Metastatic tumor evolution and organoid modeling implicate TGFBR2as a cancer driver in diffuse gastric cancer

Abstract

BackgroundGastric 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.ResultsBoth 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.ConclusionsWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-014-0428-9) contains supplementary material, which is available to authorized users.

Molecular characterization of metastatic osteosarcoma: Differentially expressed genes, transcription factors and microRNAs

“…In addition, miR-21-5p may contribute to osteosarcoma metastasis via its target genes. EGFR has been demonstrated to be associated with metastasis of osteosarcoma to the lungs (37), whereas TGFBR2 has been associated with metastasis of gastric cancer cells (51), and suppressive TPM1 may alter TGF-β tumor suppressor function and thus promote metastasis of tumor cells (52). Therefore, it is possible that miR-21-5p exerts a regulatory effect on metastasis via regulation of the expression of its target genes.…”

Genetics and Molecular Pathogenesis of Gastric Adenocarcinoma

“…[63][64][65] Emerging studies are now being performed to study patterns of GC tumor evolution and clonality, occurring either within the primary tumor, or between primary lesions and metastatic sites. 54,66 Such results will be crucial for identifying molecular events associated with GC progression rather than initiation, and may suggest improved strategies for managing patients with advanced metastatic GC.…”

Precision Oncology: The Road Ahead

“…Organoids are established by dissociating and embedding tissue in an cell-free extracellular matrix (matrigel or collagen), which can be expanded in a growth factor-enriched medium [150]. Organoids from pancreatic [151], colon [152–154], gastric [155], prostate cancer [156] and brain tumors/metastasis [157] have been established, and have the advantage of 3D growth of normal and cancer tissue, recapitulating copy number and mutation spectra, as well as other physiologically relevant aspects of disease progression in vitro [150–158]. Organoids can be established in culture from needle biopsies within a relative short time period, and have also been generated from circulating tumor cells [156].…”