Colorectal cancer (CRC) typically follows the "normal–adenoma–carcinoma" (NAC) progression, with approximately 70–90% of cases driven by an adenomatous polyposis coli (APC) mutation-dependent pathway. The Apc-mutant (Min) mouse, valuable for dissecting gene function and mechanisms in CRC, provides an important basis for cross-species analyses with human data. Here, we performed a cross-species analysis of single-cell and spatial transcriptomic data across multiple stages of colorectal tissues in both humans and Min mice, constructing a spatiotemporal atlas. Our study identified key microenvironmental regulatory networks involved in CRC progression and highlighted the central role of epithelial–macrophage interactions within the tumor microenvironment. We further validated the suitability of the Min mouse as a model for the intrinsic Consensus Molecular Subtypes 2(iCMS2) microsatellite-stable (MSS) subtype of CRC. Focusing on the crosstalk between tumor-associated macrophages (TAMs) and epithelial cells, we identified the EFNA1–EPHA4 axis as a critical regulator promoting the immunosuppressive polarization of TAMs and enhancing tumor cell stemness. In addition, inhibition of EFNA1 was found to slow tumor growth. This study not only provides a systematic framework for mapping CRC correspondence between humans and mice, but also uncovers key molecular mechanisms underlying CRC progression and proposes promising therapeutic targets. • Built a cross-species single-cell and spatial transcriptomic atlas capturing CRC progression • Validated Apc-Min mouse as a faithful model of human iCMS2 microsatellite-stable CRC • Revealed conserved epithelial–macrophage crosstalk driving malignant transformation • Identified the EFNA1–EPHA4 axis as a key regulator of TAM polarization and tumor stemness
Zhang et al. (Wed,) studied this question.