Context matters – Daxx and Atrx are not robust tumor suppressors in the murine endocrine pancreas
Genome sequencing has revealed the importance of epigenetic regulators in tumorigenesis. The genes encoding the chromatin remodeling complex DAXX:ATRX are frequently mutated in pancreatic neuroendocrine tumors; however, the underlying mechanisms of how mutations contribute to tumorigenesis are only...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
The Company of Biologists
2022-08-01
|
| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/15/8/dmm049552 |
| _version_ | 1798019121860837376 |
|---|---|
| author | Chang Sun Jeannelyn S. Estrella Elizabeth M. Whitley Gilda P. Chau Guillermina Lozano Amanda R. Wasylishen |
| author_facet | Chang Sun Jeannelyn S. Estrella Elizabeth M. Whitley Gilda P. Chau Guillermina Lozano Amanda R. Wasylishen |
| author_sort | Chang Sun |
| collection | DOAJ |
| description | Genome sequencing has revealed the importance of epigenetic regulators in tumorigenesis. The genes encoding the chromatin remodeling complex DAXX:ATRX are frequently mutated in pancreatic neuroendocrine tumors; however, the underlying mechanisms of how mutations contribute to tumorigenesis are only partially understood, in part because of the lack of relevant preclinical models. Here, we used genetically engineered mouse models combined with environmental stress to evaluate the tumor suppressor functions of Daxx and Atrx in the mouse pancreas. Daxx or Atrx loss, alone or in combination with Men1 loss, did not drive or accelerate pancreatic neuroendocrine tumorigenesis. Moreover, Daxx loss did not cooperate with environmental stresses (ionizing radiation or pancreatitis) or with the loss of other tumor suppressors (Pten or p53) to promote pancreatic neuroendocrine tumorigenesis. However, owing to promiscuity of the Cre promoter used, hepatocellular carcinomas and osteosarcomas were observed in some instances. Overall, our findings suggest that Daxx and Atrx are not robust tumor suppressors in the endocrine pancreas of mice and indicate that the context of a human genome is essential for tumorigenesis. This article has an associated First Person interview with the first author of the paper. |
| first_indexed | 2024-04-11T16:35:34Z |
| format | Article |
| id | doaj.art-1d796c1cc30249a89d86ee96573ada87 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-04-11T16:35:34Z |
| publishDate | 2022-08-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-1d796c1cc30249a89d86ee96573ada872022-12-22T04:13:50ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112022-08-0115810.1242/dmm.049552049552Context matters – Daxx and Atrx are not robust tumor suppressors in the murine endocrine pancreasChang Sun0Jeannelyn S. Estrella1Elizabeth M. Whitley2Gilda P. Chau3Guillermina Lozano4Amanda R. Wasylishen5 Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030 USA Department of Anatomic Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030 USA Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030 USA Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030 USA Genome sequencing has revealed the importance of epigenetic regulators in tumorigenesis. The genes encoding the chromatin remodeling complex DAXX:ATRX are frequently mutated in pancreatic neuroendocrine tumors; however, the underlying mechanisms of how mutations contribute to tumorigenesis are only partially understood, in part because of the lack of relevant preclinical models. Here, we used genetically engineered mouse models combined with environmental stress to evaluate the tumor suppressor functions of Daxx and Atrx in the mouse pancreas. Daxx or Atrx loss, alone or in combination with Men1 loss, did not drive or accelerate pancreatic neuroendocrine tumorigenesis. Moreover, Daxx loss did not cooperate with environmental stresses (ionizing radiation or pancreatitis) or with the loss of other tumor suppressors (Pten or p53) to promote pancreatic neuroendocrine tumorigenesis. However, owing to promiscuity of the Cre promoter used, hepatocellular carcinomas and osteosarcomas were observed in some instances. Overall, our findings suggest that Daxx and Atrx are not robust tumor suppressors in the endocrine pancreas of mice and indicate that the context of a human genome is essential for tumorigenesis. This article has an associated First Person interview with the first author of the paper.http://dmm.biologists.org/content/15/8/dmm049552daxxatrxmen1pancreatic neuroendocrine tumormouse model |
| spellingShingle | Chang Sun Jeannelyn S. Estrella Elizabeth M. Whitley Gilda P. Chau Guillermina Lozano Amanda R. Wasylishen Context matters – Daxx and Atrx are not robust tumor suppressors in the murine endocrine pancreas Disease Models & Mechanisms daxx atrx men1 pancreatic neuroendocrine tumor mouse model |
| title | Context matters – Daxx and Atrx are not robust tumor suppressors in the murine endocrine pancreas |
| title_full | Context matters – Daxx and Atrx are not robust tumor suppressors in the murine endocrine pancreas |
| title_fullStr | Context matters – Daxx and Atrx are not robust tumor suppressors in the murine endocrine pancreas |
| title_full_unstemmed | Context matters – Daxx and Atrx are not robust tumor suppressors in the murine endocrine pancreas |
| title_short | Context matters – Daxx and Atrx are not robust tumor suppressors in the murine endocrine pancreas |
| title_sort | context matters daxx and atrx are not robust tumor suppressors in the murine endocrine pancreas |
| topic | daxx atrx men1 pancreatic neuroendocrine tumor mouse model |
| url | http://dmm.biologists.org/content/15/8/dmm049552 |
| work_keys_str_mv | AT changsun contextmattersdaxxandatrxarenotrobusttumorsuppressorsinthemurineendocrinepancreas AT jeannelynsestrella contextmattersdaxxandatrxarenotrobusttumorsuppressorsinthemurineendocrinepancreas AT elizabethmwhitley contextmattersdaxxandatrxarenotrobusttumorsuppressorsinthemurineendocrinepancreas AT gildapchau contextmattersdaxxandatrxarenotrobusttumorsuppressorsinthemurineendocrinepancreas AT guillerminalozano contextmattersdaxxandatrxarenotrobusttumorsuppressorsinthemurineendocrinepancreas AT amandarwasylishen contextmattersdaxxandatrxarenotrobusttumorsuppressorsinthemurineendocrinepancreas |