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

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.