1. Caloric restriction leads to druggable LSD1-dependent cancer stem cells expansion.
- Author
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Pallavi, Rani, Gatti, Elena, Durfort, Tiphanie, Stendardo, Massimo, Ravasio, Roberto, Leonardi, Tommaso, Falvo, Paolo, Duso, Bruno Achutti, Punzi, Simona, Xieraili, Aobuli, Polazzi, Andrea, Verrelli, Doriana, Trastulli, Deborah, Ronzoni, Simona, Frascolla, Simone, Perticari, Giulia, Elgendy, Mohamed, Varasi, Mario, Colombo, Emanuela, and Giorgio, Marco
- Subjects
CANCER stem cells ,LOW-calorie diet ,ACUTE promyelocytic leukemia ,ACUTE myeloid leukemia ,TRIPLE-negative breast cancer ,INSULIN receptors - 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. Caloric restriction (CR) has been demonstrated to have a role in tumour growth and therapy response but its effects on cancer stem cells are less known. Here, in Acute Promyelocytic Leukemia, the authors show that despite initial anti-tumour effect, CR drives the selection of leukaemia-initiating cells resulting in relapse which could be prevented by ablation of LSD1. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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