PROJECT SUMMARY
Given the important roles of tumor suppressors and oncogenes in metabolic reprogramming, there is
significant translational potential in identifying and understanding how particular oncogenotypes influence tumor
metabolism, and whether these changes impose liabilities that can be exploited therapeutically. From more recent
studies, however, a nuanced picture has emerged showing that tissue context impacts the execution of metabolic
reprogramming even with the same oncogenic drivers. For example, despite having the same driver mutations,
pancreatic cancer and lung cancer exhibit differences in branched chain amino acid (BCAA) metabolism, where
lung tumors increase BCAA uptake to use them as a nitrogen source while pancreatic tumors decrease BCAA
uptake due to decreased expression of genes in BCAA metabolism compared with normal pancreas. Thus,
understanding how cell-of-origin interacts with genetic events to affect the metabolic dependence of tumors will
be critical for selecting the right treatment approaches for patients.
By analyzing the metabolome of human non-small cell lung cancer (NSCLC) samples surgically resected
from patients and comparing those with KRAS mutations (K) to those with KRAS/LKB1 co-mutations (KL), we
noted that serine-glycine one carbon (SGOC) metabolism is significantly altered in KL NSCLC, similar to KL
pancreatic cancer models. By further metabolic analyses, however, we clarified the differences in SGOC
metabolism between these two tumor types. While KL pancreatic cancer requires SGOC for DNA methylation,
KL NSCLC depends on SGOC via serine hydroxymethyltransferase (SHMT) enzymes to maintain redox
homeostasis. By establishing both molecular and metabolic platforms to measure metabolites involved in redox
balance, and utilizing clinically relevant mouse models for in vivo studies, we are now poised to define the
oncogenic role of SHMTs during lung tumorigenesis.
In Aim 1 we will interrogate the mechanistic basis of SHMT dependence in these NSCLC cells. In Aim 2
we will investigate the molecular mechanism by which LKB1 regulates SHMT. In Aim 3 we will examine 1)
whether SHMT suppression reduces tumor growth and 2) whether the combination of SHMT inhibition with
chemotherapeutic drugs that induce oxidative stress can further inhibit tumor growth using various mouse models.
While the critical role of SGOC as a methyl group donor for DNA methylation in KL pancreatic cancer has been
reported, the importance of SGOC metabolism in KL NSCLC or heterogeneity between these two diseases has
yet to be elucidated. Our studies will provide valuable information for substratification of NSCLC patients with
hyperactive SGOC metabolism as treatment responders to therapies targeting redox balance, which is pertinent
to the goals of precision medicine.