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

Rani Pallavi, Elena Gatti, Tiphanie Durfort, Massimo Stendardo, Roberto Ravasio, Tommaso Leonardi, Paolo Falvo, Bruno Achutti Duso, Simona Punzi, Aobuli Xieraili, Andrea Polazzi, Doriana Verrelli, Deborah Trastulli, Simona Ronzoni, Simone Frascolla, Giulia Perticari, Mohamed Elgendy, Mario Varasi, Emanuela Colombo, Marco Giorgio, Luisa Lanfrancone, Saverio Minucci, Luca Mazzarella () and Pier Giuseppe Pelicci ()
Additional contact information
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
Mario Varasi: IFOM ETS - The AIRC Institute of Molecular Oncology
Emanuela Colombo: Department of Experimental Oncology, IEO European Institute of Oncology IRCCS
Marco Giorgio: Department of Experimental Oncology, IEO European Institute of Oncology IRCCS
Luisa Lanfrancone: Department of Experimental Oncology, IEO European Institute of Oncology IRCCS
Saverio Minucci: Department of Experimental Oncology, IEO European Institute of Oncology IRCCS
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

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-023-44348-y

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