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Caloric restriction leads to druggable LSD1-dependent cancer stem cells expansion

Author

Listed:
  • Rani Pallavi

    (Department of Experimental Oncology, IEO European Institute of Oncology IRCCS)

  • Elena Gatti

    (Department of Experimental Oncology, IEO European Institute of Oncology IRCCS)

  • Tiphanie Durfort

    (Department of Experimental Oncology, IEO European Institute of Oncology IRCCS)

  • Massimo Stendardo

    (Department of Experimental Oncology, IEO European Institute of Oncology IRCCS)

  • Roberto Ravasio

    (Department of Experimental Oncology, IEO European Institute of Oncology IRCCS)

  • Tommaso Leonardi

    (Fondazione Istituto Italiano di Tecnologia)

  • Paolo Falvo

    (Department of Experimental Oncology, IEO European Institute of Oncology IRCCS)

  • Bruno Achutti Duso

    (Department of Experimental Oncology, IEO European Institute of Oncology IRCCS)

  • Simona Punzi

    (Department of Experimental Oncology, IEO European Institute of Oncology IRCCS)

  • Aobuli Xieraili

    (Department of Experimental Oncology, IEO European Institute of Oncology IRCCS)

  • Andrea Polazzi

    (Department of Experimental Oncology, IEO European Institute of Oncology IRCCS)

  • Doriana Verrelli

    (Department of Experimental Oncology, IEO European Institute of Oncology IRCCS)

  • Deborah Trastulli

    (Department of Experimental Oncology, IEO European Institute of Oncology IRCCS)

  • Simona Ronzoni

    (Department of Experimental Oncology, IEO European Institute of Oncology IRCCS)

  • Simone Frascolla

    (Department of Experimental Oncology, IEO European Institute of Oncology IRCCS)

  • Giulia Perticari

    (Department of Experimental Oncology, IEO European Institute of Oncology IRCCS)

  • Mohamed Elgendy

    (Department of Experimental Oncology, IEO European Institute of Oncology IRCCS
    Technische Universität Dresden
    Technische Universität Dresden
    Technische Universität Dresden)

  • Mario Varasi

    (IFOM ETS - The AIRC Institute of Molecular Oncology)

  • Emanuela Colombo

    (Department of Experimental Oncology, IEO European Institute of Oncology IRCCS
    Universita’ Statale di Milano)

  • Marco Giorgio

    (Department of Experimental Oncology, IEO European Institute of Oncology IRCCS
    University of Padova)

  • Luisa Lanfrancone

    (Department of Experimental Oncology, IEO European Institute of Oncology IRCCS)

  • Saverio Minucci

    (Department of Experimental Oncology, IEO European Institute of Oncology IRCCS
    Universita’ Statale di Milano)

  • Luca Mazzarella

    (Department of Experimental Oncology, IEO European Institute of Oncology IRCCS)

  • Pier Giuseppe Pelicci

    (Department of Experimental Oncology, IEO European Institute of Oncology IRCCS
    Universita’ Statale di Milano)

Abstract

Caloric Restriction (CR) has established anti-cancer effects, but its clinical relevance and molecular mechanism remain largely undefined. Here, we investigate CR’s impact on several mouse models of Acute Myeloid Leukemias, including Acute Promyelocytic Leukemia, a subtype strongly affected by obesity. After an initial marked anti-tumor effect, lethal disease invariably re-emerges. Initially, CR leads to cell-cycle restriction, apoptosis, and inhibition of TOR and insulin/IGF1 signaling. The relapse, instead, is associated with the non-genetic selection of Leukemia Initiating Cells and the downregulation of double-stranded RNA (dsRNA) sensing and Interferon (IFN) signaling genes. The CR-induced adaptive phenotype is highly sensitive to pharmacological or genetic ablation of LSD1, a lysine demethylase regulating both stem cells and dsRNA/ IFN signaling. CR + LSD1 inhibition leads to the re-activation of dsRNA/IFN signaling, massive RNASEL-dependent apoptosis, and complete leukemia eradication in ~90% of mice. Importantly, CR-LSD1 interaction can be modeled in vivo and in vitro by combining LSD1 ablation with pharmacological inhibitors of insulin/IGF1 or dual PI3K/MEK blockade. Mechanistically, insulin/IGF1 inhibition sensitizes blasts to LSD1-induced death by inhibiting the anti-apoptotic factor CFLAR. CR and LSD1 inhibition also synergize in patient-derived AML and triple-negative breast cancer xenografts. Our data provide a rationale for epi-metabolic pharmacologic combinations across multiple tumors.

Suggested Citation

  • Rani Pallavi & Elena Gatti & Tiphanie Durfort & Massimo Stendardo & Roberto Ravasio & Tommaso Leonardi & Paolo Falvo & Bruno Achutti Duso & Simona Punzi & Aobuli Xieraili & Andrea Polazzi & Doriana Ve, 2024. "Caloric restriction leads to druggable LSD1-dependent cancer stem cells expansion," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44348-y
    DOI: 10.1038/s41467-023-44348-y
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