University of Oulu

Piki, E., Dini, A., Raivola, J. et al. ROR1-STAT3 signaling contributes to ovarian cancer intra-tumor heterogeneity. Cell Death Discov. 9, 222 (2023).

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

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Author: Piki, Emilia1; Dini, Alice1; Raivola, Juuli2;
Organizations: 1Disease Networks Unit, Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90014, Oulu, Finland
2Applied Tumor Genomics, Research Program Unit, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland
3Institute of Biotechnology, University of Helsinki, 00014, Helsinki, Finland
4Research Program in Systems Oncology, Research Program Unit, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland
5Institute for Molecular Medicine Finland, FIMM, Helsinki Institute of Life Science (HiLIFE) University of Helsinki, 00014, Helsinki, Finland
6Department of Obstetrics and Gynecology, Tampere University Hospital and Faculty of Medicine and Health Technology, Tampere University, 33014, Tampere, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 8.1 MB)
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Language: English
Published: Springer Nature, 2023
Publish Date: 2023-08-18


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.

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Series: Cell death discovery
ISSN: 2058-7716
ISSN-E: 2058-7716
ISSN-L: 2058-7716
Volume: 9
Issue: 1
Article number: 222
DOI: 10.1038/s41420-023-01527-6
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
3122 Cancers
Funding: This work was supported by the University of Oulu and funded by the Academy of Finland (Profi6 #336449, #333583; #288475; #271845; #349787 and Finnish Center of Excellence in Tumor Genetics Research #312042); Sigrid Juselius Foundation, and Finnish Cancer Foundation (to D.U, M.V.) the European Union Horizon 2020 research and innovation program under grant agreements No. 667403 for HERCULES (to SH) and No. 965193 for DECIDER (to SH).
Copyright information: © The Author(s) 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit