Mcl-1 deficiency in murine livers leads to nuclear polyploidisation and mitotic errors: Implications for hepatocellular carcinoma
Laure-Alix Clerbaux,
Pierre Cordier,
Nina Desboeufs,
Kristian Unger,
Peter Leary,
Gabriel Semere,
Yannick Boege,
Lap Kwan Chan,
Chantal Desdouets,
Massimo Lopes,
Achim Weber
Affiliations
Laure-Alix Clerbaux
Department of Pathology and Molecular Pathology, University Hospital Zürich (USZ), Zurich, Switzerland; Institute of Molecular Cancer Research (IMCR), University of Zürich (UZH), Zurich, Switzerland; Corresponding authors. Address: Department of Pathology and Molecular Pathology, University Hospital Zürich (USZ), Rämistrasse 100, 8091 Zürich, Switzerland. Tel: +41 44 255 11 11.
Pierre Cordier
Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Paris, France; Genomic Instability, Metabolism, Immunity and Liver Tumorigenesis Laboratory, Equipe Labellisée LIGUE 2023, Paris, France
Nina Desboeufs
Department of Pathology and Molecular Pathology, University Hospital Zürich (USZ), Zurich, Switzerland; Institute of Molecular Cancer Research (IMCR), University of Zürich (UZH), Zurich, Switzerland
Kristian Unger
Research Unit Radiation Cytogenetics, Helmholtz Munich, Neuherberg, Germany; Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany; Bavarian Cancer Research Center (BZKF), Munich, Germany
Peter Leary
Institute of Molecular Cancer Research (IMCR), University of Zürich (UZH), Zurich, Switzerland; Functional Genomics Center Zurich, University of Zürich and ETH Zürich, Zurich, Switzerland
Gabriel Semere
Department of Pathology and Molecular Pathology, University Hospital Zürich (USZ), Zurich, Switzerland
Yannick Boege
Department of Pathology and Molecular Pathology, University Hospital Zürich (USZ), Zurich, Switzerland
Lap Kwan Chan
Department of Pathology and Molecular Pathology, University Hospital Zürich (USZ), Zurich, Switzerland
Chantal Desdouets
Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Paris, France; Genomic Instability, Metabolism, Immunity and Liver Tumorigenesis Laboratory, Equipe Labellisée LIGUE 2023, Paris, France
Massimo Lopes
Institute of Molecular Cancer Research (IMCR), University of Zürich (UZH), Zurich, Switzerland
Achim Weber
Department of Pathology and Molecular Pathology, University Hospital Zürich (USZ), Zurich, Switzerland; Institute of Molecular Cancer Research (IMCR), University of Zürich (UZH), Zurich, Switzerland; Corresponding authors. Address: Department of Pathology and Molecular Pathology, University Hospital Zürich (USZ), Rämistrasse 100, 8091 Zürich, Switzerland. Tel: +41 44 255 11 11.
Background & Aims: Mcl-1, an antiapoptotic protein overexpressed in many tumours, including hepatocellular carcinoma (HCC), represents a promising target for cancer treatment. Although Mcl-1 non-apoptotic roles might critically influence the therapeutic potential of Mcl-1 inhibitors, these functions remain poorly understood. We aimed to investigate the effects of hepatic Mcl-1 deficiency (Mcl-1Δhep) on hepatocyte ploidy and cell cycle in murine liver in vivo and the possible implications on HCC. Methods: Livers of young Mcl-1Δhep and wild-type (WT) mice were analysed for ploidy profile, mitotic figures, in situ chromosome segregation, gene set enrichment analysis and were subjected to two-thirds partial hepatectomy to assess Mcl-1 deficiency effect on cell cycle progression in vivo. Mcl-1Δhep tumours in older mice were analysed for ploidy profile, chromosomal instability, and mutational signatures via whole exome sequencing. Results: In young mice, Mcl-1 deficiency leads to nuclear polyploidy and to high rates of mitotic errors with abnormal spindle figures and chromosome mis-segregation along with a prolonged spindle assembly checkpoint activation signature. Chromosomal instability and altered ploidy profile are observed in Mcl-1Δhep tumours of old mice as well as a characteristic mutational signature of currently unknown aetiology. Conclusions: Our study suggests novel non-apoptotic effects of Mcl-1 deficiency on nuclear ploidy, mitotic regulation, and chromosomal segregation in hepatocytes in vivo. In addition, the Mcl-1 deficiency characteristic mutational signature might reflect mitotic issues. These results are of importance to consider when developing anti-Mcl-1 therapies to treat cancer. Impact and implications: Although Mcl-1 inhibitors represent promising hepatocellular carcinoma treatment, the still poorly understood non-apoptotic roles of Mcl-1 might compromise their successful clinical application. Our study shows that Mcl-1 deficiency leads to nuclear polyploidy, mitotic errors, and aberrant chromosomal segregation in hepatocytes in vivo, whereas hepatocellular tumours spontaneously induced by Mcl-1 deficiency exhibit chromosomal instability and a mutational signature potentially reflecting mitotic issues. These results have potential implications for the development of anti-Mcl-1 therapies to treat hepatocellular carcinoma, especially as hyperproliferative liver is a clinically relevant situation.
