Dissemination of ovarian cancer (OC) cells can lead to inoperable metastatic lesions in the bowel and omentum that cause patient death. Here we show that LRRC15, a type-I 15-leucine-rich repeat-containing membrane protein, highly overexpressed in OC bowel metastases compared to matched primary tumors and acts as a potent promoter of omental metastasis. Complementary models of OC demonstrated that LRRC15 expression leads to inhibition of anoikis-induced cell death and promotes adhesion and invasion through matrices that mimic omentum. Mechanistically, LRRC15 interacted with β1-integrin to stimulate activation of focal adhesion kinase (FAK) signaling. As a therapeutic proof of concept, targeting LRRC15 with the specific antibody-drug conjugate ABBV-085 in both early and late metastatic OC cell line xenograft models prevented metastatic dissemination, and these results were corroborated in metastatic patient-derived OC xenograft models. Furthermore, treatment of 3D-spheroid cultures of LRRC15-positive patient-derived ascites with ABBV-085 reduced cell viability. Overall, these data uncover a role for LRRC15 in promoting OC metastasis and suggest a novel and promising therapy to target OC metastases.

中文翻译：

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靶向 LRRC15 抑制卵巢癌的转移性传播

卵巢癌 (OC) 细胞的传播可导致肠道和大网膜中无法手术的转移性病变，从而导致患者死亡。在这里，我们显示 LRRC15 是一种富含 I 型 15-亮氨酸重复序列的膜蛋白，与匹配的原发性肿瘤相比，它在 OC 肠转移瘤中高度过表达，并作为网膜转移的有效促进剂。OC 的互补模型证明 LRRC15 表达导致失巢凋亡诱导的细胞死亡的抑制，并通过模拟网膜的基质促进粘附和侵袭。从机制上讲，LRRC15 与 β1-整合素相互作用以刺激粘着斑激酶 (FAK) 信号传导的激活。作为概念的治疗证明，在早期和晚期转移性 OC 细胞系异种移植模型中使用特异性抗体-药物偶联物 ABBV-085 靶向 LRRC15 可防止转移传播，这些结果在转移性患者来源的 OC 异种移植模型中得到证实。此外，用 ABBV-085 处理 LRRC15 阳性患者腹水的 3D 球体培养物会降低细胞活力。总体而言，这些数据揭示了 LRRC15 在促进 OC 转移中的作用，并提出了一种针对 OC 转移的新型且有前途的疗法。