دورية أكاديمية
FGFR2 fusion proteins drive oncogenic transformation of mouse liver organoids towards cholangiocarcinoma
| العنوان: | FGFR2 fusion proteins drive oncogenic transformation of mouse liver organoids towards cholangiocarcinoma |
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| المؤلفون: | Cristinziano G., Porru M., Lamberti D., Buglioni S., Rollo F., Amoreo C. A., Manni I., Giannarelli D., Cristofoletti C., Russo G., Borad M. J., Grazi G. L., Diodoro M. G., Giordano S., Sacconi A., Forcato M., Anastasi S., Leonetti C., Segatto O. |
| المساهمون: | Cristinziano, G., Porru, M., Lamberti, D., Buglioni, S., Rollo, F., Amoreo, C. A., Manni, I., Giannarelli, D., Cristofoletti, C., Russo, G., Borad, M. J., Grazi, G. L., Diodoro, M. G., Giordano, S., Sacconi, A., Forcato, M., Anastasi, S., Leonetti, C., Segatto, O. |
| بيانات النشر: | Elsevier B.V. |
| سنة النشر: | 2021 |
| المجموعة: | Padua Research Archive (IRIS - Università degli Studi di Padova) |
| مصطلحات موضوعية: | BGJ398, cholangiocarcinoma, FGFR2 fusion, FGFR2 gatekeeper mutation, FGFR2-BICC1, liver organoid, mouse model, targeted therapie, trametinib |
| الوصف: | Background & Aims: About 15% of intrahepatic cholangiocarcinomas (iCCAs) express fibroblast growth factor receptor 2 (FGFR2) fusion proteins (FFs), usually alongside mutational inactivation of TP53, CDKN2A or BAP1. In FFs, FGFR2 residues 1-768 fuse to sequences encoded by a diverse array of partner genes (>60) causing oncogenic FF activation. While FGFR-specific tyrosine kinase inhibitors (F-TKI) provide clinical benefit in FF+ iCCA, responses are partial and/or limited by resistance mechanisms, such as the V565F substitution in the FGFR2 gatekeeper residue. Improving on FF targeting in iCCA therefore remains a critical unmet need. Herein, we aimed to generate a murine model of FF-driven iCCA and use this to uncover actionable FF-associated dependencies. Methods: Four iCCA FFs carrying different fusion sequences were expressed in Tp53-/- mouse liver organoids. Tumorigenic properties of genetically modified liver organoids were assessed by transplantation into immuno-deficient mice. Cellular models derived from neoplastic lesions were exploited for pre-clinical studies. Results: Transplantation of FF-expressing liver organoids yielded tumors diagnosed as CCA based on histological, phenotypic and transcriptomic analyses. The penetrance of this tumorigenic phenotype was influenced by FF identity. Tumor organoids and 2D cell lines derived from CCA lesions were addicted to FF signaling via Ras-Erk, regardless of FF identity or V565F mutation. Dual blockade of FF and the Ras-Erk pathway by concomitant pharmacological inhibition of FFs and Mek1/2 provided greater therapeutic efficacy than single agent F-TKI in vitro and in vivo. Conclusions: FF-driven iCCA pathogenesis was successfully modeled on a Tp53-/- murine background, revealing biological heterogeneity among structurally different FFs. Double blockade of FF-ERK signaling deserves consideration for precision-based approaches against human FF+ iCCA. Lay summary: Intrahepatic cholangiocarcinoma (iCCA) is a rare cancer that is difficult to treat. A subtype of ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/wos/WOS:000675486300014; volume:75; issue:2; firstpage:351; lastpage:362; numberofpages:12; journal:JOURNAL OF HEPATOLOGY; https://hdl.handle.net/11577/3500947Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85105747340 |
| DOI: | 10.1016/j.jhep.2021.02.032 |
| الإتاحة: | https://doi.org/10.1016/j.jhep.2021.02.032Test https://hdl.handle.net/11577/3500947Test |
| رقم الانضمام: | edsbas.A6074324 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1016/j.jhep.2021.02.032 |
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