Molecular mechanisms of GI Tumor cell reprogramming governed by lactate metabolism

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Representing an important determinant of the cellular phenotype, cell metabolism has an essential role in tumorigenesis, A particular condition that greatly impacts on phenotype manifestation and clonal diversity is the metabolic compartmentalization and symbiosis that characterizes the ecosystem and heterogeneity in many soild and stroma-rich tumors (including pancreatic and colorectal cancer). This is controlled by extrinsic effectors like glucose and oxygen supply or by oxidative stress involving mediating transcription factors such as HIF1α, Nrf2 and ATF3. An important manifestation of metabolic compartmentalization/ symbiosis is the aerobe-glycolytic (Warburg) metabolism and the lactate dependent/OxPhos (reverse Warburg) metabolism. Here, not only biomass and energy is transferred bewteen distinct cell types, but also metabolites exerting fundamental effects on the cellular phenotype. This mainly includes direct effects on histone- and DNA-modifications, thereby greatly affecting the epigenome. Depending on these alterations, cellular traits manifest that contribute to tumor malignancy (such as resistance, metastasis formation) and that particulary favour the emergence of clonal entities with stem cell-like properties or a phenotype of cellular dormancy. Given the fact that the reverse Warburg metabolism associates with the advancement and poor prognosis in many types of solid tumors, a better understanding of these metabolite mediated effects is certainly of great relevance. The present project therefore aims at elucidating the modalities and cellular events relating to the reverse Warburg metabolism in colorectal and pancreatic cancer. The working plan will address the following issues: 1) By means of cell culture based models the association between reverse Warburg metabolites, epigenome and phenotype alterations will be elucidated; 2.) Immunohistochemical analyses of tumor tissues from pancreatic (PDAC)- and colorectal cancer (CRC) patients will validate the clinico-pathological role of the reverse Warburg metabolism; 3.) Employing the Pdx1-Flp;FSF-KrasG12D/+;Trp53frt/+ (KPF) PDAC-mouse model, which particularly allows the assessment of desmoplastic mechanisms and the temporal tumorigenesis sequence, the impact of the reverse Warburg metabolism on pancreatic carcinogenesis and metastasis will be studied in vivo.