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Expression of an Embryonic Receptor, ROR1, Defines a Targetable Ovarian Cancer Stem Cell Population /


ROR1 is a type I receptor tyrosine kinase like orphan- receptor that is expressed on embryonic and neoplastic cells, but not normal adult tissues. It is associated with poorly differentiated tumors of high metastatic potential. In this study, we evaluated ROR1 expression in human ovarian cancers and its association with phenotypical and functional characteristics of cancer stem cells (CSCs). We also examined the activity of an anti-ROR1 monoclonal antibody (UC-961), found to have activity against ROR1+ breast cancer cell lines and B-cell leukemia, against ovarian cancer. In each primary human ovarian tumor studied, we found ROR1 expression is associated with markers of CSC, specifically aldehyde dehydrogenase 1 (ALDH1). ROR1⁺ cells from the PDX samples had greater spheroid formation in vitro and engraftment in immunodeficient mice than ROR1⁻ cells from the same sample. Treatment of cancer cells with UC-961 reproducibly impaired the spheroid formation and engraftment abilities of ROR1⁺ cells. ALDH1⁺ and ALDH1⁻ cells isolated from the same PDX samples confirmed the enhanced engraftment of ALDH1⁺ cells. Treatment with UC-961, however, eliminated the difference in engraftment capacity between ALDH1⁺ and ALDH1⁻ cells. Analysis of the few tumors that did develop in mice with UC-961-treated tumor cells revealed that these tumors had lower proportions of ALDH1⁺ cells, reduced expression of Bmi1, and altered expression of EMT markers compared to the original sample. Collectively, these studies indicate that ROR1 is associated with CSC and that anti-ROR1 mAbs can interfere with CSC function and self-renewal, suggesting a therapeutic use in treatment of ovarian cancer patients

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