PUBLICATION
Cancer-associated fibroblast driven paracrine IL-6/STAT3 signaling promotes migration and dissemination in invasive lobular carcinoma
- Authors
- Bullock, E., Rozyczko, A., Shabbir, S., Tsoupi, I., Young, A.I.J., Travnickova, J., Gómez-Cuadrado, L., Mabruk, Z., Carrasco, G., Morrow, E., Pennel, K., Kloosterman, P., Houthuijzen, J.M., Jonkers, J., Avalle, L., Poli, V., Iggo, R., Xiao, X., Guo, J., Zhu, X., Mallon, E., Edwards, J., Patton, E.E., Brunton, V.G.
- ID
- ZDB-PUB-250702-1
- Date
- 2025
- Source
- Breast cancer research : BCR 27: 121121 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Signal Transduction
- Cell Line, Tumor
- Humans
- Gene Expression Regulation, Neoplastic
- Cancer-Associated Fibroblasts*/metabolism
- Cancer-Associated Fibroblasts*/pathology
- Breast Neoplasms*/genetics
- Breast Neoplasms*/metabolism
- Breast Neoplasms*/pathology
- Paracrine Communication
- Neoplasm Invasiveness
- Interleukin-6*/genetics
- Interleukin-6*/metabolism
- Female
- Carcinoma, Lobular*/genetics
- Carcinoma, Lobular*/metabolism
- Carcinoma, Lobular*/pathology
- STAT3 Transcription Factor*/genetics
- STAT3 Transcription Factor*/metabolism
- Zebrafish
- Animals
- Cell Movement
- Mice
- PubMed
- 40597443 Full text @ Breast Cancer Res.
Citation
Bullock, E., Rozyczko, A., Shabbir, S., Tsoupi, I., Young, A.I.J., Travnickova, J., Gómez-Cuadrado, L., Mabruk, Z., Carrasco, G., Morrow, E., Pennel, K., Kloosterman, P., Houthuijzen, J.M., Jonkers, J., Avalle, L., Poli, V., Iggo, R., Xiao, X., Guo, J., Zhu, X., Mallon, E., Edwards, J., Patton, E.E., Brunton, V.G. (2025) Cancer-associated fibroblast driven paracrine IL-6/STAT3 signaling promotes migration and dissemination in invasive lobular carcinoma. Breast cancer research : BCR. 27:121121.
Abstract
Background Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer after invasive ductal carcinoma of no special type (NST), accounting for 10-15% of diagnoses. Despite the myriad molecular, histological and clinical differences between ILC and NST tumors, patients are treated in the same way, and although prognosis initially is good, ILC patients have poorer long-term outcomes. Understanding the differences between these two subtypes and identifying ILC-enriched therapeutic targets is necessary to improve patient care.
Methods Human and mouse cancer-associated fibroblasts (CAFs), ILC cell lines and patient-derived organoids were used for in vitro and in vivo studies, including western blotting, migration, organotypic invasion assays and dissemination in zebrafish embryos. RNASeq was used to identify CAF and interleukin-6 (IL-6)-derived gene signatures. Bioinformatic analysis of public databases and immunohistochemical of human tumor microarrays was carried out.
Results We identified IL-6 as a paracrine CAF-derived factor that activates Signal-Transducer-and-Activator-of-Transcription-3 (STAT3) in human and mouse ILC models. Analysis of human breast tumors showed that the IL-6/JAK/STAT3 pathway is enriched in ER + ILC compared to ER + NST. A 42-gene CAF dependent IL-6 gene signature and 64-gene consensus IL-6 gene signature were generated and were significantly enriched in ER + ILC, with many of the genes overexpressed in ILC tumors. IL-6 treatment suppressed downstream estrogen signaling and also led to the acquisition of a more mesenchymal-like phenotype associated with increased migration and invasion. Finally, IL-6 treatment significantly increased ILC cell dissemination following injection into zebrafish embryos.
Conclusions CAF-derived IL-6 drives paracrine activation of the IL6/JAK/STAT3 signaling pathway which is enriched in ILC. This leads to the acquisition of pro-tumorigenic phenotypes, highlighting the pathway as a potential therapeutic target in ILC.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping