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Single cell mRNA sequencing of B cells from human endometrial cancers

ABSTRACT: Emerging data indicate that B-cells play a key role in cancer suppression, particularly when aggregated in tertiary lymphoid-like structures (TLS). Here, we used single-cell and bulk RNA sequencing of endometrial cancers (ECs) and found L1-cell adhesion molecule L1CAM to be significantly associated with TLS. Immunohistochemical (IHC) expression of L1CAM was restricted to the germinal centre (GC) of mature TLS, where it co-localised with follicular dendritic cell (FDC) marker CD21. Tumours surrounded by L1CAM-positive TLS were identified across all molecular EC subgroups, but enriched in mismatch repair deficient (MMRd) and polymerase-epsilon mutant (POLEmut) EC, especially when TP53 mutations were also present. Importantly, L1CAM-positive TLS appeared an independent favourable predictor of EC recurrence and death, and significantly improved the current prognostic molecular EC classification based on clinicopathological and molecular factors. Our data suggest a pivotal role of TLS in predicting outcome of EC patients, and establishes L1CAM as a simple and widely available biomarker of TLS in clinical care.

ORGANISM(S): Homo sapiens

PROVIDER: GSE180091 | GEO | 2021/07/15

REPOSITORIES: GEO

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Project description:In pancreatic cancer the survival rate is low, as the available treatment options usually only extend survival and seldom produce a cure. Drug resistance and disease reoccurrence is the typical reason for death after cancer diagnosis. 5-Fluorouracil (5-FU) is the main chemostatic used in first line therapy. However the majority of the tumors become resistant to treatment. To investigate acquired 5-FU resistance in pancreatic adenocarcinoma, we established chemoresistant monoclonal cell lines from the Panc03.27 cell line by long-term exposure to 5-FU. In addition to increased expression of markers associated with multidrug resistance, the 5-FU resistant clones showed alterations typical of the process of epithelial-to-mesenchymal transition (EMT), including upregulation of mesenchymal markers and increased invasiveness. Microarray analysis revealed the L1CAM pathway as one of the most upregulated pathways in the chemoresistant clones, which was confirmed on RNA and protein levels. Expression of the adhesion molecule L1CAM is associated with a chemoresistant and migratory phenotype of pancreatic cancer. Using esiRNA targeting L1CAM, or by blocking the extracellular part of L1CAM with monoclonal antibodies, we discovered that the increased invasiveness observed in the chemoresistant cells depends on L1CAM. Using esiRNA targeting β-catenin and/or Slug, we discovered that L1CAM expression depends on Slug rather than β-catenin in the 5-FU resistant cells. We demonstrate a functional link between Slug and the expression level of L1CAM in pancreatic cancer cells having undergone EMT following long-term exposure to 5-FU. Our findings provide further insight into the molecular mechanisms leading to a chemoresistant and migratory phenotype in pancreatic cancer cells and indicate the importance of Slug-induced L1CAM in refractory pancreatic cancer. Examination of expression of 5-Fluorouracil (5-FU) Panc03.27 cell line resistant clone versus expression of 5-FU sensitive clones (NT) in 4 replicates per cell lines

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Single cell mRNA sequencing of B cells from human endometrial cancers

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