Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer

Autor: Troiani, M., Colucci, M., D'Ambrosio, M., Guccini, I., Pasquini, E., Varesi, A., Valdata, A., Mosole, S., Revandkar, A., Attanasio, G., Rinaldi, A., Bolis, M., Cippa, P., Alimonti, A.
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Nature Communications, 13 (1)
ISSN: 2041-1723
DOI: 10.3929/ethz-b-000544955
Popis: Cells subjected to treatment with anti-cancer therapies can evade apoptosis through cellular senescence. Persistent senescent tumor cells remain metabolically active, possess a secretory phenotype, and can promote tumor proliferation and metastatic dissemination. Removal of senescent tumor cells (senolytic therapy) has therefore emerged as a promising therapeutic strategy. Here, using single-cell RNA-sequencing, we find that senescent tumor cells rely on the anti-apoptotic gene Mcl-1 for their survival. Mcl-1 is upregulated in senescent tumor cells, including cells expressing low levels of Bcl-2, an established target for senolytic therapy. While treatment with the Bcl-2 inhibitor Navitoclax results in the reduction of metastases in tumor bearing mice, treatment with the Mcl-1 inhibitor S63845 leads to complete elimination of senescent tumor cells and metastases. These findings provide insights on the mechanism by which senescent tumor cells survive and reveal a vulnerability that can be exploited for cancer therapy.
Nature Communications, 13 (1)
ISSN:2041-1723
Databáze: OpenAIRE
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