Targeting STAT3 in Ovarian Cancer- Center for Integrated Biomedical and Bioengineering (CIBBR)

项目摘要 卵巢癌仍然是一种致命的疾病，部分原因是卵巢癌转移。球形，卵巢簇 癌细胞，相互作用，并清除保护性间皮层，内衬腹膜在早期阶段， 卵巢癌转移关于信号通路和相关基因的知识存在空白 在间皮瘤清除中。由于不知道这些途径，这可能会影响设计药物的能力， 卵巢癌转移STAT 3信号通路在间皮细胞清除中起作用。但据 尚不清楚卵巢球状体与间皮细胞的相互作用如何影响卵巢中STAT 3的激活， 癌细胞子宫内膜异位症是一种良性疾病，可能会导致不孕，增加患卵巢癌的风险， 与卵巢癌有一些相似之处，因为类胶质细胞也与间皮细胞相互作用， 子宫内膜异位症患者的STAT 3活化水平升高。他汀类药物是HMGCR的抑制剂，通常用于 降低胆固醇;然而，有证据表明他汀类药物也抑制STAT 3。这项工作的长期目标是 是开发治疗转移性卵巢癌的药物。核心假设是， 间皮细胞调节可以用他汀类药物治疗减弱的STAT 3活性。目标1将决定 与间皮细胞相互作用对STAT 3激活的影响，并确定STAT 3抑制的机制 他汀类药物目的2将确定STAT 3靶基因表达在间皮素清除过程中的变化， 通过使用单细胞RNA-seq的他汀类药物治疗阻断。卵巢癌细胞将被比作 细胞，以潜在地识别癌症特异性STAT 3靶基因。总体而言，拟议工作的成果可能 更全面地了解STAT 3在卵巢癌转移中的作用， STAT 3在子宫内膜异位症中的作用，这两种妇科疾病可能会极大地影响女性的健康。 寿命

PROJECT SUMMARY Ovarian cancer remains a deadly disease in part due to ovarian cancer metastasis. Spheroids, clusters of ovarian cancer cells, interact and clear the protective mesothelial layer that lines the peritoneum in the early stages of ovarian cancer metastasis. There is a gap in knowledge regarding the signaling pathways and genes involved in mesothelial clearance. By not knowing these pathways, this may affect the ability to design drugs to target ovarian cancer metastasis. The STAT3 signaling pathway plays a role in mesothelial clearance. However, it is not known how the interaction of ovarian spheroids with mesothelial cells affects STAT3 activation in ovarian cancer cells. Endometriosis, a benign disease that may promote infertility and increase risk for ovarian cancer, has some similarities to ovarian cancer as the endometrioid cells also interact with the mesothelial cells, and STAT3 activation is elevated in patients with endometriosis. Statins, inhibitors of HMGCR, are often used to lower cholesterol; however, there is evidence that statins also inhibit STAT3. The long-term objective of this work is to develop drugs for the treatment of metastatic ovarian cancer. The central hypothesis is that interaction with mesothelial cells modulates STAT3 activity that can be attenuated with statin treatment. Aim 1 will determine the effects of interacting with mesothelial cells on STAT3 activation and define the mechanism of STAT3 inhibition by statins. Aim 2 will determine STAT3 target gene expression changes during mesothelial clearance that are blocked by statin treatment using single cell RNA-seq. Ovarian cancer cells will be compared to endometrioid cells to potentially identify cancer specific STAT3 target genes. Overall, the outcomes of the proposed work may provide a more complete understanding of the role of STAT3 in ovarian cancer metastasis and provide insight into the role of STAT3 in endometriosis, two gynecologic diseases that may greatly impact women across their lifespan.