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.

Global characterization of RNA editing in genetic regulation of multiple ovarian cancer subtypes

“…Ovarian cancer (OV) is a disease with clinical diversity and high histological and molecular heterogeneity, 1 , 2 , 3 and its histological phenotype is associated with distinct genetic patterns. 4 Each subtype has a different histopathology and a different response to treatment.…”

A Crosstalk between the Receptor Tyrosine Kinase-Like Orphan Receptors ROR1/2 and S1P Signaling Pathways in Lung Cancer

“…S1P-S1PR1 signalling induces persistent activation of STAT3 and leads to chronic intestinal inflammation and development of colitis-associated cancer [ 8 ]. Interestingly, ROR1 expression is induced by STAT3 [ 9 ], which is in turn being activated by S1P. Additionally, S1PR1 trans-activates receptor tyrosine kinases [ 10 ].…”

Discovery of Novel Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1) Inhibitors for Cancer Treatment

“…Increasing evidence has revealed that ROR1 is aberrantly overexpressed in several malignancies, such as lung cancer, breast cancer, and chronic lymphocytic leukemia (CLL). Upon Wnt5a stimulation, ROR1 activates multiple signaling transductions, including PI3K/AKT/mTOR, RAS/ERK, NF-κB, JAK/STAT, and/or Hippo pathways, which are involved in tumor progression and poor survival of patients by promoting cell proliferation, survival, and metastasis. − Consequently, targeting ROR1 might be a potential cancer treatment approach. Some initial progress has been achieved in cancer treatment by ROR1-targeting monoclonal antibodies, antibody-drug conjugates (ADCs), CAR-T cells, and small-molecule inhibitors (Figure ).…”