Targeting LRRC15 Inhibits Metastatic Dissemination of Ovarian Cancer

  • Cancer Res. 2022 Mar 15;82(6):1038-1054. doi: 10.1158/0008-5472.CAN-21-0622.
Upasana Ray  #  1 ,  Deok-Beom Jung  #  1  2 ,  Ling Jin  1 ,  Yinan Xiao  1 ,  Subramanyam Dasari  3 ,  Sayantani Sarkar Bhattacharya  1 ,  Prabhu Thirusangu  1 ,  Julie K Staub  1 ,  Debarshi Roy  1  4 ,  Bhaskar Roy  5 ,  S John Weroha  6 ,  Xiaonan Hou  6 ,  James W Purcell  7 ,  Jamie N Bakkum-Gamez  8 ,  Scott H Kaufmann  9 ,  Nagarajan Kannan  1 ,  Anirban K Mitra  3 ,  Viji Shridhar  1
Affiliations
  • 1. Division of Experimental Pathology and Laboratory Medicine, Mayo Clinic, Rochester, Minnesota.
  • 2. Biomedical Research Center, ASAN Medical Center, Seoul, South Korea.
  • 3. Indiana University School of Medicine-Bloomington, Indiana University, Bloomington, Indiana.
  • 4. Alcorn State University, Lorman, Missisippi.
  • 5. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
  • 6. Department of Oncology, Mayo Clinic, Rochester, Minnesota.
  • 7. Department of Oncology Drug Discovery, AbbVie, South San Francisco, California.
  • 8. Division of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota.
  • 9. Division of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota.
  • # Contributed equally.
PMID: 34654724 DOI: 10.1158/0008-5472.CAN-21-0622
Abstract

Dissemination of Ovarian Cancer 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 Ovarian Cancer bowel metastases compared with matched primary Tumors and acts as a potent promoter of omental metastasis. Complementary models of Ovarian Cancer 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 Ovarian Cancer cell line xenograft models prevented metastatic dissemination, and these results were corroborated in metastatic patient-derived Ovarian Cancer 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 Ovarian Cancer metastasis and suggest a novel and promising therapy to target Ovarian Cancer metastases.

Significance: This study identifies that LRRC15 activates β1-integrin/FAK signaling to promote Ovarian Cancer metastasis and shows that the LRRC15-targeted antibody-drug conjugate ABBV-085 suppresses Ovarian Cancer metastasis in preclinical models.

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