Reducing serine biosynthesis and utilization as a novel approach for colon cancer prevention

减少丝氨酸生物合成和利用作为预防结肠癌的新方法

• 批准号: 9505563
• 负责人: David C Montrose
• 金额: $ 22.95万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9505563
• 关键词: APC gene; Anabolism; ApcMin/+ mice; Award; Azoxymethane; Cancer Etiology; Carbon; Cell Culture System; Cell Proliferation; Cell physiology; Cells; Cessation of life; Chemopreventive Agent; Colon Carcinoma; Colonic Adenoma; Colonic Neoplasms; Colorectal Cancer; DNA Methylation; Development; Diet; Enzymes; Epithelium; Event; Excision; Feces; Future; Gene Expression; Genetically Engineered Mouse; Glucose; Goals; Growth; Growth and Development function; Human; Impairment; In Vitro; Incidence; Intervention; Intestinal Neoplasms; Intestines; K22 Award; Light; Malignant Neoplasms; Mediator of activation protein; Metabolic; Metabolism; Methods; Modeling; Mus; Neoplasms; Non-Essential Amino Acid; Organoids; Outcome; Pathway interactions; Phosphoserine aminotransferase; Polyps; Prevention; Prevention strategy; Process; Production; Research Personnel; Role; Serine; Source; Stem cells; Testing; Tumor Burden; Tumor Suppressor Genes; Tumor Tissue; United States; Work; anticancer research; cancer cell; cancer prevention; cancer therapy; cancer type; career; celecoxib; clinically relevant; colon cancer prevention; colon growth; colon tumorigenesis; colorectal cancer treatment; dietary manipulation; enzyme biosynthesis; gastrointestinal; improved; knock-down; metabolome; metabolomics; methylation pattern; microbiota; mouse model; neoplastic cell; novel; novel strategies; prevent; small hairpin RNA; tumor; tumor growth; tumor initiation; tumor metabolism; tumorigenesis

ABSTRACT 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.

摘要