Oncogenic KRAS Requires Complete Loss of BAP1 Function for Development of Murine Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is a primary biliary malignancy that harbors a dismal prognosis. Oncogenic mutations of KRAS and loss-of-function mutations of BRCA1-associated protein 1 (BAP1) have been identified as recurrent somatic al...

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Autores principales:	Rebecca Marcus, Sammy Ferri-Borgogno, Abdel Hosein, Wai Chin Foo, Bidyut Ghosh, Jun Zhao, Kimal Rajapakshe, James Brugarolas, Anirban Maitra, Sonal Gupta
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	intrahepatic cholangiocarcinoma mouse model BAP1 KRAS ferroptosis SLC7A11 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/a62495aad21549c2a67f379c1a441774
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spelling	oai:doaj.org-article:a62495aad21549c2a67f379c1a4417742021-11-25T17:02:59ZOncogenic KRAS Requires Complete Loss of BAP1 Function for Development of Murine Intrahepatic Cholangiocarcinoma10.3390/cancers132257092072-6694https://doaj.org/article/a62495aad21549c2a67f379c1a4417742021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/22/5709https://doaj.org/toc/2072-6694Intrahepatic cholangiocarcinoma (ICC) is a primary biliary malignancy that harbors a dismal prognosis. Oncogenic mutations of <i>KRAS</i> and loss-of-function mutations of <i>BRCA1-associated protein 1</i> (<i>BAP1</i>) have been identified as recurrent somatic alterations in ICC. However, an autochthonous genetically engineered mouse model of ICC that genocopies the co-occurrence of these mutations has never been developed. By crossing <i>Albumin</i>-Cre mice bearing conditional alleles of mutant <i>Kras</i> and/or floxed <i>Bap1,</i> Cre-mediated recombination within the liver was induced. Mice with hepatic expression of mutant <i>Kras</i><sup>G12D</sup> alone (KA), bi-allelic loss of hepatic <i>Bap1</i> (B<sup>homo</sup>A), and heterozygous loss of <i>Bap1</i> in conjunction with mutant <i>Kras</i><sup>G12D</sup> expression (B<sup>het</sup>KA) developed primary hepatocellular carcinoma (HCC), but no discernible ICC. In contrast, mice with homozygous loss of <i>Bap1</i> in conjunction with mutant <i>Kras</i><sup>G12D</sup> expression (B<sup>homo</sup>KA) developed discrete foci of HCC and ICC. Further, the median survival of B<sup>homo</sup>KA mice was significantly shorter at 24 weeks when compared to the median survival of ≥40 weeks in B<sup>het</sup>KA mice and approximately 50 weeks in B<sup>homo</sup>A and KA mice (<i>p</i> < 0.001). Microarray analysis performed on liver tissue from KA and B<sup>homo</sup>KA mice identified differentially expressed genes in the setting of BAP1 loss and suggests that deregulation of ferroptosis might be one mechanism by which loss of BAP1 cooperates with oncogenic Ras in hepato-biliary carcinogenesis. Our autochthonous model provides an in vivo platform to further study this lethal class of neoplasm.Rebecca MarcusSammy Ferri-BorgognoAbdel HoseinWai Chin FooBidyut GhoshJun ZhaoKimal RajapaksheJames BrugarolasAnirban MaitraSonal GuptaMDPI AGarticleintrahepatic cholangiocarcinomamouse modelBAP1KRASferroptosisSLC7A11Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5709, p 5709 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	intrahepatic cholangiocarcinoma mouse model BAP1 KRAS ferroptosis SLC7A11 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	intrahepatic cholangiocarcinoma mouse model BAP1 KRAS ferroptosis SLC7A11 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Rebecca Marcus Sammy Ferri-Borgogno Abdel Hosein Wai Chin Foo Bidyut Ghosh Jun Zhao Kimal Rajapakshe James Brugarolas Anirban Maitra Sonal Gupta Oncogenic KRAS Requires Complete Loss of BAP1 Function for Development of Murine Intrahepatic Cholangiocarcinoma
description	Intrahepatic cholangiocarcinoma (ICC) is a primary biliary malignancy that harbors a dismal prognosis. Oncogenic mutations of <i>KRAS</i> and loss-of-function mutations of <i>BRCA1-associated protein 1</i> (<i>BAP1</i>) have been identified as recurrent somatic alterations in ICC. However, an autochthonous genetically engineered mouse model of ICC that genocopies the co-occurrence of these mutations has never been developed. By crossing <i>Albumin</i>-Cre mice bearing conditional alleles of mutant <i>Kras</i> and/or floxed <i>Bap1,</i> Cre-mediated recombination within the liver was induced. Mice with hepatic expression of mutant <i>Kras</i><sup>G12D</sup> alone (KA), bi-allelic loss of hepatic <i>Bap1</i> (B<sup>homo</sup>A), and heterozygous loss of <i>Bap1</i> in conjunction with mutant <i>Kras</i><sup>G12D</sup> expression (B<sup>het</sup>KA) developed primary hepatocellular carcinoma (HCC), but no discernible ICC. In contrast, mice with homozygous loss of <i>Bap1</i> in conjunction with mutant <i>Kras</i><sup>G12D</sup> expression (B<sup>homo</sup>KA) developed discrete foci of HCC and ICC. Further, the median survival of B<sup>homo</sup>KA mice was significantly shorter at 24 weeks when compared to the median survival of ≥40 weeks in B<sup>het</sup>KA mice and approximately 50 weeks in B<sup>homo</sup>A and KA mice (<i>p</i> < 0.001). Microarray analysis performed on liver tissue from KA and B<sup>homo</sup>KA mice identified differentially expressed genes in the setting of BAP1 loss and suggests that deregulation of ferroptosis might be one mechanism by which loss of BAP1 cooperates with oncogenic Ras in hepato-biliary carcinogenesis. Our autochthonous model provides an in vivo platform to further study this lethal class of neoplasm.
format	article
author	Rebecca Marcus Sammy Ferri-Borgogno Abdel Hosein Wai Chin Foo Bidyut Ghosh Jun Zhao Kimal Rajapakshe James Brugarolas Anirban Maitra Sonal Gupta
author_facet	Rebecca Marcus Sammy Ferri-Borgogno Abdel Hosein Wai Chin Foo Bidyut Ghosh Jun Zhao Kimal Rajapakshe James Brugarolas Anirban Maitra Sonal Gupta
author_sort	Rebecca Marcus
title	Oncogenic KRAS Requires Complete Loss of BAP1 Function for Development of Murine Intrahepatic Cholangiocarcinoma
title_short	Oncogenic KRAS Requires Complete Loss of BAP1 Function for Development of Murine Intrahepatic Cholangiocarcinoma
title_full	Oncogenic KRAS Requires Complete Loss of BAP1 Function for Development of Murine Intrahepatic Cholangiocarcinoma
title_fullStr	Oncogenic KRAS Requires Complete Loss of BAP1 Function for Development of Murine Intrahepatic Cholangiocarcinoma
title_full_unstemmed	Oncogenic KRAS Requires Complete Loss of BAP1 Function for Development of Murine Intrahepatic Cholangiocarcinoma
title_sort	oncogenic kras requires complete loss of bap1 function for development of murine intrahepatic cholangiocarcinoma
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/a62495aad21549c2a67f379c1a441774
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Oncogenic KRAS Requires Complete Loss of BAP1 Function for Development of Murine Intrahepatic Cholangiocarcinoma

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