My ongoing work has focused on investigating the role of gut luminal and host metabolites in gastrointestinal neoplasia with a focus on prevention. One such study using the azoxymethane-induced mouse colon tumor model, demonstrated that targeted metabolite profiling of feces can non-invasively inform on the presence of colon adenomas. Metabolomic analysis of tumor tissue also revealed aberrant metabolism including increased serine biosynthesis. Other work has focused on the interplay between luminal and host metabolism using the APCMin/+ mouse model of intestinal tumorigenesis. In this study, I demonstrated that administration of the chemopreventive agent celecoxib shifted the gut luminal microbiota and metabolome in association with reducing intestinal stem cell proliferation and polyp burden. These findings indicate an important interplay between luminal changes and the host epithelium. In light of these findings I have been carrying out a study focused on the role of the non-essential amino acid serine in colon neoplasia. This work demonstrates that status of the tumor suppressor gene APC, loss of which is an early event in colorectal cancer (CRC) development, controls serine biosynthesis and downstream one-carbon metabolism. Moreover, I showed that the serine biosynthetic enzyme PSAT1 is elevated in multiple stages of human colon neoplasia and its high expression is correlated with poor outcome in CRC. Importantly, I've shown that deletion of PSAT1 reduces CRC cell proliferation, an effect that is accentuated by removal of exogenous serine. The studies that will be executed as part of this K22 award are a natural extension of the work described above and will directly test whether serine supports colon tumor development and growth. To test this I will utilize a novel mouse model in which PSAT1 can be knocked down. Mechanistic in vitro work will be carried out using intestinal organoids and cell culture systems to evaluate how serine utilization supports neoplastic cell proliferation. Lastly, in light of the known metabolic plasticity of neoplastic cells, I will determine whether targeting both endogenous and exogenous serine synergistically reduces colon tumor burden. Taken together, this work has the potential to reveal a novel pathway important for CRC. Beyond the scope of this award, studies will be carried out to evaluate whether this pathway is a viable target for CRC treatment and potentially other cancers. Importantly, this award will be key for enabling me to establish an independent career in cancer research.

Public Health Relevance

Colon cancer is the second-leading cause of cancer-related deaths in the United States, therefore improved methods of prevention are needed. This proposal will test whether reducing serine, a critical mediator in enhancing oncogenesis through one-carbon metabolism, can reduce colonic neoplasia. If successful, this approach could be useful for preventing the development of or treating colon cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Career Transition Award (K22)
Project #
1K22CA226033-01
Application #
9505563
Study Section
Subcommittee I - Career Development (NCI)
Program Officer
Jakowlew, Sonia B
Project Start
2019-02-01
Project End
2021-03-01
Budget Start
2019-02-01
Budget End
2019-03-01
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
State University New York Stony Brook
Department
Pathology
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794