Origins and heterogeneity of colorectal cancer.

Cell-of-origin position along the vertical axis of the intestinal crypt is linked to distinct oncogenic escape mechanisms, shaping morphologically discrete precursor lesions and later colorectal cancer heterogeneity.

• Why it matters: Regional crypt niches and morphogenetic constraints mean tumor initiation depends on how a neoplastic clone evades local homeostatic control, but how origin position maps to plasticity and outcomes is unclear.
• What they did: The work analyzes how vertical crypt position relates to stem-cell plasticity mechanisms, clonal dynamics at the pre-cancer stage, and the emergence of distinct carcinogenesis pathways and precursor lesion morphologies.
• The result: Origin-linked pathways are proposed to generate morphologically discrete precursor lesions that progress into molecularly heterogeneous colorectal cancer subtypes with different clinicopathological features, therapeutic outcomes, and phenotypic adaptation, resistance, and metastasis.

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