by promoting the shift of cancer cells and CAFs toward more malignant phenotypes, and suggest that targeting SCs in TME represents a promising therapeutic strategy for PDAC treatment. Citation Format: Meilin Xue, Yongsheng Jiang, Lijie Han, Rui Su, Cheng Xiong, Youwei Zhu, Yizhi Cao, Minmin Shi, Jianjun Chen, Baiyong Shen, Lingxi Jiang, Hao Chen. Schwann cells reshape tumor cells and cancer associated fibroblasts in pancreatic ductal adenocarcinoma microenvironment [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 3644.