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

ABSTRACT: 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.

SUBMITTER: Das BK

PROVIDER: S-EPMC10394170 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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

Das Bhaba K BK Kannan Aarthi A Velasco Graham J GJ Kunika Mikaela D MD Lambrecht Nils N Nguyen Quy Q Zhao Haibo H Wu Jie J Gao Ling L

Cell reports. Medicine 20230707 7

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 ph ...[more]

PMID: 37421947

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Project description:OPINION STATEMENT:Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. Early-stage disease can be cured with surgical resection and radiotherapy (RT). Sentinel lymph node biopsy (SLNB) is an important staging tool, as a microscopic MCC is frequently identified. Adjuvant RT to the primary excision site and regional lymph node bed may improve locoregional control. However, newer studies confirm that patients with biopsy-negative sentinel lymph nodes may not benefit from regional RT. Advanced MCC currently lacks a highly effective treatment as responses to chemotherapy are not durable. Recent work suggests that immunotherapy targeting the programmed cell death receptor 1/programmed cell death ligand 1 (PD-1/PD-L1) checkpoint holds great promise in treating advanced MCC and may provide durable responses in a portion of patients. At the same time, high-throughput sequencing studies have demonstrated significant differences in the mutational profiles of tumors with and without the Merkel cell polyomavirus (MCV). An important secondary endpoint in the ongoing immunotherapy trials for MCC will be determining if there is a response difference between the virus-positive MCC tumors that typically lack a large mutational burden and the virus-negative tumors that have a large number of somatic mutations and predicted tumor neoantigens. Interestingly, sequencing studies have failed to identify a highly recurrent activated driver pathway in the majority of MCC tumors. This may explain why targeted therapies can demonstrate exceptional responses in case reports but fail when treating all comers with MCC. Ultimately, a precision medicine approach may be more appropriate for treating MCC, where identified driver mutations are used to direct targeted therapies. At a minimum, stratifying patients in future clinical trials based on tumor viral status should be considered as virus-negative tumors are more likely to harbor activating driver mutations.

Dataset Information

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

Publications

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

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