|Title||Cancer cells escape autophagy inhibition via NRF2-induced macropinocytosis.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Su H, Yang F, Fu R, Li X, French R, Mose E, Pu X, Trinh B, Kumar A, Liu J, Antonucci L, Todoric J, Liu Y, Hu Y, Diaz-Meco MT, Moscat J, Metallo CM, Lowy AM, Sun B, Karin M|
|Date Published||2021 May 10|
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.
|Alternate Journal||Cancer Cell|
|PubMed Central ID||PMC8119368|
|Grant List||P01 DK098108 / DK / NIDDK NIH HHS / United States |
R01 CA211794 / CA / NCI NIH HHS / United States
R37 AI043477 / AI / NIAID NIH HHS / United States
Jorge Moscat, Ph.D. Maria Diaz-Meco Conde, Ph.D.