Characterization of Novel Murine and Human PDAC Cell Models: Identifying the Role of Intestine Specific Homeobox Gene ISX in Hypoxia and Disease Progression
Therapy failure and metastasis-associated mortality are stumbling blocks in the management of PDAC in patients. Failure of therapy is associated to intense hypoxic conditions of tumors. To develop effective therapies, a complete understanding of hypoxia-associated changes in genetic landscape of tum...
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| Format: | Article |
| Language: | English |
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Elsevier
2019-08-01
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| Series: | Translational Oncology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523319301822 |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Arsheed A. Ganaie Aijaz Parray Tabish Hussain Ashraf Shabaneh Anmbreen Jamroze Marina G. Ferrari Lei Wang D. Joshua Liao Shahriar Koochekpour Sanjeev Nanda Jinhua Wang Yibin Deng Sergio A Gradilone Edward H. Hinchcliffe Badrinath R. Konety Mohammad Saleem |
| spellingShingle |
Arsheed A. Ganaie Aijaz Parray Tabish Hussain Ashraf Shabaneh Anmbreen Jamroze Marina G. Ferrari Lei Wang D. Joshua Liao Shahriar Koochekpour Sanjeev Nanda Jinhua Wang Yibin Deng Sergio A Gradilone Edward H. Hinchcliffe Badrinath R. Konety Mohammad Saleem Characterization of Novel Murine and Human PDAC Cell Models: Identifying the Role of Intestine Specific Homeobox Gene ISX in Hypoxia and Disease Progression Translational Oncology |
| author_facet |
Arsheed A. Ganaie Aijaz Parray Tabish Hussain Ashraf Shabaneh Anmbreen Jamroze Marina G. Ferrari Lei Wang D. Joshua Liao Shahriar Koochekpour Sanjeev Nanda Jinhua Wang Yibin Deng Sergio A Gradilone Edward H. Hinchcliffe Badrinath R. Konety Mohammad Saleem |
| author_sort |
Arsheed A. Ganaie |
| title |
Characterization of Novel Murine and Human PDAC Cell Models: Identifying the Role of Intestine Specific Homeobox Gene ISX in Hypoxia and Disease Progression |
| title_short |
Characterization of Novel Murine and Human PDAC Cell Models: Identifying the Role of Intestine Specific Homeobox Gene ISX in Hypoxia and Disease Progression |
| title_full |
Characterization of Novel Murine and Human PDAC Cell Models: Identifying the Role of Intestine Specific Homeobox Gene ISX in Hypoxia and Disease Progression |
| title_fullStr |
Characterization of Novel Murine and Human PDAC Cell Models: Identifying the Role of Intestine Specific Homeobox Gene ISX in Hypoxia and Disease Progression |
| title_full_unstemmed |
Characterization of Novel Murine and Human PDAC Cell Models: Identifying the Role of Intestine Specific Homeobox Gene ISX in Hypoxia and Disease Progression |
| title_sort |
characterization of novel murine and human pdac cell models: identifying the role of intestine specific homeobox gene isx in hypoxia and disease progression |
| publisher |
Elsevier |
| series |
Translational Oncology |
| issn |
1936-5233 |
| publishDate |
2019-08-01 |
| description |
Therapy failure and metastasis-associated mortality are stumbling blocks in the management of PDAC in patients. Failure of therapy is associated to intense hypoxic conditions of tumors. To develop effective therapies, a complete understanding of hypoxia-associated changes in genetic landscape of tumors during disease progression is needed. Because artificially immortalized cell lines do not rightly represent the disease progression, studying genetics of tumors in spontaneous models is warranted. In the current study, we generated a spectrum of spontaneous human (UM-PDC1; UM-PDC2) and murine (HI-PanL, HI-PancI, HI-PanM) models representing localized, invasive, and metastatic PDAC from a patient and transgenic mice (K-rasG12D/Pdxcre/Ink4a/p16-/). These spontaneous models grow vigorously under hypoxia and exhibit activated K-ras signaling, progressive loss of PTEN, and tumorigenicity in vivo. Whereas UM-PDC1 form localized tumors, the UM-PDC2 metastasize to lungs in mice. In an order of progression, these models exhibit genomic instability marked by gross chromosomal rearrangements, centrosome-number variations, Aurora-kinase/H2AX colocalization, loss of primary cilia, and α-tubulin acetylation. The RNA sequencing of hypoxic models followed by qRT-PCR validation and gene-set enrichment identified Intestine-Specific Homeobox factor (ISX)–driven molecular pathway as an indicator PDAC aggressivness. TCGA-PAAD clinical data analysis showed high ISX expression correlation to poor survival of PDAC patients, particularly women. The functional studies showed ISX as a regulator of i) invasiveness and migratory potential and ii) VEGF, MMP2, and NFκB activation in PDAC cells. We suggest that ISX is a potential druggable target and newly developed spontaneous cell models are valuable tools for studying mechanism and testing therapies for PDAC. |
| url |
http://www.sciencedirect.com/science/article/pii/S1936523319301822 |
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doaj-8b84d9c2c20e45bc9e8e04634c0dff6a2020-11-25T01:21:15ZengElsevierTranslational Oncology1936-52332019-08-0112810561071Characterization of Novel Murine and Human PDAC Cell Models: Identifying the Role of Intestine Specific Homeobox Gene ISX in Hypoxia and Disease ProgressionArsheed A. Ganaie0Aijaz Parray1Tabish Hussain2Ashraf Shabaneh3Anmbreen Jamroze4Marina G. Ferrari5Lei Wang6D. Joshua Liao7Shahriar Koochekpour8Sanjeev Nanda9Jinhua Wang10Yibin Deng11Sergio A Gradilone12Edward H. Hinchcliffe13Badrinath R. Konety14Mohammad Saleem15Department of Urology, Masonic Cancer Center, University of Minnesota, Minneapolis, MNDepartment of Urology, Masonic Cancer Center, University of Minnesota, Minneapolis, MN; Translational Research Institute, Academic Health Systems Hamad Medical Corporation, Doha, QatarDepartment of Urology, Masonic Cancer Center, University of Minnesota, Minneapolis, MN; MD Anderson Cancer Center, Science Park, Smithville, TXInstitute for Health Informatics, Masonic Cancer Center, University of Minnesota, Minneapolis, MNHormel Institute, University of Minnesota, Austin, MNDepartment of Urology, Masonic Cancer Center, University of Minnesota, Minneapolis, MNDepartment of Cancer Genetics, Hormel Institute, University of Minnesota, Austin, MNDepartment of Cancer Genetics, Hormel Institute, University of Minnesota, Austin, MNDepartment of Urology, University of Florida, Jacksonville, FloridaDepartment of General Internal Medicine, Mayo Clinic, Rochester, MNInstitute for Health Informatics, Masonic Cancer Center, University of Minnesota, Minneapolis, MNDepartment of Cancer Genetics, Hormel Institute, University of Minnesota, Austin, MNCancer Cell Biology and Translational Research Section, Hormel Institute, University of Minnesota, Austin, MNCellular Dynamics Section, The Hormel Institute, University of MinnesotaDepartment of Urology, Masonic Cancer Center, University of Minnesota, Minneapolis, MNDepartment of Urology, Masonic Cancer Center, University of Minnesota, Minneapolis, MN; Address all correspondence to: Mohammad Saleem, PhD, Associate Professor, Department of Urology, Masonic Cancer Center, University of Minnesota, 2231, 6th St. SE, Minneapolis, MN.Therapy failure and metastasis-associated mortality are stumbling blocks in the management of PDAC in patients. Failure of therapy is associated to intense hypoxic conditions of tumors. To develop effective therapies, a complete understanding of hypoxia-associated changes in genetic landscape of tumors during disease progression is needed. Because artificially immortalized cell lines do not rightly represent the disease progression, studying genetics of tumors in spontaneous models is warranted. In the current study, we generated a spectrum of spontaneous human (UM-PDC1; UM-PDC2) and murine (HI-PanL, HI-PancI, HI-PanM) models representing localized, invasive, and metastatic PDAC from a patient and transgenic mice (K-rasG12D/Pdxcre/Ink4a/p16-/). These spontaneous models grow vigorously under hypoxia and exhibit activated K-ras signaling, progressive loss of PTEN, and tumorigenicity in vivo. Whereas UM-PDC1 form localized tumors, the UM-PDC2 metastasize to lungs in mice. In an order of progression, these models exhibit genomic instability marked by gross chromosomal rearrangements, centrosome-number variations, Aurora-kinase/H2AX colocalization, loss of primary cilia, and α-tubulin acetylation. The RNA sequencing of hypoxic models followed by qRT-PCR validation and gene-set enrichment identified Intestine-Specific Homeobox factor (ISX)–driven molecular pathway as an indicator PDAC aggressivness. TCGA-PAAD clinical data analysis showed high ISX expression correlation to poor survival of PDAC patients, particularly women. The functional studies showed ISX as a regulator of i) invasiveness and migratory potential and ii) VEGF, MMP2, and NFκB activation in PDAC cells. We suggest that ISX is a potential druggable target and newly developed spontaneous cell models are valuable tools for studying mechanism and testing therapies for PDAC.http://www.sciencedirect.com/science/article/pii/S1936523319301822 |