Abstract 776: A cancer cell intrinsic program for matrix remodeling and CAF recruitment in slow growing, poor prognosis colorectal cancers.

Abstract To investigate how the molecular programs of cancer cells shape their crosstalk with the tumor microenvironment, we generated mouse xenografts from 19 human colorectal cancer (CRC) cell lines and performed RNA sequencing, separately profiling human (cancer) and murine (stromal) transcriptomes. Xenograft growth rates varied markedly across lines and correlated with stromal abundance: slower-growing tumors accumulated more stroma. Cancer cells from these stroma-rich, slow tumors displayed a coordinated transcriptional program involving epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) remodeling, which we termed the EMT-Matrix Remodeling (EMR) signature. The corresponding stromal fibroblasts exhibited matrix-remodeling activity defined by a matrix-remodeling cancer-associated fibroblast (mrCAF) signature. Integration of human CRC bulk, single-cell, and spatial transcriptomics confirmed the co-occurrence and spatial proximity of EMR cancer cells and mrCAFs, both associated with adverse clinical outcome. A pan-cancer analysis revealed that EMR and mrCAF signatures recur across multiple tumor types, where they similarly mark aggressive disease. Collectively, these findings uncover a conserved mechanism of ECM remodeling driven by reciprocal cancer-stromal interactions: cancer cells with an EMT-like, matrix-remodeling phenotype recruit and instruct CAFs to reshape the tumor microenvironment, thereby promoting tumor progression. Citation Format: Claudio Isella, Anna Cassisa, Consalvo Petti, Alexandra Ambra Ulla, Jie Zhou, Carlo Leonardi, Roberta Porporato, Daniela Cantarella, Letizia Franco, Cinzia Benetti, Jill Carol Rubinstein, Jessica Erriquez, Mariangela Russo, Francesco Sassi, Elena Grassi, Ymera Pignochino, Alberto Puliafito, Ivan Molineris, Rebecca Senetta, Andrea Bertotti, Livio Trusolino, Jeffrey H. Chuang, Alberto Bardelli, Enzo Medico. A cancer cell intrinsic program for matrix remodeling and CAF recruitment in slow growing, poor prognosis colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 776.