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Single-cell dissection of remodeled inflammatory ecosystem in primary and metastatic gallbladder carcinoma. | LitMetric

Single-cell dissection of remodeled inflammatory ecosystem in primary and metastatic gallbladder carcinoma.

Cell Discov

International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.

Published: October 2022

AI Article Synopsis

  • Gallbladder carcinoma (GBC) is the most prevalent cancer in the biliary tract and is linked to chronic inflammation, leading to low survival rates; a study was conducted to understand its progression from inflammation to cancer and metastasis through single-cell RNA sequencing.
  • The research identified key cellular changes, including the overexpression of the PLA2G2A gene in GBC cells, which is associated with early-stage cancer development and marked shifts in the tumor microenvironment that facilitate cancer's progression.
  • Findings revealed a shift from a benign inflammatory state to a suppressive and aggressive environment in GBC, characterized by distinct immune responses and specific fibroblast behaviors that enhance tumor migration and invasion, providing insights into the underlying mechanisms of GBC

Article Abstract

Gallbladder carcinoma (GBC) is the most common biliary tract malignancy with the lowest survival rate, primarily arising from chronic inflammation. To better characterize the progression from inflammation to cancer to metastasis, we performed single-cell RNA sequencing across samples of 6 chronic cholecystitis, 12 treatment-naive GBCs, and 6 matched metastases. Benign epithelial cells from inflamed gallbladders displayed resting, immune-regulating, and gastrointestinal metaplastic phenotypes. A small amount of PLA2G2A epithelial cells with copy number variation were identified from a histologically benign sample. We validated significant overexpression of PLA2G2A across in situ GBCs, together with increased proliferation and cancer stemness in PLA2G2A-overexpressing GBC cells, indicating an important role for PLA2G2A during early carcinogenesis. Malignant epithelial cells displayed pervasive cancer hallmarks and cellular plasticity, differentiating into metaplastic, inflammatory, and mesenchymal subtypes with distinct transcriptomic, genomic, and prognostic patterns. Chronic cholecystitis led to an adapted microenvironment characterized by MDSC-like macrophages, CD8 T cells, and CCL2 immunity-regulating fibroblasts. By contrast, GBC instigated an aggressive and immunosuppressive microenvironment, featured by tumor-associated macrophages, Treg cells, CD8 T cells, and STMN1 tumor-promoting fibroblasts. Single-cell and bulk RNA-seq profiles consistently showed a more suppressive immune milieu for GBCs with inflammatory epithelial signatures, coupled with strengthened epithelial-immune crosstalk. We further pinpointed a subset of senescence-like fibroblasts (FN1TGM2) preferentially enriched in metastatic lesions, which promoted GBC migration and invasion via their secretory phenotype. Collectively, this study provides comprehensive insights into epithelial and microenvironmental reprogramming throughout cholecystitis-propelled carcinogenesis and metastasis, laying a new foundation for the precision therapy of GBC.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9534837PMC
http://dx.doi.org/10.1038/s41421-022-00445-8DOI Listing

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