Dissecting mitochondrial lysine and tryptophan metabolism to target metabolic symbiosis in lung adenocarcinoma

Background Lung adenocarcinoma (LUAD) is the most common histological type of lung cancer with mutations in EGFR and KRAS, translocation of ALK, and loss of LKB1 as the most frequent oncogenic alterations. These alterations have been shown to drive different metabolic programs of LUAD cells. Most of the studies focused on glucose and glutamine metabolism neglecting the role of alternative amino acids, such as tryptophan and lysine, in driving aggressiveness and immune escape. Despite the relevance of lysine and tryptophan metabolism for LUAD onset and progression has come to light, their role in supporting the mitochondrial bioenergetics and dynamics of LUAD cells remains elusive. Hypothesis Based on our preliminary results we identify the oxoadipate carrier (ODC), also known as SLC25A21 that drives the mitochondrial catabolism of tryptophan and lysine intermediates, as a key modulator of the malignant phenotype of lung cancer cells. ODC, through epigenetic mechanisms, sustains the expression of mismatch repair genes lowering the tumor mutational burden and the immunogenicity of the LUAD cells. Hence its targeting will rewire the crosstalk between cancer cells and immune cells. Aims This project combines my background in mitochondrial metabolism and cancer biology to identify: (i) the metabolic and epigenetic mechanisms by which ODC modulates the aggressiveness and the response to therapies of LUAD cells, (ii) the role of ODC-driven tryptophan and lysine metabolism in the establishment of an immune-tolerant microenvironment, (iii) ODC in human samples as a novel metabolic target correlated with LUAD progression, spread and immune evasion. Experimental Design Through in vitro/vivo approaches, we will elucidate the mechanisms of metabolic adaptation, switching and alterations of immune and lung cancer cells in response to ODC modulation. In particular, genomic analysis techniques, NanoString Technologies, CIBERSORT-based deconvolution methods and validated bioinformatics analysis pipelines will be employed to unveil ODC-driven epigenetic mechanisms of immunoediting in LUAD. Furthermore human tissue microarrays will be used in order to disclose a possible correlation between ODC expression, oncogenic drivers, tumor invasiveness and immunogenicity. Expected Results This study is expected to 1) decipher the metabolic and epigenetic consequences of ODC modulation in LUAD; 2) unravel the functional link with relevant oncogenic mutations; 3) unmask the role of ODC in the metabolic dynamics (competition and/or symbiosis) between cancer cells and their microenvironment and in immunotherapy response; 4) define ODC as a novel synthetic lethality and potential therapeutic target. Impact On Cancer The outcome of this research might offer proof-of-concept that pharmacological inhibition of mitochondrial tryptophan and lysine catabolism can reduce cancer progression and improve the response to classical chemotherapy and/or advanced therapies (immune checkpoint inhibitors, KRASG12C inhibitors). ODC is just the tip of the "mitochondrial" iceberg where two essential amino acids degradation pathways converge. The deep diving into mitochondrial tryptophan and lysine metabolism could provide novel insights into the understanding of the metabolic adaptation mechanisms of LUAD disease and may pave the way for indentifying new metabolic targets to fight LUAD.