Metastatic Tumor Evolution and Organoid Modeling Implicate TGFBR2 as a Cancer Driver in Diffuse Gastric Cancer

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dc.contributor.authorNadauld, Lincoln
dc.contributor.authorGarcia, Sarah
dc.contributor.authorNatsoulis, Georges
dc.contributor.authorBell, John M
dc.contributor.authorMiotke, Laura
dc.contributor.authorHopmans, Erik S
dc.contributor.authorXu, Hua
dc.contributor.authorPai, Reetesh K
dc.contributor.authorPalm, Curt
dc.contributor.authorRegan, John F
dc.contributor.authorChen, Hao
dc.contributor.authorFlaherty, Patrick
dc.contributor.authorOotani, Akifumi
dc.contributor.authorZhang, Nancy R
dc.contributor.authorFord, James M
dc.contributor.authorKuo, Calvin J
dc.contributor.authorJi, Hanlee P
dc.date2023-05-17T17:51:04.000
dc.date.accessioned2023-05-23T03:37:02Z
dc.date.available2023-05-23T03:37:02Z
dc.date.issued2014-08-01
dc.date.submitted2017-08-23T12:42:58-07:00
dc.description.abstractBackground: Gastric cancer is the second-leading cause of global cancer deaths, with metastatic disease representing the primary cause of mortality. To identify candidate drivers involved in oncogenesis and tumor evolution, we conduct an extensive genome sequencing analysis of metastatic progression in a diffuse gastric cancer. This involves a comparison between a primary tumor from a hereditary diffuse gastric cancer syndrome proband and its recurrence as an ovarian metastasis. Results: Both the primary tumor and ovarian metastasis have common biallelic loss-of-function of both the CDH1 and TP53 tumor suppressors, indicating a common genetic origin. While the primary tumor exhibits amplification of the Fibroblast growth factor receptor 2 (FGFR2) gene, the metastasis notably lacks FGFR2 amplification but rather possesses unique biallelic alterations of Transforming growth factor-beta receptor 2 (TGFBR2), indicating the divergent in vivo evolution of a TGFBR2-mutant metastatic clonal population in this patient. As TGFBR2 mutations have not previously been functionally validated in gastric cancer, we modeled the metastatic potential of TGFBR2 loss in a murine three-dimensional primary gastric organoid culture. The Tgfbr2 shRNA knockdown within Cdh1-/-; Tp53-/- organoids generates invasion in vitro and robust metastatic tumorigenicity in vivo, confirming Tgfbr2 metastasis suppressor activity. Conclusions: We document the metastatic differentiation and genetic heterogeneity of diffuse gastric cancer and reveal the potential metastatic role of TGFBR2 loss-of-function. In support of this study, we apply a murine primary organoid culture method capable of recapitulating in vivo metastatic gastric cancer. Overall, we describe an integrated approach to identify and functionally validate putative cancer drivers involved in metastasis
dc.identifier.urihttps://repository.upenn.edu/handle/20.500.14332/47893
dc.legacy.articleid1556
dc.legacy.fields10.1186/s13059-014-0428-9
dc.legacy.fulltexturlhttps://repository.upenn.edu/cgi/viewcontent.cgi?article=1556&context=statistics_papers&unstamped=1
dc.source.beginpage1
dc.source.endpage18
dc.source.issue50
dc.source.issue428
dc.source.journalStatistics Papers
dc.source.journaltitleGenome Biology
dc.source.peerreviewedtrue
dc.source.statuspublished
dc.source.volume15
dc.subject.otherLife Sciences
dc.subject.otherMedicine and Health Sciences
dc.subject.otherPhysical Sciences and Mathematics
dc.titleMetastatic Tumor Evolution and Organoid Modeling Implicate TGFBR2 as a Cancer Driver in Diffuse Gastric Cancer
dc.typeArticle
digcom.contributor.authorNadauld, Lincoln
digcom.contributor.authorGarcia, Sarah
digcom.contributor.authorNatsoulis, Georges
digcom.contributor.authorBell, John M
digcom.contributor.authorMiotke, Laura
digcom.contributor.authorHopmans, Erik S
digcom.contributor.authorXu, Hua
digcom.contributor.authorPai, Reetesh K
digcom.contributor.authorPalm, Curt
digcom.contributor.authorRegan, John F
digcom.contributor.authorChen, Hao
digcom.contributor.authorFlaherty, Patrick
digcom.contributor.authorOotani, Akifumi
digcom.contributor.authorZhang, Nancy R
digcom.contributor.authorFord, James M
digcom.contributor.authorKuo, Calvin J
digcom.contributor.authorJi, Hanlee P
digcom.identifierstatistics_papers/50
digcom.identifier.contextkey10649605
digcom.identifier.submissionpathstatistics_papers/50
digcom.typearticle
dspace.entity.typePublication
upenn.schoolDepartmentCenterStatistics Papers
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