Single-cell multimodal profiling of pan-cancer cell lines uncovers gene regulatory principles underlying intrinsic cell states and environmental features.
| Publication Type | Academic Article |
| Authors | Xu Z, Ugurbil A, Kwan J, Schaefer C, Abdulraouf A, Lu Z, Tang E, Zhou W, Cao J |
| Journal | Nat Commun |
| Volume | 17 |
| Issue | 1 |
| Date Published | 07/23/2026 |
| ISSN | 2041-1723 |
| Keywords | Single-Cell Analysis, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Neoplasms |
| Abstract | Cancer arises from genetic and epigenetic alterations that reshape chromatin, transcriptional regulation, and malignant cell states. To chart cancer-intrinsic regulatory programs, we build a pan-cancer single-cell atlas of 60 cancer cell lines spanning 16 tissue origins and 20 cancer types, comprising 240,957 snRNA-seq and 223,347 snATAC-seq profiles. Integrative analyses reveal cell-state heterogeneity, core gene-regulatory networks, and a conserved EMT axis transcending tissue of origin; copy-number analysis identifies transcription factor amplification and hyperactivation as drivers of state reprogramming. Comparing cutaneous melanoma with acral melanoma, a rare subtype underrepresented in previous studies, uncovers a universal inflammation-suppressive program in acral and an inflamed landscape in cutaneous melanoma, with JAK-STAT activity as the central discriminator. Integrating data across models and patient cohorts links tumor-intrinsic regulation to microenvironmental composition and therapeutic response. By profiling rare alongside common subtypes, this atlas offers a resource for mapping pan-cancer and subtype-specific regulatory programs shaping cell-state plasticity. |
| DOI | 10.1038/s41467-026-75360-7 |
| PubMed ID | 42493507 |
| PubMed Central ID | PMC13396447 |