How Biophysical Forces Regulate Human B Cell Lymphomas
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
Affiliations
F. Apoorva
Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY 14853, USA
Alexander M. Loiben
Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
Shivem B. Shah
Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
Alberto Purwada
Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
Lorena Fontan
Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA
Rebecca Goldstein
Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA
Brian J. Kirby
Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY 14853, USA; Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA
Ari M. Melnick
Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA
Benjamin D. Cosgrove
Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
Ankur Singh
Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY 14853, USA; Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA; Englander Institute for Precision Medicine, Weill Cornell Medical College, New York, NY 10021, USA; Corresponding author
Summary: 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. : Apoorva et al. report a lymphoma micro-reactor to understand biophysical factors that regulate lymphoma growth and their therapeutic responses. They describe the role of fluid forces, from lymphatics and neo-vessels, in mechanomodulation of integrin and B cell receptor signaling. These insights shed light on the heterogeneous nature of lymphomas and may allow faster translation of therapeutics. Keywords: signaling, chemotherapy, B cell receptor, fluid, shear stress, mutation, integrin, mechanomodulation, lymph node, lymphatics
