报告题目：胰腺表观遗传失调与微环境重塑

报 告 人：薛   婧，研究员

主 持 人：逄秀凤，教授

报告时间：2024年10月22日13:30-15:00

报告地点：闵行校区bevictor伟德官网534小会议室

报告人简介：

薛婧博士， 现任上海交通大学医学院附属仁济医院，及肿瘤系统医学全国重点实验室研究员，博导。 2010年毕业于中国科学院上海生命科学研究院营养科学研究所，获博士学位。随后在美国斯坦福大学医学院从事博士后研究。2015年9月回国成立胰腺肿瘤和炎症病理机制课题组，主要从免疫调控、表观调控等方面展开相关病理机制和靶向策略研究。 近几年以通讯作者发表研究成果于Cancer Cell，Gut (2024, 2020), Gastroenterology, Advanced Science和 Cell Reports 等国际权威杂志。获得国家优青、上海市东方学者、上海市青年拔尖等人才项目资助。现任中国生理学会基质生物学分会委员，中华医学会肿瘤学分会青年委员，Cellular Oncology副主编， Journal of Pancreatology 编委等。

报告内容简介：

Epigenetic alterations in tumor cells are widespread and impact tumorigenesis. Beyond their role in tumor cells, emerging evidences underscore the influence of epigenetic dysregulation on the TME, enabling adaptation to immune and metabolic stresses during tumor development. SETD2 is a primary histone H3K36 trimethyl-transferase, with mutations and/or copy number variation (CNV) being prevalent in various tumor types, including pancreatic cancer. Our previous studies link SETD2 deficiency to pancreatic tumorigenesis and immune evasion. How SETD2-deficient pancreatic tumor cells adapted to metabolic stress during development remain poorly understood. Through single-cell RNA sequencing, we identify a lipid-laden CAF subpopulation marked by ABCA8a in Setd2-deficient pancreatic tumors. Our findings reveal that tumor-intrinsic SETD2 loss unleashes BMP2 signaling via ectopic gain of H3K27Ac, leading to CAFs differentiation toward lipid-rich phenotype. Lipid-laden CAFs then enhance tumor progression by providing lipids for mitochondrial oxidative phosphorylation via ABCA8a transporter. Together, our study links CAF heterogeneity to epigenetic dysregulation in tumor cells, highlighting a previously unappreciated metabolic interaction between CAFs and pancreatic tumor cells.  Our findings illuminated the role of SETD2 loss in reshaping CAFs to support tumor energy demands, suggesting OXPHOS targeting as a potential strategy for SETD2-deficient PDAC patients.