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Abstract Deciphering disease progression and the sophisticated tumor ecosystems is imperative for exploring tumorigenesis mechanisms and developing novel prevention strategies. Here, we dissected heterogeneous tissue microenvironments during malignant transitions by leveraging data from 4,972,145 single cells in 1396 samples from 62 datasets spanning 13 major tissue types. Within transitional stem-like subpopulations highly enriched in precancerous lesions and cancers, we identified 30 recurring cellular states, including hypoxia and epithelial senescence, revealing a high degree of plasticity in epithelial stem cells. By characterizing the dynamics of stem-cell crosstalk with the microenvironment along the pseudotime axis, we uncovered distinct roles of ANXA1 at different stages of tumor development. ANXA1 expression levels in stem cells were decreased from the healthy to the precancerous stages, which promoted inflammatory responses by recruiting neutrophils and regulating monocyte differentiation towards M1 macrophages. In contrast, during malignant progression, upregulated ANXA1 fostered M2 macrophage polarization and cancer-associated fibroblast transformation. Our spatiotemporal analysis further provided insights into mechanisms responsible for immunosuppression. Collectively, this study provided a systematic view of cancer origins, and suggested that restoring and maintaining the balance of inflammation and their mediators (e.g., AnxA1/FPRs signaling) may represent a novel approach to control the evolution of precancerous lesions and mitigate the risk for cancer development. Citation Format: Ruihan Luo. Single-cell landscape deciphering cancer cell-of-origin and cellular heterogeneity in malignant transformation of 13 major tissues abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr A026.
Ruihan Luo (Mon,) studied this question.