Single-cell dissection of Merkel cell carcinoma heterogeneity unveils transcriptomic plasticity and therapeutic vulnerabilities

• Published in: Cell reports. Medicine Vol. 4; no. 7; p. 101101
• Main Authors: Das, Bhaba K., Kannan, Aarthi, Velasco, Graham J., Kunika, Mikaela D., Lambrecht, Nils, Nguyen, Quy, Zhao, Haibo, Wu, Jie, Gao, Ling
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.07.2023; Elsevier
• Subjects: Carcinoma, Merkel Cell - drug therapy; Carcinoma, Merkel Cell - genetics; Carcinoma, Merkel Cell - pathology; cellular plasticity; copanlisib; epigenetics; Gene Expression Profiling; Humans; Immunotherapy; immunotherapy resistance; Merkel cell carcinoma; neuroendocrine carcinoma; single cell RNA-seq; skin cancer; Skin Neoplasms - drug therapy; Skin Neoplasms - genetics; Skin Neoplasms - pathology; Transcriptome - genetics; tumor cell state; tumor heterogeneity; skin cancer; single cell RNA-seq; Merkel cell carcinoma; copanlisib; neuroendocrine carcinoma; cellular plasticity; tumor cell state; immunotherapy resistance; epigenetics; tumor heterogeneity
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2023.101101

Merkel cell carcinoma (MCC), a rare but aggressive skin cancer, remains a challenge in the era of precision medicine. Immune checkpoint inhibitors (ICIs), the only approved therapy for advanced MCC, are impeded by high primary and acquired resistance. Hence, we dissect transcriptomic heterogeneity at single-cell resolution in a panel of patient tumors, revealing phenotypic plasticity in a subset of treatment-naive MCC. The tumor cells in a “mesenchymal-like” state are endowed with an inflamed phenotype that portends a better ICI response. This observation is also validated in the largest whole transcriptomic dataset available from MCC patient tumors. In contrast, ICI-resistant tumors predominantly express neuroepithelial markers in a well-differentiated state with “immune-cold” landscape. Importantly, a subtle shift to “mesenchymal-like” state reverts copanlisib resistance in primary MCC cells, highlighting potential strategies in patient stratification for therapeutics to harness tumor cell plasticity, augment treatment efficacy, and avert resistance. [Display omitted] •Tumor cell states and distinct immune landscapes in MCC patient tumors•“Mesenchymal-like” state with an inflamed phenotype•“Well-differentiated neuroepithelial” state in “immune-cold” ICI-resistant MCC•Subtle shift to “mesenchymal-like” state reverts copanlisib insensitivity Das et al. utilize single-cell RNA sequencing to uncover transcriptomic heterogeneity with distinct immune landscapes in Merkel cell carcinoma patient tumors. The inherent cell states are present in patient-derived cell lines devoid of tumor microenvironment, underscoring intrinsic cellular plasticity amenable to manipulation to avert and revert therapeutic resistance, a potential clinically actionable finding.