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在研究肠道管腔和宿主代谢物在 胃肠道肿瘤的重点是预防。一项这样的研究使用氧化偶氮甲烷诱导的小鼠 结肠肿瘤模型，证明粪便的靶向代谢物谱可以非侵入性地告知 结肠腺瘤的存在。肿瘤组织的代谢组学分析也揭示了异常代谢 包括增加的丝氨酸生物合成。其他的工作集中在鲁米那和宿主之间的相互作用上 使用肠肿瘤发生的APCMin/+小鼠模型测定代谢。在这项研究中，我证明， 化学预防剂塞来昔布的施用改变了肠腔微生物群和代谢组， 与减少肠干细胞增殖和息肉负担相关。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 开展了一项研究，重点是非必需氨基酸丝氨酸在结肠肿瘤形成中的作用。这项工作 表明肿瘤抑制基因APC的状态，其丢失是结直肠癌的早期事件， 癌症（CRC）发展，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PSAT 1在人类结肠肿瘤的多个阶段升高 并且其高表达与CRC的不良预后相关。重要的是，我已经证明了PSAT 1的缺失 减少CRC细胞增殖，这是一种通过去除外源丝氨酸而增强的效果。 将作为K22奖项的一部分执行的研究是工作的自然延伸 并且将直接测试丝氨酸是否支持结肠肿瘤的发展和生长。测试 这将利用一种新的小鼠模型，其中PSAT 1可以被敲除。机械体外工作将是 使用肠道类器官和细胞培养系统进行，以评估丝氨酸利用如何支持 肿瘤细胞增殖。最后，根据肿瘤细胞已知的代谢可塑性，我将确定 靶向内源性和外源性丝氨酸是否协同降低结肠肿瘤负荷。采取 总之，这项工作有可能揭示一种对CRC重要的新途径。不进行 该研究将评估该途径是否是CRC治疗的可行靶点， 可能是其他癌症。重要的是，这个奖项将是关键，使我能够建立一个独立的 从事癌症研究。

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.