Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors

Abstract Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous population of neoplasms that arise from hormone-secreting islet cells of the pancreas and have increased markedly in incidence over the past four decades. Non-functional PanNETs, which occur more frequently than hormone-secretin...

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Autores principales:	Angela M. Carter, Nilesh Kumar, Brendon Herring, Chunfeng Tan, Rachael Guenter, Rahul Telange, Wayne Howse, Fabrice Viol, Tyler R. McCaw, Hayden H. Bickerton, Priyanka Gupta, Frank Gillardon, Eugene A. Woltering, Deepti Dhall, John Totenhagen, Ronadip R. Banerjee, Elizabeth M. Kurian, Sushanth Reddy, Herbert Chen, Joerg Schrader, J. Bart Rose, M. Shahid Mukhtar, James A. Bibb
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/21cdb33eda954fce8c488ba99cf2f677
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spelling	oai:doaj.org-article:21cdb33eda954fce8c488ba99cf2f6772021-12-05T12:10:55ZCdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors10.1038/s41389-021-00372-52157-9024https://doaj.org/article/21cdb33eda954fce8c488ba99cf2f6772021-12-01T00:00:00Zhttps://doi.org/10.1038/s41389-021-00372-5https://doaj.org/toc/2157-9024Abstract Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous population of neoplasms that arise from hormone-secreting islet cells of the pancreas and have increased markedly in incidence over the past four decades. Non-functional PanNETs, which occur more frequently than hormone-secreting tumors, are often not diagnosed until later stages of tumor development and have poorer prognoses. Development of successful therapeutics for PanNETs has been slow, partially due to a lack of diverse animal models for pre-clinical testing. Here, we report development of an inducible, conditional mouse model of PanNETs by using a bi-transgenic system for regulated expression of the aberrant activator of Cdk5, p25, specifically in β-islet cells. This model produces a heterogeneous population of PanNETs that includes a subgroup of well-differentiated, non-functional tumors. Production of these tumors demonstrates the causative potential of aberrantly active Cdk5 for generation of PanNETs. Further, we show that human PanNETs express Cdk5 pathway components, are dependent on Cdk5 for growth, and share genetic and transcriptional overlap with the INS-p25OE model. The utility of this model is enhanced by the ability to form tumor-derived allografts. This new model of PanNETs will facilitate molecular delineation of Cdk5-dependent PanNETs and the development of new targeted therapeutics.Angela M. CarterNilesh KumarBrendon HerringChunfeng TanRachael GuenterRahul TelangeWayne HowseFabrice ViolTyler R. McCawHayden H. BickertonPriyanka GuptaFrank GillardonEugene A. WolteringDeepti DhallJohn TotenhagenRonadip R. BanerjeeElizabeth M. KurianSushanth ReddyHerbert ChenJoerg SchraderJ. Bart RoseM. Shahid MukhtarJames A. BibbNature Publishing GrouparticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENOncogenesis, Vol 10, Iss 12, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Angela M. Carter Nilesh Kumar Brendon Herring Chunfeng Tan Rachael Guenter Rahul Telange Wayne Howse Fabrice Viol Tyler R. McCaw Hayden H. Bickerton Priyanka Gupta Frank Gillardon Eugene A. Woltering Deepti Dhall John Totenhagen Ronadip R. Banerjee Elizabeth M. Kurian Sushanth Reddy Herbert Chen Joerg Schrader J. Bart Rose M. Shahid Mukhtar James A. Bibb Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors
description	Abstract Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous population of neoplasms that arise from hormone-secreting islet cells of the pancreas and have increased markedly in incidence over the past four decades. Non-functional PanNETs, which occur more frequently than hormone-secreting tumors, are often not diagnosed until later stages of tumor development and have poorer prognoses. Development of successful therapeutics for PanNETs has been slow, partially due to a lack of diverse animal models for pre-clinical testing. Here, we report development of an inducible, conditional mouse model of PanNETs by using a bi-transgenic system for regulated expression of the aberrant activator of Cdk5, p25, specifically in β-islet cells. This model produces a heterogeneous population of PanNETs that includes a subgroup of well-differentiated, non-functional tumors. Production of these tumors demonstrates the causative potential of aberrantly active Cdk5 for generation of PanNETs. Further, we show that human PanNETs express Cdk5 pathway components, are dependent on Cdk5 for growth, and share genetic and transcriptional overlap with the INS-p25OE model. The utility of this model is enhanced by the ability to form tumor-derived allografts. This new model of PanNETs will facilitate molecular delineation of Cdk5-dependent PanNETs and the development of new targeted therapeutics.
format	article
author	Angela M. Carter Nilesh Kumar Brendon Herring Chunfeng Tan Rachael Guenter Rahul Telange Wayne Howse Fabrice Viol Tyler R. McCaw Hayden H. Bickerton Priyanka Gupta Frank Gillardon Eugene A. Woltering Deepti Dhall John Totenhagen Ronadip R. Banerjee Elizabeth M. Kurian Sushanth Reddy Herbert Chen Joerg Schrader J. Bart Rose M. Shahid Mukhtar James A. Bibb
author_facet	Angela M. Carter Nilesh Kumar Brendon Herring Chunfeng Tan Rachael Guenter Rahul Telange Wayne Howse Fabrice Viol Tyler R. McCaw Hayden H. Bickerton Priyanka Gupta Frank Gillardon Eugene A. Woltering Deepti Dhall John Totenhagen Ronadip R. Banerjee Elizabeth M. Kurian Sushanth Reddy Herbert Chen Joerg Schrader J. Bart Rose M. Shahid Mukhtar James A. Bibb
author_sort	Angela M. Carter
title	Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors
title_short	Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors
title_full	Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors
title_fullStr	Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors
title_full_unstemmed	Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors
title_sort	cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/21cdb33eda954fce8c488ba99cf2f677
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Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors

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