Stroma-Dominant Colorectal Cancer Harbors CAF-Rich Spatial Architecture and EMT-Associated Cancer Cell Plasticity...

Colorectal cancers (CRCs) include stroma-dominant tumors with desmoplasia and differentiated, gland-forming tumors with little stroma. We asked whether this difference reflects stromal abundance alone or also involves a distinct cancer cell state. HEST-1K sections were classified as M-type (stroma-dominant; five patient/tissue units) or D-type (differentiated and cancer cell-dominant; seven units). Prespecified EMT/pEMT, ECM/integrin, YAP/TAZ-TEAD, and DTP/persister gene sets were examined across spatial, bulk, and single-cell datasets and patient-derived malignant ascites cultures. M-type tumors contained broader CAF-rich compartments and higher activity of all four programs in EPCAM/KRT-high regions, including epithelial-dense tumor cores. Activity was greatest near CAF-rich areas. In GSE39582, EMT/pEMT, ECM/integrin, DTP/persister, and invasive epithelial programs were independently associated with recurrence. Ascites-derived cultures from stroma-dominant tumors showed higher ECM/integrin and survival programs. Independent institutional analyses supported the public data findings: focused real-time PCR showed higher MAPK/TGF-beta-related gene expression in M-type-derived than in D-type-derived ascites cells, and IHC showed stronger epithelial CD44v6 expression in M-type primary tumors and metastatic lymph node lesions. CAF co-culture increased VIM-promoter activity. These findings characterize stroma-dominant CRC as a spatially organized ecosystem in which a CAF-rich compartment is associated with stress-adapted cancer cell programs. Its poor prognosis may therefore involve not only stromal abundance but also a morphology-associated cancer cell state detectable after dissemination.