Aims: To determine the effect of transplantation of undifferentiated and cardiac pre-differentiated adipose stem cells compared with bone marrow mononuclear cells (BM-MNC) in a chronic model of myocardial infarction. Methods: Ninety-five Sprague–Dawley rats underwent left coronary artery ligation and after 1month received by direct intramyocardial injection either adipose derived stem cells (ADSC), cardiomyogenic cells (AD-CMG) or BM-MNC from enhanced-Green Fluorescent Protein (eGFP) mice. The control group was treated with culture medium. Heart function was assessed by echocardiography and 18F-FDG microPET. Cell engraftment, differentiation, angiogenesis and fibrosis in the scar tissue were also evaluated by (immuno)histochemistry and immunofluorescence. Results: One month after cell transplantation, ADSC induced a significant improvement in heart function (LVEF 46.3±9.6% versus 27.7±8% pre-transplant) and tissue viability (64.78±7.2% versus 55.89±6.3% pre-transplant). An increase in the degree of angiogenesis and a decrease in fibrosis were also detected. Although transplantation of AD-CMG or BM-MNC also had a positive, albeit smaller, effect on angiogenesis and fibrosis in the infarcted hearts, this benefit did not translate into a significant improvement in heart function or tissue viability. Conclusion: These results indicate that transplantation of adipose derived cells in chronic infarct provides a superior benefit to cardiac pre-differentiated ADSC and BM-MNC.

The triple-negative breast cancer (TN BC) subtype is the most aggressive form of invasive BC. Despite intensive efforts to improve BC treatments, patients with TN BC continue to exhibit poor survival, with half developing resistance to chemotherapy. Here we identify autophagy as a key mechanism in the progression and chemoresistance of a subset of TN tumors. We demonstrate that LC3B, a protein involved in autophagosome formation, is a reliable marker of poor prognosis in TN BC, validating this prognostic value at both the mRNA and protein levels in several independent cohorts. We also show that LC3B has no prognostic value for other BC subtypes (Luminal or HER2 BC), thus revealing a specific impact of autophagy on TN tumors. Autophagy is essential for the proliferative and invasive properties in 3D of TN BC cells characterized by high LC3B levels. Interestingly, the activity of the transcriptional co-activator YAP1 (Yes-associated protein 1) is regulated by the autophagy process and we identify YAP1 as a new actor in the autophagy-dependent proliferative and invasive properties of high-LC3B TN BC. Finally, inhibiting autophagy by silencing ATG5 or ATG7 significantly impaired high-LC3B TN tumor growth in vivo. Moreover, using a patient-derived TN tumor transplanted into mice, we show that an autophagy inhibitor, chloroquine, potentiates the effects of chemotherapeutic agents. Overall, our data identify LC3B as a new prognostic marker for TN BC and the inhibition of autophagy as a promising therapeutic strategy for TN BC patients.

Autophagy has been associated with oncogenesis with one of its emerging key functions being its contribution to the metabolism of tumors. Therefore, deciphering the mechanisms of how autophagy supports tumor cell metabolism is essential. Here, we demonstrate that the inhibition of autophagy induces an accumulation of lipid droplets (LD) due to a decrease in fatty acid β-oxidation, that leads to a reduction of oxidative phosphorylation (OxPHOS) in acute myeloid leukemia (AML), but not in normal cells. Thus, the autophagic process participates in lipid catabolism that supports OxPHOS in AML cells. Interestingly, the inhibition of OxPHOS leads to LD accumulation with the concomitant inhibition of autophagy. Mechanistically, we show that the disruption of mitochondria–endoplasmic reticulum (ER) contact sites (MERCs) phenocopies OxPHOS inhibition. Altogether, our data establish that mitochondria, through the regulation of MERCs, controls autophagy that, in turn finely tunes lipid degradation to fuel OxPHOS supporting proliferation and growth in leukemia.

Key Points: Bortezomib induces the degradation of FLT3-ITD through an autophagy-dependent mechanism that contributes to cell death. This finding provides a mechanism-based rationale for the study of proteasome inhibitors in FLT3-ITD–mutant acute myeloid leukemia.