Cancer arises from extensive genetic and epigenetic alterations that reshape chromatin, transcriptional regulation, and malignant cell states. To systematically chart cancer-intrinsic regulatory programs, we constructed a pan-cancer single-cell transcriptomic and epigenomic atlas encompassing 60 human cell lines representing 16 tissue origins and 20 cancer types, comprising 240,957 single-nucleus RNA-seq and 223,347 single-nucleus ATAC-seq profiles. Integrative analyses revealed extensive pan-cancer cell-state heterogeneity, core gene-regulatory networks, and a conserved epithelial-mesenchymal transition (EMT) axis that transcends tissue of origin. Copy-number variation analysis identified transcription factor amplification and downstream hyperactivation as key drivers of cancer cell-state reprogramming. To further examine how regulatory programs diverge within a cancer lineage and contribute to clinically divergent outcomes, we performed a focused comparison of cutaneous melanoma with acral melanoma, a rare, UV-independent subtype underrepresented in existing pan-cancer atlases. The comparison uncovered a universal inflammation-suppressive program in acral melanoma and an inflamed regulatory landscape in cutaneous melanoma, with the JAK-STAT pathway and downstream transcriptional responses as central discriminators. Integration of single-cell and bulk datasets across models and patient cohorts further linked in vitro tumor-intrinsic gene regulations with in vivo microenvironmental composition and immunotherapy responses. Together, by extending single-cell multi-omic profiling to rare alongside common cancer subtypes, this atlas offers a resource for mapping pan-cancer and subtype-specific gene-regulatory programs that shape cancer cell-state plasticity.
Xu, Z., Ugurbil, A., Kwan, J., Schaefer, C., Abdulraouf, A., Lu, Z., Tang, E., Zhou, W., Cao, J.
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