Project Summary
Colorectal cancer (CRC) is the second leading cause of cancer-related death in the US, with a 5-year
survival rate of only 60%. The poor disease outcome associated with CRC highlights an urgent need to
understand the cellular mechanisms that influence initiation and progression of CRC. Several of the
well-known genetic drivers of CRC such as KRas and PIK3CA are dominant regulators of metabolic
reprogramming during cancer progression. Altered tumor metabolism facilitates generation of
molecules important for cell growth, signaling, and survival; yet, our knowledge of the precise
mechanisms that regulate metabolism and survival in chemotherapy resistant CRC remains incomplete.
One family of proteins important in coordinating metabolism with cellular survival and stress responses
is the NAD+-dependent sirtuin superfamily. Our preliminary data demonstrate that the loss of a
mitochondrial localized sirtuin, SIRT4, occurs in CRC and results in the reprogramming of nucleotide
biosynthesis to shift metabolites away from salvage nucleotide metabolism and upregulate de novo
nucleotide biosynthesis. We hypothesize this metabolic switch contributes to increased CRC cell
proliferation and resistance to chemotherapy. Our proposal will test this hypothesis in two
complementary, but independent Aims. First, using a biochemical approach, Aim 1 will examine the
mechanism by which SIRT4-mediated metabolic reprogramming increases cell proliferation by
examining SIRT4 activity and substrates. We will also examine the role of the metabolic by-products
downstream of SIRT4-mediated activity. Next, Aim 2 will test the consequence of clinically relevant
SIRT4 loss in physiological models of CRC using organoids, novel genetically engineered mouse
models, and patient derived xenograft (PDX) models. Finally, we will examine the consequences of
SIRT4 loss on CRC metabolism and chemotherapy resistance in vivo. This project will provide an
unprecedented map of metabolic reprogramming in CRC at a single cell level and improve
understanding of how CRC metabolism changes in the context of chemotherapy resistance, opening
the door for development of novel therapeutic strategies that leverage mitochondrial metabolism to treat
chemotherapy resistant cancers.