PKM2 Isoform-Specific Deletion Reveals a Differential Requirement for Pyruvate Kinase in Tumor Cells
Menée à l'aide d'un modèle murin, cette étude met en évidence des mécanismes par lesquels l'absence d'expression de PKM2 favorise la croissance d'une tumeur mammaire associée à la perte de BRCA1
The pyruvate kinase M2 isoform (PKM2) is expressed in cancer and plays a role in regulating anabolic metabolism. To determine whether PKM2 is required for tumor formation or growth, we generated mice with a conditional allele that abolishes PKM2 expression without disrupting PKM1 expression. PKM2 deletion accelerated mammary tumor formation in a Brca1-loss-driven model of breast cancer. PKM2 null tumors displayed heterogeneous PKM1 expression, with PKM1 found in nonproliferating tumor cells and no detectable pyruvate kinase expression in proliferating cells. This suggests that PKM2 is not necessary for tumor cell proliferation and implies that the inactive state of PKM2 is associated with the proliferating cell population within tumors, whereas nonproliferating tumor cells require active pyruvate kinase. Consistent with these findings, variable PKM2 expression and heterozygous PKM2 mutations are found in human tumors. These data suggest that regulation of PKM2 activity supports the different metabolic requirements of proliferating and nonproliferating tumor cells. "PKM2 is not required by all tumor cells "The need for pyruvate kinase is most apparent in nonproliferating tumor cells "PKM2 expression is variable in human cancers "Recurrent point mutations disrupting pyruvate kinase are found in human cancers Loss of PKM2, an isoform of pyruvate kinase that was previously associated with a number of cancers, is in fact found to exacerbate tumor growth. Proliferating tumor cells do not seem to require M1 isoform either, suggesting that it is the inactive state of PKM2 that these cells seem to prefer.