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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,11,11]]},"abstract":"<jats:p>\n                    The MEK\u2013ERK pathway is a key driver of hepatocellular carcinoma (HCC) pathogenesis, and BRAF mutations, particularly BRAF\n                    <jats:sup>V600E<\/jats:sup>\n                    , can contribute to its activation. Although BRAF\n                    <jats:sup>V600E<\/jats:sup>\n                    mutations are rare in human HCC, they do occur, yet their physiologic impact in liver cells, especially when combined with frequent comutations in tumor suppressor genes, remains poorly understood. Moreover, the effect of BRAF inhibitors on HCC progression and metastasis is not well-defined. Therefore, we developed mouse models with hepatocyte-specific BRAF\n                    <jats:sup>V600E<\/jats:sup>\n                    expression and Trp53 or Cdkn2a deletion to assess tumor development, subtypes, and metastatic patterns. We found that BRAF\n                    <jats:sup>V600E<\/jats:sup>\n                    expression caused hepatomegaly, vascular congestion, and ductal reactions, and led to reduced liver function and early mortality. Codeletion of Trp53 or Cdkn2a markedly increased primary liver tumor incidence and enabled sarcomatoid metastasis. While the BRAF inhibitor PLX4720 effectively reduced primary tumors and extended survival, it paradoxically increased sarcomatoid metastases. Mechanistically, PLX4720 and other RAF inhibitors induced TGF\u03b22 expression which promoted epithelial-to-mesenchymal transition (EMT) and enhanced tumorigenicity. The effects of RAF inhibitors on TGF\u03b22 expression were validated in BRAF\n                    <jats:sup>V600E<\/jats:sup>\n                    -mutant human melanoma cells. We conclude that BRAF\n                    <jats:sup>V600E<\/jats:sup>\n                    drives diverse primary tumors but only one type of metastasis and that RAF inhibition, while effective against primary tumors, may promote metastasis through TGF\u03b22-mediated EMT. Although RAF inhibitors remain promising therapies, their unintended role in enhancing metastasis raises concerns that may extend beyond liver cancer to other BRAF\n                    <jats:sup>V600E<\/jats:sup>\n                    -driven malignancies.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2503044122","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T16:08:23Z","timestamp":1762445303000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["BRAF inhibition increases TGF\u03b22 production and stimulates metastasis in mice with endogenous BRAF\n                    <sup>V600E<\/sup>\n                    -induced hepatocellular carcinoma"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7788-3903","authenticated-orcid":false,"given":"Jaroslaw","family":"Cisowski","sequence":"first","affiliation":[{"name":"Sahlgrenska Center for Cancer Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg","place":["Gothenburg, Sweden"]},{"name":"Faculty of Biochemistry, Biophysics and Biotechnology, Department of General Biochemistry, Jagiellonian University","place":["Krakow, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6177-6142","authenticated-orcid":false,"given":"Ahmed Ezat","family":"El Zowalaty","sequence":"additional","affiliation":[{"name":"Sahlgrenska Center for Cancer Research, Department of Surgery, Institute of Clinical Sciences, University of Gothenburg","place":["Gothenburg, Sweden"]},{"name":"Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg","place":["Gothenburg, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1993-3487","authenticated-orcid":false,"given":"Sama I.","family":"Sayin","sequence":"additional","affiliation":[{"name":"Sahlgrenska Center for Cancer Research, Department of Surgery, Institute of Clinical Sciences, University of Gothenburg","place":["Gothenburg, Sweden"]},{"name":"Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg","place":["Gothenburg, Sweden"]},{"name":"Department of Oncology, Sahlgrenska University Hospital","place":["Gothenburg, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2304-8781","authenticated-orcid":false,"given":"Piotr","family":"Czarnota","sequence":"additional","affiliation":[{"name":"Faculty of Biochemistry, Biophysics and Biotechnology, Department of General Biochemistry, Jagiellonian University","place":["Krakow, Poland"]},{"name":"Doctoral School of Exact and Natural Sciences, Jagiellonian University","place":["Krakow, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6905-2886","authenticated-orcid":false,"given":"Tomasz","family":"Gromowski","sequence":"additional","affiliation":[{"name":"Faculty of Biochemistry, Biophysics and Biotechnology, Department of General Biochemistry, Jagiellonian University","place":["Krakow, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ella A.","family":"Eklund","sequence":"additional","affiliation":[{"name":"Sahlgrenska Center for Cancer Research, Department of Surgery, Institute of Clinical Sciences, University of Gothenburg","place":["Gothenburg, Sweden"]},{"name":"Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg","place":["Gothenburg, Sweden"]},{"name":"Department of Oncology, Sahlgrenska University Hospital","place":["Gothenburg, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Kashif","sequence":"additional","affiliation":[{"name":"Department of Medicine, Karolinska Institutet","place":["Huddinge, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5499-9655","authenticated-orcid":false,"given":"Angana A. H.","family":"Patel","sequence":"additional","affiliation":[{"name":"Sahlgrenska Center for Cancer Research, Department of Surgery, Institute of Clinical Sciences, University of Gothenburg","place":["Gothenburg, Sweden"]},{"name":"Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg","place":["Gothenburg, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Molinaro","sequence":"additional","affiliation":[{"name":"Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital","place":["Gothenburg, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per","family":"Lindahl","sequence":"additional","affiliation":[{"name":"Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital","place":["Gothenburg, 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