Targeting LRRC15 Inhibits Metastatic Dissemination of Ovarian Cancer

Abstract

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.

Identification of leucine-rich repeat-containing protein 59 (LRRC59) located in the endoplasmic reticulum as a novel prognostic factor for urothelial carcinoma

“…S6B–D). Among these, LRRC15 has been recently reported as a novel therapeutic target for multiple solid tumor indications [ [22] , [23] – 24 ]. The LRRC15 + CAF (carcinoma-associated fibroblasts) subpopulation was found to be driven by TGF-β and correlated with a poor response to anti-PD-L1 therapy.…”

Identification and Validation of Hub Genes for Predicting Treatment Targets and Immune Landscape in Rheumatoid Arthritis

“…Previous studies have also demonstrated that LRRC15 may play a vital role in reducing bone resorption and promoting bone formation by acting as a suppressor of NF- κ B [ 56 ]. Furthermore, LRRC15 was found to be overexpressed in aggressive cancer cells, such as breast cancer [ 57 ], ovarian cancer [ 58 ], and osteosarcoma [ 59 ].…”

Efficacy evaluation of multi-immunotherapy in ovarian cancer: From bench to bed

“…RNA sequencing analysis also suggested that stress promoted chemoresistance, which provided targets to overcome chemo resistance (157). In addition, targeting LRRC15 could inhibit metastatic dissemination through b1-integrin/FAK signaling (158). Apart from preclinical studies, several clinical trials revealed that MEK inhibitor trametinib, Wee1 inhibitor adavosertib, and CDK4/6 inhibitor ribociclib showed preliminary efficacy in ovarian cancer (159)(160)(161).…”