Metabolic plasticity and glucose transporter redundancy dictate lung adenocarcinoma growth

Lung cancers represent the leading cause of cancer-related deaths worldwide. These pulmonary cancers count several histological subgroups, whose non-small cell lung cancers, subject of our study. We were precisely interested in the most common subtype of non-small cell lung cancers, the adenocarcinomas, that are frequently mutated for the oncogene Kras and the tumor suppressors Tp53 and Lkb1. These tumors seeking to ensure their survival and their uncontrolled proliferation, especially modify their metabolism to sustain their increased and essential nutrient requirements. These cancer cells thus overexpress glucose transporters to augment their sugar uptake and maintain their functions. Although the high expression of certain transporters in pulmonary adenocarcinomas is associated with a poor vital prognostic, their implication in tumorigenesis remains poorly understood. Also, we focused on the two most expressed transporters in lung adenocarcinomas, GLUT1 and GLUT3, to determine and understand their putative role in the tumor cell-of-origin, but also in the initiation and growth of adenocarcinomas. To investigate these questions in vivo, we used genetically engineered mouse models, based on the frequent genetic alterations Kras, Tp53 and Lkb1. These models closely mimic human non-small cell lung cancer development. The intratracheal instillation of these mice with viral particles expressing Cre-recombinase allows the genetic recombinations and the subsequent initiation of pulmonary tumors. Being interesting in glucose transporters, we interbred the murine models KrasLSL-G12D/WT (K), KrasLSL-G12D/WT; Tp53lox/lox (KP), and KrasLSL-G12D/WT; Lkb1lox/lox (KL) with the models Slc2a1lox/lox (G1) and/or Slc2a3lox/lox (G3). Thus, we could specifically initiate the development of tumors expressing the oncogenic mutation KrasG12D, the deletion or not of Tp53 or Lkb1, and with or without glucose transporter Glut1 and/or Glut3. Our in vivo study then revealed that the only deletion of Glut1 in tumor cells was insufficient to impair their growth, and this, independently of the cell-of-origin or the stage of the lesions. Using electron microscopy and 13C-glucose tracing with correlated nanoscale secondary ion mass spectrometry (NanoSIMS), we demonstrated that the glucose-derived biomass accumulated into lamellar body-like organelles of the tumor cells. Moreover, this accumulation partially depends on Glut1. Ex vivo analyses showed besides that glycolysis in cancer cells was diminished in Glut1 absence, except when Glut3 was highly expressed. Similarly to Glut1, Glut3 expression suppression in cancer cells affects neither the initiation, nor the tumor expansion. In contrast, the combined deletion of Glut1 and Glut3 significantly decreases non-small cell lung cancer growth. Our results demonstrate the requirement to target both glucose transporters to impair pulmonary adenocarcinomas tumorigenesis.