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

摘要 我正在进行的工作集中于研究肠道、腔和宿主代谢物在 注重预防的胃肠道肿瘤。一项这样的研究使用了偶氮甲烷诱导的小鼠 结肠肿瘤模型，表明粪便的靶向代谢物图谱可以非侵入性地 结肠腺瘤的存在。肿瘤组织的代谢组学分析也显示代谢异常 包括增加丝氨酸的生物合成。其他工作的重点是鲁米娜和宿主之间的相互作用。 利用APCMin/+小鼠肠道肿瘤发生模型进行代谢研究。在这项研究中，我证明了 化学预防药物塞来昔布的应用改变了肠道微生物区系和代谢组。 与减少肠道干细胞增殖和息肉负担有关。这些发现表明 管腔变化和宿主上皮之间的重要相互作用。根据这些发现，我一直在 开展了一项关于非必需氨基酸丝氨酸在结肠肿瘤中的作用的研究。这部作品 表明肿瘤抑制基因APC的状态，该基因的丢失是结直肠癌的早期事件 癌症(CRC)的发展，控制丝氨酸的生物合成和下游的一碳代谢。此外，我 显示丝氨酸生物合成酶PSAT1在人类结肠肿瘤的多个阶段中升高 其高表达与结直肠癌预后不良相关。重要是，我已经展示了PSAT1的删除 减少结直肠癌细胞的增殖，这种作用因去除外源性丝氨酸而加重。 将作为K22奖的一部分执行的研究是工作的自然延伸 并将直接测试丝氨酸是否支持结肠癌的发展和生长。为了测试 我将利用一种新型的小鼠模型，在这种模型中，PSAT1可以被击倒。机械性的体外工作将是 使用肠道有机体和细胞培养系统来评估丝氨酸利用如何支持 肿瘤细胞增殖。最后，根据已知的肿瘤细胞的代谢可塑性，我将确定 靶向内源性和外源性丝氨酸是否协同降低了结肠癌的负担。已被占用 综上所述，这项工作有可能揭示出一条对CRC重要的新途径。超出了本文的范围 获奖后，将进行研究，以评估这一途径是否为治疗结直肠癌的可行靶点 可能是其他癌症。重要的是，这个奖项将是使我能够建立一个独立的 从事癌症研究的职业。

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.