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
  • 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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