Cancer Stem Cell News
Cell Therapy News
Dermal Cell News
Endothelial Cell News
ESC & iPSC News
Extracellular Matrix News
Hematopoiesis News
Hepatic Cell News
Human Immunology News
Immune Regulation News
Intestinal Cell News
Mammary Cell News
Mesenchymal Cell News
Muscle Cell News
Neural Cell News
Organoid News
Pancreatic Cell News
Prostate Cell News
Pulmonary Cell NewsTumor organoids and 2D cell lines derived from CCA lesions were addicted to FF signaling via Ras-Erk, regardless of FF identity or V565F mutation.
[Journal of Hepatology]
6445218 X54A9ZYH items 1 apa 0 default asc 1 160274 https://www.stemcellsciencenews.com/wp-content/plugins/zotpress/
%7B%22status%22%3A%22success%22%2C%22updateneeded%22%3Afalse%2C%22instance%22%3A%22zotpress-6e3e81d747defebf7decf3af14eab0ef%22%2C%22meta%22%3A%7B%22request_last%22%3A0%2C%22request_next%22%3A0%2C%22used_cache%22%3Atrue%7D%2C%22data%22%3A%5B%7B%22key%22%3A%22X54A9ZYH%22%2C%22library%22%3A%7B%22id%22%3A6445218%7D%2C%22meta%22%3A%7B%22creatorSummary%22%3A%22Cristinziano%20et%20al.%22%2C%22parsedDate%22%3A%222021-03-17%22%2C%22numChildren%22%3A1%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3ECristinziano%2C%20G.%2C%20Porru%2C%20M.%2C%20Lamberti%2C%20D.%2C%20Buglioni%2C%20S.%2C%20Rollo%2C%20F.%2C%20Amoreo%2C%20C.%20A.%2C%20Manni%2C%20I.%2C%20Giannarelli%2C%20D.%2C%20Cristofoletti%2C%20C.%2C%20Russo%2C%20G.%2C%20Borad%2C%20M.%20J.%2C%20Grazi%2C%20G.%20L.%2C%20Diodoro%2C%20M.%20G.%2C%20Giordano%2C%20S.%2C%20Sacconi%2C%20A.%2C%20Forcato%2C%20M.%2C%20Anastasi%2C%20S.%2C%20Leonetti%2C%20C.%2C%20%26amp%3B%20Segatto%2C%20O.%20%282021%29.%20FGFR2%20fusion%20proteins%20drive%20oncogenic%20transformation%20of%20mouse%20liver%20organoids%20towards%20cholangiocarcinoma.%20%3Ci%3EJournal%20of%20Hepatology%3C%5C%2Fi%3E.%20%3Ca%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1016%5C%2Fj.jhep.2021.02.032%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1016%5C%2Fj.jhep.2021.02.032%3C%5C%2Fa%3E%20%3Ca%20title%3D%27Cite%20in%20RIS%20Format%27%20class%3D%27zp-CiteRIS%27%20href%3D%27https%3A%5C%2F%5C%2Fwww.stemcellsciencenews.com%5C%2Fwp-content%5C%2Fplugins%5C%2Fzotpress%5C%2Flib%5C%2Frequest%5C%2Frequest.cite.php%3Fapi_user_id%3D6445218%26amp%3Bitem_key%3DX54A9ZYH%27%3ECite%3C%5C%2Fa%3E%20%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22FGFR2%20fusion%20proteins%20drive%20oncogenic%20transformation%20of%20mouse%20liver%20organoids%20towards%20cholangiocarcinoma%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Giulia%22%2C%22lastName%22%3A%22Cristinziano%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Manuela%22%2C%22lastName%22%3A%22Porru%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Dante%22%2C%22lastName%22%3A%22Lamberti%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Simonetta%22%2C%22lastName%22%3A%22Buglioni%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Francesca%22%2C%22lastName%22%3A%22Rollo%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Carla%20Azzurra%22%2C%22lastName%22%3A%22Amoreo%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Isabella%22%2C%22lastName%22%3A%22Manni%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Diana%22%2C%22lastName%22%3A%22Giannarelli%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Cristina%22%2C%22lastName%22%3A%22Cristofoletti%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Giandomenico%22%2C%22lastName%22%3A%22Russo%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Mitesh%20J.%22%2C%22lastName%22%3A%22Borad%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Gian%20Luca%22%2C%22lastName%22%3A%22Grazi%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Maria%20Grazia%22%2C%22lastName%22%3A%22Diodoro%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Silvia%22%2C%22lastName%22%3A%22Giordano%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Andrea%22%2C%22lastName%22%3A%22Sacconi%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Mattia%22%2C%22lastName%22%3A%22Forcato%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sergio%22%2C%22lastName%22%3A%22Anastasi%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Carlo%22%2C%22lastName%22%3A%22Leonetti%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Oreste%22%2C%22lastName%22%3A%22Segatto%22%7D%5D%2C%22abstractNote%22%3A%22Background%20and%20aims%5CnAbout%2015%25%20of%20intrahepatic%20cholangiocarcinoma%20%28iCCA%29%20express%20fibroblast%20growth%20factor%20receptor%202%20%28FGFR2%29%20fusion%20proteins%20%28FFs%29%2C%20most%20often%20in%20concert%20with%20mutational%20inactivation%20of%20TP53%2C%20CDKN2A%20or%20BAP1.%20In%20FFs%2C%20FGFR2%20residues%201-768%20are%20fused%20to%20sequences%20encoded%20by%20a%20diverse%20array%20of%20partner%20genes%20%28%3E60%29%2C%20a%20configuration%20that%20causes%20oncogenic%20FF%20activation.%20While%20FGFR-specific%20tyrosine%20kinase%20inhibitors%20%28F-TKI%29%20provide%20clinical%20benefit%20in%20FF%2B%20iCCA%2C%20responses%20are%20partial%20and%5C%2For%20limited%20by%20resistance%20mechanisms%2C%20including%20FF%20tyrosine%20kinase%20domain%20mutations%2C%20such%20as%20the%20V565F%20substitution%20in%20the%20FGFR2%20gatekeeper%20residue.%20Improving%20on%20FF%20targeting%20in%20iCCA%20therefore%20remains%20a%20critical%20and%20unmet%20need.%20Herein%2C%20we%20present%20the%20generation%20of%20FF-driven%20murine%20iCCA%20models%20and%20their%20exploitation%20for%20discovering%20actionable%20FF-associated%20dependencies.%5CnMethods%5CnFour%20iCCA%20FFs%20carrying%20different%20fusion%20sequences%20were%20expressed%20in%20Tp53-%5C%2F-%20mouse%20liver%20organoids.%20Tumorigenic%20properties%20of%20genetically%20modified%20liver%20organoids%20were%20assessed%20by%20transplantation%20in%20immuno-deficient%20mice.%20Cellular%20models%20derived%20from%20neoplastic%20lesions%20were%20exploited%20for%20pre-clinical%20studies.%5CnResults%5CnTransplantation%20of%20FF-expressing%20liver%20organoids%20yielded%20tumors%20diagnosed%20as%20CCA%20based%20on%20histological%2C%20phenotypic%20and%20transcriptomic%20analyses.%20The%20penetrance%20of%20this%20tumorigenic%20phenotype%20was%20influenced%20by%20FF%20identity.%20Tumor%20organoids%20and%202D%20cell%20lines%20derived%20from%20CCA%20lesions%20were%20addicted%20to%20FF%20signaling%20via%20Ras-Erk%2C%20regardless%20of%20FF%20identity%20or%20V565F%20mutation.%20Dual%20blockade%20of%20FF%20and%20Ras-Erk%20pathway%20by%20concomitant%20pharmacological%20inhibition%20of%20FFs%20and%20Mek1%5C%2F2%20provided%20greater%20therapeutic%20efficacy%20than%20single%20agent%20F-TKI%20in%20vitro%20and%20in%20vivo.%5CnConclusions%5CnFF-driven%20iCCA%20pathogenesis%20was%20successfully%20modeled%20in%20murine%20Tp53-%5C%2F-background%2C%20revealing%20biological%20heterogeneity%20among%20structurally%20different%20FFs.%20Double%20blockade%20of%20FF-Erk%20signaling%20deserves%20consideration%20for%20precision-based%20approaches%20against%20human%20FF%2B%20iCCA.%5CnLay%20summary%5CnIntrahepatic%20cholangiocarcinoma%20%28iCCA%29%20is%20a%20difficult-to-treat%20rare%20type%20of%20cancer.%20A%20subtype%20of%20iCCA%20is%20caused%20by%20genomic%20alterations%20that%20generate%20oncogenic%20drivers%20known%20as%20FGFR2%20fusions.%20CCA%20patients%20with%20FGFR2%20fusions%20respond%20to%20FGFR%20inhibitors%2C%20but%20clinical%20responses%20are%20often%20of%20modest%20duration.%20We%20generated%20animal%20and%20cellular%20models%20of%20iCCA%20driven%20by%20FGFR2%20fusions%2C%20which%20showed%20sensitivity%20to%20FGFR%20inhibitors.%20In%20addition%2C%20we%20showed%20that%20FGFR2%20fusions%20require%20the%20activity%20of%20a%20downstream%20effector%20named%20Mek1%5C%2F2.%20We%20found%20that%20dual%20blockade%20of%20FGFR2%20fusions%20and%20Mek1%5C%2F2%20in%20iCCA%20was%20more%20effective%20than%20isolated%20inhibition%20of%20FGR2%20fusions%2C%20pointing%20to%20potential%20clinical%20utility%20of%20dual%20FGFR2-MEK1%5C%2F2%20blockade.%22%2C%22date%22%3A%22March%2017%2C%202021%22%2C%22language%22%3A%22en%22%2C%22DOI%22%3A%2210.1016%5C%2Fj.jhep.2021.02.032%22%2C%22ISSN%22%3A%220168-8278%22%2C%22url%22%3A%22https%3A%5C%2F%5C%2Fwww.sciencedirect.com%5C%2Fscience%5C%2Farticle%5C%2Fpii%5C%2FS0168827821001720%22%2C%22collections%22%3A%5B%5D%2C%22dateModified%22%3A%222021-03-18T23%3A09%3A10Z%22%7D%7D%5D%7D
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. (2021). FGFR2 fusion proteins drive oncogenic transformation of mouse liver organoids towards cholangiocarcinoma. Journal of Hepatology. https://doi.org/10.1016/j.jhep.2021.02.032 Cite
