How Biophysical Forces Regulate Human B Cell Lymphomas.
How Biophysical Forces Regulate Human B Cell Lymphomas.
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DOI：
10.1016/j.celrep.2018.03.069
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发表时间：
2018-04-10
期刊：
影响因子：
8.8
通讯作者：
Singh A
中科院分区：
文献类型：
--
作者：
Apoorva F;Loiben AM;Shah SB;Purwada A;Fontan L;Goldstein R;Kirby BJ;Melnick AM;Cosgrove BD;Singh A
微环境介导的生物物理力在人类淋巴瘤中的作用仍不明确。弥漫性大B细胞淋巴瘤（DLBCL）是异质性肿瘤，起源于高度增殖的生发中心B细胞。这些肿瘤及其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生存信号中。在此，我们表明流体流动可促进增殖并调节DLBCL对特定治疗药物的反应。流体流动上调具有CD79A/B突变或野生型B细胞受体（BCR）的活化B细胞样弥漫性大B细胞淋巴瘤（ABC - DLBCL）亚群中B细胞受体和整合素受体的表面表达，这与在小鼠中移植的人类肿瘤所观察到的情况相似。流体流动差异性地上调ABC - DLBCL中的信号靶点，如脾酪氨酸激酶（SYK）和p70S6K。通过选择性敲低CD79B并抑制信号靶点，我们对流体流动如何在ABC - DLBCL中对BCR和整合素进行机械调节提供了机制方面的见解。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，并且对于测试靶向治疗至关重要。
Apoorva等人报道了一种淋巴瘤微反应器，以了解调节淋巴瘤生长及其治疗反应的生物物理因素。他们描述了来自淋巴管和新生血管的流体动力在整合素和B细胞受体信号传导的机械调节中的作用。这些见解揭示了淋巴瘤的异质性，可能有助于更快地转化治疗方法。
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.
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影响因子：
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作者：
Cosgrove, Benjamin D.;Alexopoulos, Leonidas G.;Hang, Ta-chun;Hendriks, Bart S.;Sorger, Peter K.;Griffith, Linda G.;Lauffenburger, Douglas A.
通讯作者：
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影响因子：
11.2
作者：
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影响因子：
11.2
作者：
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影响因子：
20.3
作者：
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Alicia Cremaschi, Graciela
影响因子：
50.3
作者：
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通讯作者：
Müschen M