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Differential B-Cell Receptor Signaling Requirement for Adhesion of Mantle Cell Lymphoma Cells to Stromal Cells.

ABSTRACT: Interactions between lymphoma cells and stromal cells play a key role in promoting tumor survival and development of drug resistance. We identified differences in key signaling pathways between the JeKo-1 and REC-1 mantle cell lymphoma (MCL) cell lines, displaying different patterns of stromal cell adhesion and chemotaxis towards stroma-conditioned medium. The identified adhesion-regulated genes reciprocated important aspects of microenvironment-mediated gene modulation in MCL patients. Five-hundred and ninety genes were differently regulated between the cell lines upon adhesion to stromal cells, while 32 genes were similarly regulated in both cell lines. Regulation of B-cell Receptor (BCR) signature genes in adherent cells was specific for JeKo-1. Inhibition of BCR using siRNA or clinically approved inhibitors, Ibrutinib and Acalabrutinib, decreased adhesion of JeKo-1, but not REC-1 cells. Cell surface levels of chemokine receptor CXCR4 were higher in JeKo-1, facilitating migration and adhesion of JeKo-1 but not REC-1 cells. Surface levels of ICAM1 adhesion protein differ for REC-1 and JeKo-1. While ICAM1 played a positive role in adherence of both cell lines to stromal cells, S1PR1 had an inhibitory effect. Our results provide a model framework for further investigation of mechanistic differences in patient-response to new pathway-specific drugs.

SUBMITTER: Sadeghi L

PROVIDER: S-EPMC7281289 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Differential B-Cell Receptor Signaling Requirement for Adhesion of Mantle Cell Lymphoma Cells to Stromal Cells.

Sadeghi Laia L Arvidsson Gustav G Merrien Magali M M Wasik Agata A Görgens André A Smith C I Edvard CIE Sander Birgitta B Wright Anthony P AP

Cancers 20200502 5

Interactions between lymphoma cells and stromal cells play a key role in promoting tumor survival and development of drug resistance. We identified differences in key signaling pathways between the JeKo-1 and REC-1 mantle cell lymphoma (MCL) cell lines, displaying different patterns of stromal cell adhesion and chemotaxis towards stroma-conditioned medium. The identified adhesion-regulated genes reciprocated important aspects of microenvironment-mediated gene modulation in MCL patients. Five-hun ...[more]

PMID: 32370190

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Project description:Lymphoma cells interact with specific microenvironment cell subsets, such as stromal cells, from which they receive survival and proliferation stimuli. These interactions negatively influence therapeutic response and increase the risk for drug resistance and relapse. It is still not clear why clinically similar tumors in different patients respond differently to established treatment regimens. Objective: The main aim of this study was to identify and compare key signaling pathways related to stromal cell adhesion in different mantle cell lymphoma (MCL) cell lines.Methods: Human MCL cells (JeKo1 and REC1) were cultured alone or in co-culture with mouse MS-5 stromal cells. Differentially expressed genes in adherent cells were identified by RNA sequencing and species-specific read sorting. The cell surface levels of proteins encoded by selected differentially expressed genes were quantified using flow cytometry in adherent and suspension cells. Selective inhibitors or siRNA were used to assess their significance for adherence to stromal cells. Results: Jeko1 and REC1 cells exhibited different time-dependent patterns of adhesion to stromal cells. 590 genes that were differently regulated upon adhesion in each cell line individually, showed significant differences in the extent or direction of regulation between the two cell lines. From this set, there was a significant increase in transcript levels for B-cell Receptor (BCR) pathway signature genes in adherent JeKo1 cell but not in adherent REC1 cells. Inhibition of BCR signaling using siRNA or the clinically approved inhibitor, Ibrutinib, decreased the number of adherent JeKo1 cells but had no such effect on REC1 cells. The cell surface levels of CXCR4 were higher in JeKo1 cells compared to REC1 cells and CXCR4 inhibition disrupted the adhesion of JeKo1 but not REC1 cells to the stromal cells. ICAM1 cell surface levels were induced in JeKo1 cells upon adhesion while REC1 showed a high level of ICAM1 in non-adherent cells. Depletion of ICAM1 levels by siRNA reduced the stromal cell adhesion of both JeKo1 and REC1 cells. Conclusions: The results suggest that different MCL cell lines exhibit different signaling profiles and pathway dependencies during microenvironment interaction. In this study BCR signaling pathways were shown to be important for stromal cell adhesion of JeKo1 cells but not REC1 cells. This provides a possible mechanism to account for the differential responsiveness of MCL patients to treatment with the Bruton’s Tyrosine Kinase inhibitor, Ibrutinib, an inhibitor of BCR signaling that is clinically approved for MCL.

Dataset Information

Differential B-Cell Receptor Signaling Requirement for Adhesion of Mantle Cell Lymphoma Cells to Stromal Cells.

Publications

Differential B-Cell Receptor Signaling Requirement for Adhesion of Mantle Cell Lymphoma Cells to Stromal Cells.

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