TY - JOUR
T1 - Wnt Signaling Shapes the Histologic Variation in Diffuse Gastric Cancer
AU - Togasaki, Kazuhiro
AU - Sugimoto, Shinya
AU - Ohta, Yuki
AU - Nanki, Kosaku
AU - Matano, Mami
AU - Takahashi, Sirirat
AU - Fujii, Masayuki
AU - Kanai, Takanori
AU - Sato, Toshiro
N1 - Funding Information:
Funding This work was supported in part by Japan Society for the Promotion of Science (JSPS) KAKENHI (grant numbers JP17H06176 and JP20J12287 ), by Japan Agency for Medical Research and Development (AMED) (grant number JP20cm0106206) and by the Takeda Science Foundation . Kazuhiro Togasaki was supported by the JSPS Research Fellowships for Young Scientists.
Publisher Copyright:
© 2021 The Authors
PY - 2021/2
Y1 - 2021/2
N2 - Background and Aims: Diffuse-type gastric cancer (GC) is currently subdivided into signet-ring cell carcinoma (SRCC) and non-SRCC, referred to as poorly cohesive carcinoma not otherwise specified (PCC-NOS). Although these subtypes are considered to be independent, they often coexist in the same tumors, raising a question of whether they clonally differ or not. To tackle this question, we established an experimental platform for human diffuse GC that enables accurate modeling of histologic subtypes. Methods: Seven patient-derived diffuse GC organoid lines were established, characterized by histopathologic analysis, in situ hybridization, and gene expression analysis. For genetic modeling of diffuse GC, we knocked out CDH1 and/or TP53 in human normal gastric organoids. Green fluorescent protein–labeled GC organoids were xenotransplanted into immune-deficient mice for in vivo assessment. Results: PCC-NOS organoids transformed into SRCC-like structures on removal of Wnt and R-spondin from the culture medium. This morphologic change paralleled downregulation of Wnt-target and gastric stem cell genes, including LGR5, and elevation of differentiation markers, such as KRT20 and MUCs. The association between Wnt target gene expression and histologic subtypes was confirmed in 3 patient-derived GC tissues. In vivo, single clone-derived organoids formed tumors that comprised 2 distinct histologic compartments, each corresponding to SRCC and PCC-NOS. The transition from PCC-NOS to SRCC histology reflected the abundance of surrounding R-spondin–expressing fibroblasts. Conclusions: SRCC and PCC-NOS were clonally identical, and their morphology was regulated by extracellular Wnt and R-spondin expression. Our results decoded how genetic mutations and the tumor environment shape pathohistologic and biologic phenotypes in human diffuse GCs.
AB - Background and Aims: Diffuse-type gastric cancer (GC) is currently subdivided into signet-ring cell carcinoma (SRCC) and non-SRCC, referred to as poorly cohesive carcinoma not otherwise specified (PCC-NOS). Although these subtypes are considered to be independent, they often coexist in the same tumors, raising a question of whether they clonally differ or not. To tackle this question, we established an experimental platform for human diffuse GC that enables accurate modeling of histologic subtypes. Methods: Seven patient-derived diffuse GC organoid lines were established, characterized by histopathologic analysis, in situ hybridization, and gene expression analysis. For genetic modeling of diffuse GC, we knocked out CDH1 and/or TP53 in human normal gastric organoids. Green fluorescent protein–labeled GC organoids were xenotransplanted into immune-deficient mice for in vivo assessment. Results: PCC-NOS organoids transformed into SRCC-like structures on removal of Wnt and R-spondin from the culture medium. This morphologic change paralleled downregulation of Wnt-target and gastric stem cell genes, including LGR5, and elevation of differentiation markers, such as KRT20 and MUCs. The association between Wnt target gene expression and histologic subtypes was confirmed in 3 patient-derived GC tissues. In vivo, single clone-derived organoids formed tumors that comprised 2 distinct histologic compartments, each corresponding to SRCC and PCC-NOS. The transition from PCC-NOS to SRCC histology reflected the abundance of surrounding R-spondin–expressing fibroblasts. Conclusions: SRCC and PCC-NOS were clonally identical, and their morphology was regulated by extracellular Wnt and R-spondin expression. Our results decoded how genetic mutations and the tumor environment shape pathohistologic and biologic phenotypes in human diffuse GCs.
KW - Cancer Stem Cell
KW - Gastric Cancer
KW - Signet-Ring Cell
KW - Wnt
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UR - http://www.scopus.com/inward/citedby.url?scp=85100433589&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2020.10.047
DO - 10.1053/j.gastro.2020.10.047
M3 - Short survey
C2 - 33217450
AN - SCOPUS:85100433589
SN - 0016-5085
VL - 160
SP - 823
EP - 830
JO - Gastroenterology
JF - Gastroenterology
IS - 3
ER -