Abstract 4589: Deciphering collagen-responsive mechanism in pancreatic tumor progression and immunology at single-cell resolution
Authors: Chen Yang 
Published: June 2023

A hallmark feature of PDAC is its desmoplastic stroma. However, clinical trials of generic strategies targeting PDAC stromal components have mostly failed or, in some cases, even accelerated tumor progression. These findings prompt us to re-evaluate the functional heterogeneity and selective targeting of the tumor stroma. Tumor stroma involves the prominent accumulation of type I collagen (Col1), the most abundant protein in PDAC and the human body. However, the precise molecular and mechanistic contributions of Col1 to PDAC remain unknown, due to the lack of mouse models for precise knockout of Col1. I have established a variety of novel transgenic mouse models that allow specific genetic deletion of Col1 in various cell populations including fibroblasts or cancer cells of spontaneous PDAC (Chen et al., Cancer Cell, 2022; Chen et al., Cancer Cell, 2021; Chen et al., Nature Communications, 2021). In addition, my prior studies underscore the importance of deciphering the functional heterogeneity of tumor microenvironment with both tumor-restraining and tumor-promoting functions (McAndrew, Chen, Darpolor et al., Cancer Discovery, 2022; Chen et al., Nature Reviews Clinical Oncology, 2021; Chen et al., EMBO Molecular Medicine, 2018; Chen et al., PLoS Biology, 2018). Specifically, my recent studies identified that Col1 deletion in fibroblasts significantly aggravates tumor progression and immune suppression, with enriched myeloid-derived suppressor cells (MDSCs) and inhibited T/B cells (Chen et al., Cancer Cell, 2021). On the contrary, Col1 deletion in cancer cells inhibited PDAC progression and immunosuppression, leading to beneficial intra-tumoral microbiome and enhanced efficacy of immunotherapy (Chen et al., Cancer Cell, 2022). In contrast to the normal Col1 heterotrimer (α1/α2/α1) produced by fibroblasts, pancreatic cancer cells produce abnormal oncogenic Col1 homotrimer (α1/α1/α1). Col1 homotrimers produced by cancer cells exhibits potent tumor-promoting functions, in contrast to the tumor-restraining functions of Col1 heterotrimers produced by fibroblasts. These findings, as validated in both transgenic mouse models and pancreatic tumor patient datasets, identify the distinct impact of various Col1 subtypes on tumor progression, immune landscape, and microbiome profile. Furthermore, my results underscore the need for new therapeutic strategy preferably targeting Col1 homotrimer-specific oncogenic effects in cancer cells via cancer-specific receptors, without disturbing Col1 heterotrimer-induced tumor-restraining functions. My current studies aim to dissect the cancer cell-intrinsic response and immune response to Col1 homotrimer versus Col1 heterotrimer, which may unravel the fundamental collagen-responsive mechanism by which cancer cells survive in the desmoplastic microenvironment, revealing potential vulnerabilities of PDAC.

Citation Format: Yang Chen. Deciphering collagen-responsive mechanism in pancreatic tumor progression and immunology at single-cell resolution. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4589.