How Biophysical Forces Regulate Human B Cell Lymphomas

Integrins QH301-705.5 Microfluidics Receptors, Antigen, B-Cell Apoptosis Article Mice 03 medical and health sciences Mice, Inbred NOD Cell Line, Tumor Tumor Microenvironment Animals Humans Biology (General) RNA, Small Interfering 0303 health sciences Up-Regulation src-Family Kinases Doxorubicin Cytokines RNA Interference Lymphoma, Large B-Cell, Diffuse Shear Strength CD79 Antigens Signal Transduction
DOI: 10.1016/j.celrep.2018.03.069 Publication Date: 2018-04-10T15:45:00Z
ABSTRACT
The role of microenvironment-mediated biophysical forces in human lymphomas remains elusive. Diffuse large B cell lymphomas (DLBCLs) are heterogeneous tumors, which originate from highly proliferative germinal center B cells. These tumors, their associated neo-vessels, and lymphatics presumably expose cells to particular fluid flow and survival signals. Here, we show that fluid flow enhances proliferation and modulates response of DLBCLs to specific therapeutic agents. Fluid flow upregulates surface expression of B cell receptors (BCRs) and integrin receptors in subsets of ABC-DLBCLs with either CD79A/B mutations or WT BCRs, similar to what is observed with xenografted human tumors in mice. Fluid flow differentially upregulates signaling targets, such as SYK and p70S6K, in ABC-DLBCLs. By selective knockdown of CD79B and inhibition of signaling targets, we provide mechanistic insights into how fluid flow mechanomodulates BCRs and integrins in ABC-DLBCLs. These findings redefine microenvironment factors that regulate lymphoma-drug interactions and will be critical for testing targeted therapies.
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