2. Academic Validation
  3. Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer

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

  • Nat Commun. 2022 Apr 21;13(1):2177. doi: 10.1038/s41467-022-29824-1.
Martina Troiani  # 1 2 3,  Manuel Colucci  # 1 2 4,  Mariantonietta D'Ambrosio 1 2 4,  Ilaria Guccini 5,  Emiliano Pasquini 1 2,  Angelica Varesi 1 2,  Aurora Valdata 1 2,  Simone Mosole 1 2,  Ajinkya Revandkar 1 2 6,  Giuseppe Attanasio 1 2,  Andrea Rinaldi 1 2,  Anna Rinaldi 7 8,  Marco Bolis 1 2 3 9,  Pietro Cippà 7 8,  Andrea Alimonti 10 11 12 13
Affiliations

Affiliations

  • 1 Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland (IOSI), CH6500, Bellinzona, Switzerland.
  • 2 Università della Svizzera Italiana, CH6900, Lugano, Switzerland.
  • 3 Bioinformatics Core Unit, Swiss Institute of Bioinformatics, TI, 6500, Bellinzona, Switzerland.
  • 4 Faculty of Biology and Medicine, University of Lausanne UNIL, CH1011, Lausanne, Switzerland.
  • 5 Institute of Molecular Health Sciences, ETH Zurich, CH8093, Zurich, Switzerland.
  • 6 Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, 02129, USA.
  • 7 Department of Medicine, Division of Nephrology, Ente Ospedaliero Cantonale, Lugano, Switzerland.
  • 8 Laboratories for Translational Research, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.
  • 9 Computational Oncology Unit, Department of Oncology, Istituto di Ricerche Farmacologiche 'Mario Negri' IRCCS, 20156, Milano, Italy.
  • 10 Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland (IOSI), CH6500, Bellinzona, Switzerland. [email protected].
  • 11 Università della Svizzera Italiana, CH6900, Lugano, Switzerland. [email protected].
  • 12 Department of Health Sciences and Technology (D-HEST) ETH Zurich, 8093, Zurich, CH, Switzerland. [email protected].
  • 13 Department of Medicine & Veneto Institute of Molecular Medicine, University of Padova, Padova, Italy. [email protected].
  • # Contributed equally.
PMID: 35449130 DOI: 10.1038/s41467-022-29824-1
Abstract

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.

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