How Biophysical Forces Regulate Human B Cell Lymphomas

• DOI: 10.1016/j.celrep.2018.03.069
• Publication Date: 2018-04-10T15:45:00Z
• Authors: F. Apoorva; Alexander M. Loiben; Shivem B. Shah; Alberto Purwada; Lorena Fontan; Rebecca Goldstein; Brian J. Kirby; Ari M. Melnick; Benjamin D. Cosgrove; Ankur Singh
• Keywords: 0301 basic medicine; 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; 2. Zero hunger; 0303 health sciences; Up-Regulation; 3. Good health; src-Family Kinases; Doxorubicin; Cytokines; RNA Interference; Lymphoma, Large B-Cell, Diffuse; Shear Strength; CD79 Antigens; Signal Transduction

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.