title: Metastatic tumor evolution and organoid modeling implicate TGFBR2 as a cancer driver in diffuse gastric cancer.
abstract: BACKGROUND
  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.
authors.forename: Lincoln D
authors.initials: LD
authors.lastname: Nadauld
authors.forename: Sarah
authors.initials: S
authors.lastname: Garcia
authors.forename: Georges
authors.initials: G
authors.lastname: Natsoulis
authors.forename: John M
authors.initials: JM
authors.lastname: Bell
authors.forename: Laura
authors.initials: L
authors.lastname: Miotke
authors.forename: Erik S
authors.initials: ES
authors.lastname: Hopmans
authors.forename: Hua
authors.initials: H
authors.lastname: Xu
authors.forename: Reetesh K
authors.initials: RK
authors.lastname: Pai
authors.forename: Curt
authors.initials: C
authors.lastname: Palm
authors.forename: John F
authors.initials: JF
authors.lastname: Regan
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.forename: Patrick
authors.initials: P
authors.lastname: Flaherty
authors.forename: Akifumi
authors.initials: A
authors.lastname: Ootani
authors.forename: Nancy R
authors.initials: NR
authors.lastname: Zhang
authors.forename: James M
authors.initials: JM
authors.lastname: Ford
authors.forename: Calvin J
authors.initials: CJ
authors.lastname: Kuo
authors.forename: Hanlee P
authors.initials: HP
authors.lastname: Ji
mesh_terms: D000328:Adult; D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics; D019143:Evolution, Molecular; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007725:Krukenberg Tumor / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D018125:Receptors, Transforming Growth Factor beta; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II