Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer.

Metabolic reprogramming is key for cancer development, yet the mechanism that sustains triple-negative breast cancer (TNBC) cell growth despite deficient pyruvate kinase M2 (PKM2) and tumor glycolysis remains to be determined. Here, we find that deficiency in tumor glycolysis activates a metabolic switch from glycolysis to fatty acid ß-oxidation (FAO) to fuel TNBC growth. We show that, in TNBC cells, PKM2 directly interacts with histone methyltransferase EZH2 to coordinately mediate epigenetic silencing of a carnitine transporter, SLC16A9. Inhibition of PKM2 leads to impaired EZH2 recruitment to SLC16A9, and in turn de-represses SLC16A9 expression to increase intracellular carnitine influx, programming TNBC cells to an FAO-dependent and luminal-like cell state. Together, these findings reveal a new metabolic switch that drives TNBC from a metabolically heterogeneous-lineage plastic cell state to an FAO-dependent-lineage committed cell state, where dual targeting of EZH2 and FAO induces potent synthetic lethality in TNBC.

Construction of n-type homogeneous to improve interfacial carrier transfer for enhanced photoelectrocatalytic hydrolysis.

Photoelectrocatalyzed hydrogen production plays an important role in the path to carbon neutrality. The construction of heterojunctions provides an ideal example of an oxygen precipitation reaction. In this work, the performance of the n-n type heterojunction CeBTC@FeBTC/NIF in the photoelectronically coupled catalytic oxygen evolution reaction (OER) reaction is presented. The efficient transfer of carriers between components enhances the catalytic activity. Besides, the construction of heterojunctions optimizes the energy level structure and increases the absorption of light, and the microstructure forms holes with a blackbody effect that also enhances light absorption. Consequently, CeBTC@FeBTC/NIF has excellent photoelectric coupling catalytic properties and requires an overpotential of only 300 mV to drive a current density of 100 mA cm-2 under illumination. More importantly, the n-n heterojunction was found to be effective in enhancing charge and photogenerated electron migration by examining the carrier density of each component and carrier diffusion at the interface.

Inhibition of ADAM9 promotes the selective degradation of KRAS and sensitizes pancreatic cancers to chemotherapy.

Kirsten rat sarcoma virus (KRAS) signaling drives pancreatic ductal adenocarcinoma (PDAC) malignancy, which is an unmet clinical need. Here, we identify a disintegrin and metalloproteinase domain (ADAM)9 as a modulator of PDAC progression via stabilization of wild-type and mutant KRAS proteins. Mechanistically, ADAM9 loss increases the interaction of KRAS with plasminogen activator inhibitor 1 (PAI-1), which functions as a selective autophagy receptor in conjunction with light chain 3 (LC3), triggering lysosomal degradation of KRAS. Suppression of ADAM9 by a small-molecule inhibitor restricts disease progression in spontaneous models, and combination with gemcitabine elicits dramatic regression of patient-derived tumors. Our findings provide a promising strategy to target the KRAS signaling cascade and demonstrate a potential modality to enhance sensitivity to chemotherapy in PDAC.