Abstract 4281: BMP signaling impaired telocytes-Foxl1+disrupt the extracellular matrix network enabling the development of colitis-associated cancer

Abstract

Abstract The relationship between colon stem cells (SCs), its surrounding niche microenvironment like the extracellular matrix (ECM) and the mesenchymal niche cells is complex and dynamic. ECM proteins are not only a scaffolding system for SCs, but their biophysical properties also contribute to localizing signals and creating gradients leading to the SCs homeostasis. Foxl1+-Telocytes (TCFoxL1+) are mesenchymal niche cells implicated in cell-cell communication and the production of BMP ligands. Upon chronic inflammation, mice lacking BMP signaling in TCFoxL1+ (BmpR1aΔFoxL1+), developed colonic tumors with microenvironment exhibiting abnormal TCFoxL1+ structure, increased BMP expression and myofibroblastic-like cancer-associated fibroblasts (myCAF) subpopulation. Yet, how the TCFoxL1+ influences SCs niche ECM proteins during tumorigenesis is less understood. We aimed to investigate how the loss of BMP signaling in TCFoxL1+ affects ECM network impacting the niche microenvironment promoting the development of CAC. DSS-based chronic inflammatory challenge in mutant and control mice, quantitative-MS-based strategy was performed to determine the proteome of the transformed regions solely in epithelial-mesenchymal tissue following colon deconstruction. Expression of the proteins of interest were validated by Western Blots or immunostainings. Quantitative analysis of collagen network was assessed using phyton pipeline U-net in Sirius red-stained colon analyzed under polarized light. Differential significant expression of 798 proteins, with 342 upregulated and 456 downregulated, were found in the tumors of mutant mice compared to controls. Mfap5 involved in CAF activation was the highest upregulated protein. We found upregulated, laminin subunits α4 and β2, decorin, lumican as well as transgelin (myCAF marker), which are proteins known for contributing to the stiffening of the ECM during colorectal cancer. Adamdec1 which prevents aberrant ECM accumulation and thrombospodin-1, an ECM glycoprotein whose low levels have been related to tumor growth, were both found to be downregulated. Data extracted from Python's U-Net pipeline demonstrated that tumors, in mutant mice, exhibited higher frequencies of straighter collagen fibers compared to wavier fibers in controls. Collagen fiber distribution was shown to present an even angle distribution in controls whereas BmpR1aΔFoxL1+ mice presented a preferential orientation. These results suggest that defective TCFoxL1+ commits the surrounding niche microenvironment, especially its ECM, toward the development and progression of CAC. Citation Format: Vilcy Reyes Nicolas, Alain B. Alfonso, Jennifer Raisch, François M. Boisvert, Marc-Antoine Lauzon, Nathalie Perreault. BMP signaling impaired telocytes-Foxl1+disrupt the extracellular matrix network enabling the development of colitis-associated cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4281.