Investigation of the Role and Underlying Mechanism of Methylenetetrahydrofolate Dehydrogenase 2(Mthfd2) in the Cancer Stem Cell Properties and Tumorigenesis of Lung Cancer

It is well documented that reprogrammed metabolism is hallmark of cancer. The metabolic profile of cancer stem cell (CSC) has attracted much attention due to tits potential as a target to develop novel therapeutic strategies; nevertheless, it is still largely unknown. Although alterations in glucose and glutamine metabolism are important to malignant transformation, recent studies have focused on the effects of nonessential amino acids (serine, glycine) on cancer development. Moreover, serine catabolism maintains redox balance which is critical for maintaining CSC properties. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a NAD(P)-dependent metabolic enzyme involved in mitochondrial folate one-carbon metabolism, which contributes to serine/glycine catabolism, nucleotide metabolism, purine synthesis, NAD(P)/NAD(P) homeostasis, and redox balance. Recent studies Emerging evidence shows that MTHFD2 is upregulated and promotes tumor cell proliferation and invasion in various cancers. Previously, we found MTHFD2 is associated with the stem cell-induced reprogramming of lung cancer cells. Our preliminary results showed that MTHFD2 expression is upregulated in malignant human lung tissues and lung cancer cell lines. We further found that MTHFD2 raises its expression in tumor sphere condition. Thus, the proposed project aims to identify the role of MTHFD2 in the characteristics of lung cancer CSCs followed by mechanistic investigation of underlying signaling pathways and to investigate its impacts on in vivo tumorigenesis. The completion of this study will not only provide mechanistic explanation of the contribution of MTHFD2 in CSC properties and tumorigenesis in lung cancer but also suggest a potential therapeutic target for further development of therapeutic intervention.