DDR2 confers ferroptosis resistance to cancer-associated fibroblasts and attenuates PARPi sensitivity of ovarian tumor cells.

IF 4.7 2区 医学 Q2 CELL BIOLOGY
Julien Lesage, Alessandra DiMauro, Angela M Schab, Seth Stidham, Mary M Mullen, Katherine C Fuh, Gregory D Longmore
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引用次数: 0

Abstract

In ovarian cancer, resistance to conventional treatments has prompted the search for alternative targets and/or cells within the tumor microenvironment (TME) that could enhance tumor cell death. Ferroptosis, an iron-dependent, lipid peroxide-triggered form of cell death, is one such pathway. Cancer‑associated fibroblasts (CAFs) are key stromal cells in the ovarian TME that can impact therapeutic responses. Using various genetic approaches, we generated multiple DDR2‑expressing and DDR2‑deficient human ovarian tumor and mouse breast tumor CAFs. We find that DDR2 expression in CAFs protects these cells from ferroptosis by regulating the xCT-GSH-GPX4 antioxidant pathway and cellular iron metabolism. Specifically, DDR2 regulates xCT expression through non-canonical p62‑dependent NRF2 activation and the labile iron pool (LIP) by controlling ferritinophagy. CAFs secrete factors, in a DDR2-dependent manner, that provide protection to ovarian tumor cells against Olaparib‑induced cell death, a clinically relevant PARP inhibitor (PARPi). Finally, we find that high expression of DDR2 in the stromal cells of human ovarian tumors is associated with poor response to PARPi in clinical trials. These findings suggest that ferroptotic regulation by DDR2 in ovarian tumor CAFs could impact therapeutic sensitivity and resistance to PARPi. Implications: The action of the collagen receptor tyrosine kinase DDR2 in CAFs confers PARPi protection to Ovarian tumor cells, by protecting CAFs from ferroptosis.

DDR2赋予对癌症相关成纤维细胞的铁下垂抗性,并减弱卵巢肿瘤细胞对PARPi的敏感性。
在卵巢癌中,对常规治疗的耐药性促使人们在肿瘤微环境(TME)中寻找可促进肿瘤细胞死亡的替代靶点和/或细胞。铁下垂是一种依赖铁的、脂质过氧化触发的细胞死亡形式,就是这样一种途径。癌症相关成纤维细胞(CAFs)是卵巢TME中的关键基质细胞,可以影响治疗反应。使用多种遗传方法,我们生成了多个表达DDR2和缺乏DDR2的人卵巢肿瘤和小鼠乳腺肿瘤CAFs。我们发现DDR2在CAFs中的表达通过调节xCT-GSH-GPX4抗氧化途径和细胞铁代谢来保护这些细胞免于铁凋亡。具体来说,DDR2通过非规范p62依赖性NRF2激活和不稳定铁池(LIP)通过控制铁蛋白自噬来调节xCT表达。CAFs以ddr2依赖的方式分泌因子,保护卵巢肿瘤细胞免受奥拉帕尼诱导的细胞死亡,奥拉帕尼是一种临床相关的PARP抑制剂(PARPi)。最后,我们在临床试验中发现,DDR2在人卵巢肿瘤基质细胞中的高表达与PARPi的不良反应相关。这些发现表明,DDR2在卵巢肿瘤CAFs中的嗜铁调节可能影响PARPi的治疗敏感性和耐药性。意义:胶原受体酪氨酸激酶DDR2在CAFs中的作用通过保护CAFs免于铁下垂,赋予PARPi保护卵巢肿瘤细胞。
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来源期刊
Molecular Cancer Research
Molecular Cancer Research 医学-细胞生物学
CiteScore
9.90
自引率
0.00%
发文量
280
审稿时长
4-8 weeks
期刊介绍: Molecular Cancer Research publishes articles describing novel basic cancer research discoveries of broad interest to the field. Studies must be of demonstrated significance, and the journal prioritizes analyses performed at the molecular and cellular level that reveal novel mechanistic insight into pathways and processes linked to cancer risk, development, and/or progression. Areas of emphasis include all cancer-associated pathways (including cell-cycle regulation; cell death; chromatin regulation; DNA damage and repair; gene and RNA regulation; genomics; oncogenes and tumor suppressors; signal transduction; and tumor microenvironment), in addition to studies describing new molecular mechanisms and interactions that support cancer phenotypes. For full consideration, primary research submissions must provide significant novel insight into existing pathway functions or address new hypotheses associated with cancer-relevant biologic questions.
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