代谢异常是肿瘤的基本特征，肿瘤细胞通过代谢重塑与生长信号相适应共同维持恶性表型。BRAFV600E结直肠癌细胞的代谢特征及其如何与MAPK信号通路适应和协作的分子机制尚不清楚。我们前期发现BRAFV600E结直肠癌细胞能够重塑鞘脂代谢，细胞内累积的代谢产物S1P通过非受体介导的方式调控MAPK信号通路活化。本项目拟以临床标本、基因编辑细胞模型和肿瘤公共数据为研究对象，进一步阐明BRAFV600E结直肠癌细胞代谢重塑生成S1P并与E3泛素酶PJA2竞争结合KSR1，增强KSR1蛋白稳定性，从而调控MAPK信号通路和肿瘤恶性表型的分子机制。本研究不仅可以从细胞代谢角度阐明BRAFV600E结直肠癌维持MAPK信号通路活化和恶性生物学行为的新机制，而且有望为以SPHK1/S1P为靶标的BRAFV600E结直肠癌分子分型和精准治疗提供新的理论和实验依据。

Aberrant metabolism is a hallmark of cancer. Cancer cells sustain their malignancy potential by coordination between metabolic reprogramming and signaling pathways. However, metabolic characteristics of BRAFV600E colorectal cancer and how they adapt and cooperate with MAPK signaling remain obscure. Our preliminary study revealed that BRAFV600E colorectal cancer cells reprogramed sphingolipid metabolism to produce S1P, thus modulating MAPK signaling via a receptor independent manner. Based on clinical specimens, established in vivo/in vitro models by genetically edited cell lines as well as public databases, this project aims to further investigate the hypothesis that S1P, produced by metabolic reprogramming in BRAFV600E colorectal cancer, participate in MAPK signaling and malignancies through competitive binding with KSR1 thus protecting KSR1 from PJA2 mediated ubiquitin-dependent protein degradation. We will also explore the application potential of SPHK1/S1P inhibitor for treating BRAFV600E colorectal cancer. The project warrants further understanding of the mechanism by which BRAFV600E colorectal cancer cells sustain MAPK signaling and malignancies through metabolic shifting and also provides theoretical and experimental basis for clinical utilization of SPHK1/S1P as target to precisely subtype and treat BRAFV600E colorectal cancer.