In vivo selection of highly metastatic human ovarian cancer sublines reveals role for AMIGO2 in intra-peritoneal metastatic regulation

• Published in: Cancer letters 2021-04, Vol.503, p.163-173
• Main Authors: Liu, Yueying, Yang, Jing, Shi, Zonggao, Tan, Xuejuan, Jin, Norman, O'Brien, Catlin, Ott, Connor, Grisoli, Anna, Lee, Eric, Volk, Kelly, Conroy, Meghan, Franz, Emily, Bryant, Annamarie, Campbell, Leigh, Crowley, Brian, Grisoli, Stephen, Alexandrou, Aris T., Li, Chunyan, Harper, Elizabeth I., Asem, Marwa, Johnson, Jeff, Leonard, Annemarie, Santanello, Katie, Klein, Ashley, Wang, Qingfei, Zhang, Siyuan, Hilliard, Tyvette S., Stack, M. Sharon
• Format: Article
• Language: English
• Subjects: AMIGO2; Animals; Ascites; Cancer therapies; Cell Adhesion; Cell adhesion & migration; Cell Line, Tumor; Cell Movement; Cell Survival; Comparative analysis; CRISPR; Female; Gene expression; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Intra-peritoneal metastasis; Invasion; Kinases; Metastases; Metastasis; Mice; Multi-cellular aggregate; Mutation; Neoplasm Transplantation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; p53 Protein; Peritoneal Neoplasms - genetics; Peritoneal Neoplasms - metabolism; Peritoneal Neoplasms - pathology; Peritoneal Neoplasms - secondary; Peritoneum; Protein folding; Spheroid; Tumor cell lines; Tumor Suppressor Protein p53 - genetics; Tumors; Tumorsphere [deleted adhesion; Up-Regulation; Womens health
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2021.01.024

The majority of women with ovarian cancer are diagnosed with metastatic disease, therefore elucidating molecular events that contribute to successful metastatic dissemination may identify additional targets for therapeutic intervention and thereby positively impact survival. Using two human high grade serous ovarian cancer cell lines with inactive TP53 and multiple rounds of serial in vivo passaging, we generated sublines with significantly accelerated intra-peritoneal (IP) growth. Comparative analysis of the parental and IP sublines identified a common panel of differentially expressed genes. The most highly differentially expressed gene, upregulated by 60-65-fold in IP-selected sublines, was the type I transmembrane protein AMIGO2. As the role of AMIGO2 in ovarian cancer metastasis remains unexplored, CRISPR/Cas9 was used to reduce AMIGO2 expression, followed by in vitro and in vivo functional analyses. Knockdown of AMIGO2 modified the sphere-forming potential of ovarian cancer cells, reduced adhesion and invasion in vitro, and significantly attenuated IP metastasis. These data highlight AMIGO2 as a new target for a novel anti-metastatic therapeutic approach aimed at blocking cohesion, survival, and adhesion of metastatic tumorspheres. •Most women with ovarian cancer are diagnosed with diffuse intra-peritoneal (IP) metastases and succumb to metastatic burden.•Ovarian cancer cells selected in vivo for IP metastatic aggressiveness display altered gene expression.•The adhesion molecule AMIGO2 is upregulated in IP metastatic sublines and modulates ovarian cancer tumorsphere compaction.•AMIGO2 represents a novel anti-metastatic target in ovarian cancer.