Caloric restriction leads to druggable LSD1-dependent cancer stem cells expansion.
Rani PallaviElena GattiTiphanie DurfortMassimo StendardoRoberto RavasioTommaso LeonardiPaolo FalvoBruno Achutti DusoSimona PunziAobuli XierailiAndrea PolazziDoriana VerrelliDeborah TrastulliSimona RonzoniSimone FrascollaGiulia PerticariMohamed ElgendyMario VarasiEmanuela ColomboMarco GiorgioLuisa LanfranconeSaverio MinucciLuca MazzarellaPier Giuseppe PelicciPublished in: Nature communications (2024)
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.
Keyphrases
- acute myeloid leukemia
- type diabetes
- cell cycle arrest
- cell cycle
- dendritic cells
- stem cells
- pi k akt
- bone marrow
- cell death
- drug induced
- induced apoptosis
- oxidative stress
- signaling pathway
- liver failure
- endoplasmic reticulum stress
- genome wide
- immune response
- binding protein
- diabetic rats
- high glucose
- glycemic control
- clinical trial
- cancer stem cells
- insulin resistance
- respiratory failure
- mouse model
- dna methylation
- high fat diet induced
- adipose tissue
- helicobacter pylori infection
- big data
- gene expression
- high resolution
- atrial fibrillation
- aortic dissection
- allogeneic hematopoietic stem cell transplantation
- artificial intelligence
- endothelial cells
- radiofrequency ablation
- single molecule