TY - JOUR
T1 - ROR1-STAT3 signaling contributes to ovarian cancer intra-tumor heterogeneity
AU - Piki, Emilia
AU - Dini, Alice
AU - Raivola, Juuli
AU - Salokas, Kari
AU - Zhang, Kaiyang
AU - Varjosalo, Markku
AU - Pellinen, Teijo
AU - Välimäki, Katja
AU - Veskimäe, Kristina Tabor
AU - Staff, Synnöve
AU - Hautaniemi, Sampsa
AU - Murumägi, Astrid
AU - Ungureanu, Daniela
N1 - Funding Information:
We would like to thank the patients and their families for participating in the study. We also thank the excellent staff and resources provided by the FIMM Technology Center and the Proteomics Unit, Institute of Biotechnology & HiLIFE at the University of Helsinki. We thank Dr. Hanna Karvonen, Wilhelmiina Niininen, Sari Toivola, and Annabrita Schoonenberg for excellent technical assistance. These operations thank Biocenter Finland for instrument 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).
Funding Information:
We would like to thank the patients and their families for participating in the study. We also thank the excellent staff and resources provided by the FIMM Technology Center and the Proteomics Unit, Institute of Biotechnology & HiLIFE at the University of Helsinki. We thank Dr. Hanna Karvonen, Wilhelmiina Niininen, Sari Toivola, and Annabrita Schoonenberg for excellent technical assistance. These operations thank Biocenter Finland for instrument 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).
Publisher Copyright:
© 2023, The Author(s).
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
U2 - 10.1038/s41420-023-01527-6
DO - 10.1038/s41420-023-01527-6
M3 - Article
AN - SCOPUS:85163955730
SN - 2058-7716
VL - 9
JO - Cell Death Discovery
JF - Cell Death Discovery
IS - 1
M1 - 222
ER -
