Facultyseminar: When cancer cells don’t die: links between metabolic stress, inflammation and cachexia

Glucose and oxygen deficiency frequently occur during tumorigenesis. However, tumors can adapt by restoring blood flow through neoangiogenesis. We analyzed responses of tumor cells to starvation, which included cell death (in acute settings) and the secretion of cytokines and inflammatory factors that rewire immune context. Moreover, cells subjected to glucose limitation or hypoxia, but not other conditions of metabolic stress, secrete LIF, an IL-6 family cytokine implicated in the development of solid tumors and cachexia. LIF release was prevented by mannose, which sustained multiple metabolic pathways in the absence of glucose. LIF release was associated to impairment of N-glycosylation and activation of MEK MAP kinases. In mouse models of non small cell lung carcinoma (NSCLC), reduction of LIF impaired angiogenesis and tumor growth, rewired the immune system towards an anti-tumor phenotype, and impaired implantation of tumors in the lung. In patients with NSCLC, LIF mRNA correlates with hypoxia and angiogenesis. Moreover, the presence of LIF and other IL-6 family cytokines in serum associates with the development of cachexia. Therefore, LIF is one of the factors produced by hypoxic/hypoglycemic cells that could be targeted to impair angiogenesis, immune suppression and tumor growth.