ROR2/Wnt5a Signaling Regulates Directional Cell Migration and Early Tumor Cell Invasion in Ovarian Cancer.

IF 4.1 2区医学 Q2 CELL BIOLOGY Molecular Cancer Research Pub Date : 2024-05-02 DOI:10.1158/1541-7786.MCR-23-0616

Whitney R Grither, Breanna Baker, Vasilios A Morikis, Ma Xenia G Ilagan, Katherine C Fuh, Gregory D Longmore

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Abstract

Adhesion to and clearance of the mesothelial monolayer are key early events in metastatic seeding of ovarian cancer. ROR2 is a receptor tyrosine kinase that interacts with Wnt5a ligand to activate noncanonical Wnt signaling and has been previously shown to be upregulated in ovarian cancer tissue. However, no prior study has evaluated the mechanistic role of ROR2 in ovarian cancer. Through a cellular high-throughput genetic screen, we independently identified ROR2 as a driver of ovarian tumor cell adhesion and invasion. ROR2 expression in ovarian tumor cells serves to drive directed cell migration preferentially toward areas of high Wnt5a ligand, such as the mesothelial lined omentum. In addition, ROR2 promotes ovarian tumor cell adhesion and clearance of a mesothelial monolayer. Depletion of ROR2, in tumor cells, reduces metastatic tumor burden in a syngeneic model of ovarian cancer. These findings support the role of ROR2 in ovarian tumor cells as a critical factor contributing to the early steps of metastasis. Therapeutic targeting of the ROR2/Wnt5a signaling axis could provide a means of improving treatment for patients with advanced ovarian cancer.

Implications: This study demonstrates that ROR2 in ovarian cancer cells is important for directed migration to the metastatic niche and provides a potential signaling axis of interest for therapeutic targeting in ovarian cancer.

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ROR2/Wnt5a信号调节卵巢癌的定向细胞迁移和早期肿瘤细胞侵袭。

粘附和清除间皮单层是卵巢癌转移播种的早期关键事件。ROR2 是一种受体酪氨酸激酶，它与 Wnt5a 配体相互作用，激活非经典的 Wnt 信号传导，以前曾有研究表明 ROR2 在卵巢癌组织中上调。然而，此前没有研究评估过 ROR2 在卵巢癌中的机理作用。通过细胞高通量基因筛选，我们独立鉴定出 ROR2 是卵巢肿瘤细胞粘附和侵袭的驱动因子。ROR2 在卵巢肿瘤细胞中的表达可驱动细胞向 Wnt5a 配体含量高的区域（如间皮细胞衬里的网膜）定向迁移。此外，ROR2 还能促进卵巢肿瘤细胞粘附并清除间皮单层。在卵巢癌的共生模型中，消耗肿瘤细胞中的 ROR2 可减少转移性肿瘤的负担。这些研究结果支持 ROR2 在卵巢肿瘤细胞中的作用，认为它是导致早期转移的关键因素。针对 ROR2/Wnt5a 信号轴的治疗可为改善晚期卵巢癌患者的治疗提供一种方法。意义：这项研究表明，卵巢癌细胞中的 ROR2 对定向迁移到转移龛非常重要，为卵巢癌的治疗提供了一个潜在的信号轴靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

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.