Cancer cells escape autophagy inhibition via NRF2-induced macropinocytosis
Menée in vitro et à l'aide de xénogreffes d'adénocarcinome canalaire du pancréas sur des modèles murins, cette étude met en évidence un mécanisme par lequel les cellules cancéreuses, via la macropinocytose induite par le facteur de transcription NRF2, peuvent s'alimenter et se développer malgré l'inhibition de l'autophagie
Many cancers, including pancreatic ductal adenocarcinoma (PDAC), depend on autophagy-mediated scavenging and recycling of intracellular macromolecules, suggesting that autophagy blockade should cause tumor starvation and regression. However, until now autophagy-inhibiting monotherapies have not demonstrated potent anti-cancer activity. We now show that autophagy blockade prompts established PDAC to upregulate and utilize an alternative nutrient procurement pathway: macropinocytosis (MP) that allows tumor cells to extract nutrients from extracellular sources and use them for energy generation. The autophagy to MP switch, which may be evolutionarily conserved and not cancer cell restricted, depends on activation of transcription factor NRF2 by the autophagy adaptor p62/SQSTM1. NRF2 activation by oncogenic mutations, hypoxia, and oxidative stress also results in MP upregulation. Inhibition of MP in autophagy-compromised PDAC elicits dramatic metabolic decline and regression of transplanted and autochthonous tumors, suggesting the therapeutic promise of combining autophagy and MP inhibitors in the clinic.
Cancer Cell 2021