2. Academic Validation
  3. CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer

CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer

  • Nat Commun. 2025 Jan 9;16(1):541. doi: 10.1038/s41467-024-55605-z.
Dorian V Ziegler 1,  Kanishka Parashar 1,  Lucia Leal-Esteban 1,  Jaime López-Alcalá 1 2,  Wilson Castro 3,  Nadège Zanou 4,  Laia Martinez-Carreres 1,  Katharina Huber 1,  Xavier Pascal Berney 1,  María M Malagón 2 5,  Catherine Roger 1,  Marie-Agnès Berger 6,  Yves Gouriou 6,  Giulia Paone 1,  Hector Gallart-Ayala 7,  George Sflomos 8,  Carlos Ronchi 8,  Julijana Ivanisevic 7,  Cathrin Brisken 8 9,  Jennifer Rieusset 6,  Melita Irving 3,  Lluis Fajas 10 11
Affiliations

Affiliations

  • 1 Center for Integrative Genomics, University of Lausanne, Faculty of Biology and Medicine, Lausanne, Switzerland.
  • 2 Department of Cell Biology, Physiology and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/University of Córdoba/Reina Sofía University Hospital, Córdoba, Spain.
  • 3 Ludwig Institute for Cancer Research, University of Lausanne, Faculty of Biology and Medicine, Lausanne, Switzerland.
  • 4 Institute of Sport Sciences and Department of Biomedical Sciences, University of Lausanne, Faculty of Biology and Medicine, Lausanne, Switzerland.
  • 5 CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain.
  • 6 Laboratoire CarMeN, UMR INSERM U1060/INRA U1397, Université Claude Bernard Lyon1, F-69310, Pierre-Bénite, France.
  • 7 Metabolomics Platform, University of Lausanne, Faculty of Biology and Medicine, Rue du Bugnon 19, 1005, Lausanne, Switzerland.
  • 8 ISREC-Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
  • 9 The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
  • 10 Center for Integrative Genomics, University of Lausanne, Faculty of Biology and Medicine, Lausanne, Switzerland. lluis.fajas@unil.ch.
  • 11 Inserm, Occitanie Méditerranée, Montpellier, France. lluis.fajas@unil.ch.
PMID: 39788939 DOI: 10.1038/s41467-024-55605-z
Abstract

The energetic demands of proliferating cells during tumorigenesis require close coordination between the cell cycle and metabolism. While CDK4 is known for its role in cell proliferation, its metabolic function in Cancer, particularly in triple-negative breast Cancer (TNBC), remains unclear. Our study, using genetic and pharmacological approaches, reveals that CDK4 inactivation only modestly impacts TNBC cell proliferation and tumor formation. Notably, CDK4 depletion or long-term CDK4/6 inhibition confers resistance to Apoptosis in TNBC cells. Mechanistically, CDK4 enhances mitochondria-endoplasmic reticulum contact (MERCs) formation, promoting mitochondrial fission and ER-mitochondrial calcium signaling, which are crucial for TNBC metabolic flexibility. Phosphoproteomic analysis identified CDK4's role in regulating PKA activity at MERCs. In this work, we highlight CDK4's role in mitochondrial Apoptosis inhibition and suggest that targeting MERCs-associated metabolic shifts could enhance TNBC therapy.

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