Genetic Analysis Reveals AMPK Is Required to Support Tumor Growth in Murine Kras-Dependent Lung Cancer Models

Abstract

Highlights d AMPK does not phenocopy the lung tumor-suppressor role of its activator LKB1 d AMPK deletion reduces tumor burden in KrasG12D and Kras p53 À/À lung cancer models d AMPK is required during glucose deprivation to induce Tfeb and Tfe3 activation d Tfe3 activity is required for growth of mouse lung tumors

AMPK-Mediated Lysosome Biogenesis in Lung Cancer Growth

“…Cancer cells must adapt to metabolic stress during tumor progression. In this issue of Cell Metabolism, Eichner et al (2019) report that lung cancer development in genetically engineered mice requires the energy sensor AMP-activated protein kinase (AMPK). Their findings suggest that AMPK-mediated induction of lysosomal function supports cancer cell fitness, particularly during the early stages of tumorigenesis.…”

“…By contrast, studies using cancer cell lines and transformed primary cells have shown that AMPK deficiency leads to metabolic defects that attenuate malignant growth (Chhipa et al, 2018;Jeon et al, 2012;Laderoute et al, 2006;Saito et al, 2015). In this issue of Cell Metabolism, Eichner and colleagues address this question in the context of the initiation and progression of tumors arising from normal cells in their native tissue setting using genetically engineered mouse models (GEMMs) (Eichner et al, 2019). Eichner et al (2019) focused on lung cancer, a malignancy in which LKB1/ STK11 loss-of-function mutations are common and frequently co-exist with KRAS-activating mutations.…”

“…In this issue of Cell Metabolism, Eichner and colleagues address this question in the context of the initiation and progression of tumors arising from normal cells in their native tissue setting using genetically engineered mouse models (GEMMs) (Eichner et al, 2019). Eichner et al (2019) focused on lung cancer, a malignancy in which LKB1/ STK11 loss-of-function mutations are common and frequently co-exist with KRAS-activating mutations. Focal activation of mutant Kras G12D in the mouse lung epithelium promotes adenoma (K mice) and synergizes with p53 or Lkb1 inactivation (KP and KL models) to drive adenoma to adenocarcinoma progression.…”

“…The strongest impact was seen in KP mice in which AMPK loss markedly reduced the number of large invasive adenocarcinomas and decreased overall tumor cell proliferation rates. Eichner et al (2019) speculated that this deleterious effect was due to a requirement for AMPK in metabolic stress resistance. Using cultured KP lung cancer cell lines, they found that ablation of AMPK impeded growth in low-glucose medium but not in nutrient-replete conditions.…”

“…This effect was associated with failure to upregulate autophagy and lysosomal genes that normally facilitate nutrient scavenging and recycling ( Figure 1A) (Perera and Zoncu, 2016). Eichner et al (2019) relate this defect to a requirement for AMPK in activating the Tfe3 and Tfeb transcription factors. Accordingly, genetic inactivation of Tfe3 impaired tumor growth of implanted KP tumor cells in vivo.…”