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

0582786 - ÚMG 2025 RIV US eng J - Článek v odborném periodiku
Pallavi, R. - Gatti, E. - Durfort, T. - Stendardo, M. - Ravasio, R. - Leonardi, T. - Falvo, P. - Duso, B. A. - Punzi, S. - Xieraili, A. - Polazzi, A. - Verrelli, D. - Trastulli, D. - Ronzoni, S. - Frascolla, S. - Perticari, G. - Elgendy, Mohamed - Varasi, M. - Colombo, E. - Giorgio, M. - Lanfrancone, L. - Minucci, S. - Mazzarella, L. - Pelicci, P. G.
Caloric restriction leads to druggable LSD1-dependent cancer stem cells expansion.
Nature Communications. Roč. 15, č. 1 (2024), č. článku 828. E-ISSN 2041-1723
Institucionální podpora: RVO:68378050
Klíčová slova: growth-factor-i * expression analysis * gene-expression * acute-leukemia * apoptosis * differentiation * activation * trail * alpha * proliferation
Obor OECD: Cell biology
Impakt faktor: 16.6, rok: 2022
Způsob publikování: Open access
https://www.nature.com/articles/s41467-023-44348-y

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 similar to 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.
Trvalý link: https://hdl.handle.net/11104/0352875