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.
Cell Rep. 2018 Apr 10;23(2):499-511. doi: 10.1016/j.celrep.2018.03.069.
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.
微环境介导的生物物理力在人类淋巴瘤中的作用仍难以捉摸。弥漫性大 B 细胞淋巴瘤（DLBCL）是一种异质性肿瘤，起源于高度增殖的生发中心 B 细胞。这些肿瘤、它们相关的新生血管和淋巴管可能使细胞暴露于特定的流体流动和存活信号中。在这里，我们表明流体流动增强了增殖，并调节了 DLBCL 对特定治疗药物的反应。流体流动上调了 ABC-DLBCL 中具有 CD79A/B 突变或 WT BCR 的亚群的 B 细胞受体（BCR）和整合素受体的表面表达，类似于在小鼠中异种移植的人类肿瘤中观察到的情况。流体流动在 ABC-DLBCL 中差异地上调信号靶标，如 SYK 和 p70S6K。通过选择性敲低 CD79B 和抑制信号靶标，我们提供了关于流体流动如何在 ABC-DLBCL 中机械调节 BCR 和整合素的机制见解。这些发现重新定义了调节淋巴瘤-药物相互作用的微环境因素，对于测试靶向治疗至关重要。
