ROR1-STAT3 signaling contributes to ovarian cancer intra-tumor heterogeneity

Abstract

Wnt pathway dysregulation through genetic and non-genetic alterations occurs in multiple cancers, including ovarian cancer (OC). The aberrant expression of the non-canonical Wnt signaling receptor ROR1 is thought to contribute to OC progression and drug resistance. However, the key molecular events mediated by ROR1 that are involved in OC tumorigenesis are not fully understood. Here, we show that ROR1 expression is enhanced by neoadjuvant chemotherapy, and Wnt5a binding to ROR1 can induce oncogenic signaling via AKT/ERK/STAT3 activation in OC cells. Proteomics analysis of isogenic ROR1-knockdown OC cells identified STAT3 as a downstream effector of ROR1 signaling. Transcriptomics analysis of clinical samples (n = 125) revealed that ROR1 and STAT3 are expressed at higher levels in stromal cells than in epithelial cancer cells of OC tumors, and these findings were corroborated by multiplex immunohistochemistry (mIHC) analysis of an independent OC cohort (n = 11). Our results show that ROR1 and its downstream STAT3 are co-expressed in epithelial as well as stromal cells of OC tumors, including cancer-associated fibroblasts or CAFs. Our data provides the framework to expand the clinical utility of ROR1 as a therapeutic target to overcome OC progression.