TitleHow Biophysical Forces Regulate Human B Cell Lymphomas.
Publication TypeJournal Article
Year of Publication2018
AuthorsApoorva, F, Loiben Alexander M., Shah Shivem B., Purwada Alberto, Fontan Lorena, Goldstein Rebecca, Kirby Brian J., Melnick Ari M., Cosgrove Benjamin D., and Singh Ankur
JournalCell Rep
Volume23
Issue2
Pagination499-511
Date Published2018 Apr 10
ISSN2211-1247
KeywordsAnimals, Apoptosis, CD79 Antigens, Cell Line, Tumor, Cytokines, Doxorubicin, Humans, Integrins, Lymphoma, Large B-Cell, Diffuse, Mice, Mice, Inbred NOD, Microfluidics, Receptors, Antigen, B-Cell, RNA Interference, RNA, Small Interfering, Shear Strength, Signal Transduction, src-Family Kinases, Tumor Microenvironment, Up-Regulation
Abstract

<p>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.</p>

DOI10.1016/j.celrep.2018.03.069
Alternate JournalCell Rep
PubMed ID29642007
PubMed Central IDPMC5965297
Grant ListR00 AG042491 / AG / NIA NIH HHS / United States
R01 AI132738 / AI / NIAID NIH HHS / United States
R01 CA187492 / CA / NCI NIH HHS / United States
R33 CA212968 / CA / NCI NIH HHS / United States