RT info:eu-repo/semantics/article
T1 Cancer-associated fibroblast driven paracrine IL-6/STAT3 signaling promotes migration and dissemination in invasive lobular carcinoma
A1 Bullock, Esme
A1 Rozyczko, Aleksandra
A1 Shabbir, Sana
A1 Tsoupi, Ifigenia
A1 Young, Adelaide I.J.
A1 Travnickova, Jana
A1 Gómez Cuadrado, Laura
A1 Mabruk, Zeanap
A1 Carrasco, Giovana
A1 Morrow, Elizabeth
A1 Pennel, Kathryn
A1 Kloosterman, Pim
A1 Houthuijzen, Julia M
A1 Jonkers, Jos
A1 Avalle, Lidia
A1 Poli, Valeria
A1 Iggo, Richard
A1 Xiao, Xue
A1 Guo, Jingjing
A1 Zhu, Xuan
A1 Mallon, Elizabeth
A1 Edwards, Joanne
A1 Patton, E. Elizabeth
A1 Brunton, Valerie G.
K1 Mamas-Cáncer
K1 Breast-Cancer
AB 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.
PB BioMed Central
SN 1465-5411
YR 2025
FD 2025-07
LK https://hdl.handle.net/10259/10648
UL https://hdl.handle.net/10259/10648
LA eng
NO This work was funded by Cancer Research UK (C157/A24837) to V.G.B. and (CANTAC721\100018) to E.B.; an NHS Lothian Charity award (S3181) to V.G.B; an Endeavour Scholarship (734/2018/878) to Z.M.; Punjab Educational Endowment Funds, Pakistan-programme 2020–2024 to S.S.; Medical Research Council (MC_UU_00035/13), Melanoma Research Alliance and Rosetrees Trust (MRA Awards 68730 and 917226) to E.E.P.; Sichuan Science and Technology Program (NO. 2022YFS0601) and Sichuan Provincial People’s Hospital to X.X. This work was supported by the Cancer Research UK Scotland Centre (CTRQQR-2021\100006).
DS Repositorio Institucional de la Universidad de Burgos
RD 19-abr-2026