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

基本信息

批准号：
10115638
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
项目类别：
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/10115638
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 Enzymes Epithelial Event Excision Feces Future Gene Expression Genetically Engineered Mouse Glucose Goals Growth Growth and Development function Human Impairment In Vitro Incidence Intervention 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 Small Intestinal Neoplasm Source 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 dietary manipulation enzyme biosynthesis gastrointestinal improved intestinal tumorigenesis knock-down metabolome metabolomics methylation pattern microbiota mouse model neoplastic cell novel novel strategies prevent small hairpin RNA stem cell proliferation tumor tumor growth tumor initiation tumor metabolism tumorigenesis

项目摘要

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.

抽象的我正在进行的工作重点是研究肠道和宿主代谢物在胃肠道肿瘤侧重于预防。一项使用二甲烷诱导的小鼠的研究结肠肿瘤模型表明，靶向粪便的代谢物分析可以无创地告知结肠腺瘤的存在。肿瘤组织的代谢组分析还显示出异常的代谢包括增加的丝氨酸生物合成。其他工作重点是腔与宿主之间的相互作用使用肠道肿瘤发生的APCMIN/+小鼠模型的代谢。在这项研究中，我证明了化学预防剂塞来昔布的给药改变了肠道腔菌群和代谢组与减少肠道干细胞增殖和息肉负担的关联。这些发现表明管腔变化与宿主上皮之间的重要相互作用。鉴于这些发现我已经进行一项研究，重点是非必需氨基酸丝氨酸在结肠肿瘤中的作用。这项工作证明肿瘤抑制基因APC的状态，其中损失是结直肠癌的早期事件癌症（CRC）发育，控制丝氨酸生物合成和下游一碳代谢。而且，我表明丝氨酸生物合成酶PSAT1在人类肿瘤的多个阶段升高它的高表达与CRC的结果不佳相关。重要的是，我已经证明了PSAT1的删除减少了CRC细胞增殖，这种作用通过去除外源丝氨酸而突出。将作为该K22奖的一部分进行的研究是工作的自然扩展上述描述，并将直接测试丝氨酸是否支持结肠肿瘤的发育和生长。测试我将利用一种新型的鼠标模型，其中PSAT1可以被击倒。体外工作的机理将是使用肠道器官和细胞培养系统进行的，以评估丝氨酸的利用方式肿瘤细胞增殖。最后，鉴于已知的肿瘤细胞的代谢可塑性，我将确定靶向内源性丝氨酸和外源丝氨酸是否协同降低结肠肿瘤负担。拍摄这项工作共同揭示了对CRC重要的新型途径。超越了这个范围奖励，将进行研究以评估该途径是否是CRC治疗和潜在的其他癌症。重要的是，该奖项将是使我能够建立独立的关键癌症研究职业。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Induction of colitis-associated neoplasia in mice using azoxymethane and dextran sodium sulfate.

使用氧化偶氮甲烷和葡聚糖硫酸钠诱导小鼠结肠炎相关肿瘤。

DOI：
10.1016/bs.mcb.2020.09.008
发表时间：
2021
期刊：
Methods in cell biology
影响因子：
0
作者：
Montrose,DavidC;Makino,Tomoki;Basu,Srijani;Ito,Naotake;Dannenberg,AndrewJ
通讯作者：
Dannenberg,AndrewJ

Exogenous and Endogenous Sources of Serine Contribute to Colon Cancer Metabolism, Growth, and Resistance to 5-Fluorouracil.

DOI：
10.1158/0008-5472.can-20-1541
发表时间：
2021-05-01
期刊：
Cancer research
影响因子：
11.2
作者：
Montrose DC;Saha S;Foronda M;McNally EM;Chen J;Zhou XK;Ha T;Krumsiek J;Buyukozkan M;Verma A;Elemento O;Yantiss RK;Chen Q;Gross SS;Galluzzi L;Dow LE;Dannenberg AJ
通讯作者：
Dannenberg AJ

Emergent impact of lifestyle on tumor progression and response to therapy.

生活方式对肿瘤进展和治疗反应的新兴影响。

DOI：
10.1016/s1937-6448(22)00132-0
发表时间：
2022
期刊：
International review of cell and molecular biology
影响因子：
0
作者：
Buqué,Aitziber;Montrose,DavidC;Galluzzi,Lorenzo
通讯作者：
Galluzzi,Lorenzo

Modifying dietary amino acids in cancer patients.

改变癌症患者的膳食氨基酸。

DOI：
10.1016/bs.ircmb.2022.02.004
发表时间：
2022
期刊：
International review of cell and molecular biology
影响因子：
0
作者：
Connolly-Schoonen,Josephine;Biamonte,StevenF;Danowski,Lorraine;Montrose,DavidC
通讯作者：
Montrose,DavidC

Targeting Serine in Cancer: Is Two Better Than One?