TY - JOUR
T1 - Apposition of Fibroblasts With Metaplastic Gastric Cells Promotes Dysplastic Transition
AU - Lee, Su Hyung
AU - Contreras Panta, Ela W.
AU - Gibbs, David
AU - Won, Yoonkyung
AU - Min, Jimin
AU - Zhang, Changqing
AU - Roland, Joseph T.
AU - Hong, Se Hoon
AU - Sohn, Yoojin
AU - Krystofiak, Evan
AU - Jang, Bogun
AU - Ferri, Lorenzo
AU - Sangwan, Veena
AU - Ragoussis, Jiannis
AU - Camilleri-Broët, Sophie
AU - Caruso, Joseph
AU - Chen-Tanyolac, Chira
AU - Strasser, Michael
AU - Gascard, Philippe
AU - Tlsty, Thea D.
AU - Huang, Sui
AU - Choi, Eunyoung
AU - Goldenring, James R.
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/8
Y1 - 2023/8
N2 - Background & Aims: Elements of field cancerization, including atrophic gastritis, metaplasia, and dysplasia, promote gastric cancer development in association with chronic inflammation. However, it remains unclear how stroma changes during carcinogenesis and how the stroma contributes to progression of gastric preneoplasia. Here we investigated heterogeneity of fibroblasts, one of the most important elements in the stroma, and their roles in neoplastic transformation of metaplasia. Methods: We used single-cell transcriptomics to evaluate the cellular heterogeneity of mucosal cells from patients with gastric cancer. Tissue sections from the same cohort and tissue microarrays were used to identify the geographical distribution of distinct fibroblast subsets. We further evaluated the role of fibroblasts from pathologic mucosa in dysplastic progression of metaplastic cells using patient-derived metaplastic gastroids and fibroblasts. Results: We identified 4 subsets of fibroblasts within stromal cells defined by the differential expression of PDGFRA, FBLN2, ACTA2, or PDGFRB. Each subset was distributed distinctively throughout stomach tissues with different proportions at each pathologic stage. The PDGFRα+ subset expanded in metaplasia and cancer compared with normal, maintaining a close proximity with the epithelial compartment. Co-culture of metaplasia- or cancer-derived fibroblasts with gastroids showing the characteristics of spasmolytic polypeptide-expressing metaplasia–induced disordered growth, loss of metaplastic markers, and increases in markers of dysplasia. Culture of metaplastic gastroids with conditioned media from metaplasia- or cancer-derived fibroblasts also promoted dysplastic transition. Conclusions: These findings indicate that fibroblast associations with metaplastic epithelial cells can facilitate direct transition of metaplastic spasmolytic polypeptide-expressing metaplasia cell lineages into dysplastic lineages.
AB - Background & Aims: Elements of field cancerization, including atrophic gastritis, metaplasia, and dysplasia, promote gastric cancer development in association with chronic inflammation. However, it remains unclear how stroma changes during carcinogenesis and how the stroma contributes to progression of gastric preneoplasia. Here we investigated heterogeneity of fibroblasts, one of the most important elements in the stroma, and their roles in neoplastic transformation of metaplasia. Methods: We used single-cell transcriptomics to evaluate the cellular heterogeneity of mucosal cells from patients with gastric cancer. Tissue sections from the same cohort and tissue microarrays were used to identify the geographical distribution of distinct fibroblast subsets. We further evaluated the role of fibroblasts from pathologic mucosa in dysplastic progression of metaplastic cells using patient-derived metaplastic gastroids and fibroblasts. Results: We identified 4 subsets of fibroblasts within stromal cells defined by the differential expression of PDGFRA, FBLN2, ACTA2, or PDGFRB. Each subset was distributed distinctively throughout stomach tissues with different proportions at each pathologic stage. The PDGFRα+ subset expanded in metaplasia and cancer compared with normal, maintaining a close proximity with the epithelial compartment. Co-culture of metaplasia- or cancer-derived fibroblasts with gastroids showing the characteristics of spasmolytic polypeptide-expressing metaplasia–induced disordered growth, loss of metaplastic markers, and increases in markers of dysplasia. Culture of metaplastic gastroids with conditioned media from metaplasia- or cancer-derived fibroblasts also promoted dysplastic transition. Conclusions: These findings indicate that fibroblast associations with metaplastic epithelial cells can facilitate direct transition of metaplastic spasmolytic polypeptide-expressing metaplasia cell lineages into dysplastic lineages.
KW - Fibroblasts
KW - Gastric Carcinogenesis
KW - Metaplasia
KW - PDGFRA
KW - SPEM
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UR - http://www.scopus.com/inward/citedby.url?scp=85163325172&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2023.04.038
DO - 10.1053/j.gastro.2023.04.038
M3 - Article
C2 - 37196797
AN - SCOPUS:85163325172
SN - 0016-5085
VL - 165
SP - 374
EP - 390
JO - Gastroenterology
JF - Gastroenterology
IS - 2
ER -