Chemical Tools for Selective Activity Profiling of Endogenously Expressed MMP-14 in Multicellular Models.
Chemical Tools for Selective Activity Profiling of Endogenously Expressed MMP-14 in Multicellular Models.
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DOI：
10.1021/acschembio.8b00562
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发表时间：
2018-09-21
影响因子：
4
通讯作者：
Bogyo M
中科院分区：
文献类型：
--
作者：
Amara N;Tholen M;Bogyo M
基质金属蛋白酶（MMP）是一个锌依赖性内肽酶大家族，参与多种生理和病理过程，最显著的是癌症。目前用于成像和定量MMP活性的方法缺乏足够的选择性和时空分辨率以允许在体内研究特定MMP功能。以前，我们报道了一种策略，选择性地通过设计一个功能沉默的半胱氨酸突变，使高度特异性的共价修饰的活性为基础的探针（ABP）的MMPs的目标。在这里，我们描述了该技术的翻译成小鼠模型的乳腺癌和随后的演示的实用程序的方法的研究MMP-14在肿瘤微环境中的激活。使用这种方法，我们发现MMP-14在晚期肿瘤中是有活性的，并且主要与已经被肿瘤细胞产生的特异性信号分子（例如TGFβ）激活的基质细胞群相关。我们的数据表明，这种方法的适用性，在整个生物体中的MMP功能的研究，并确定重要的调节机制，MMP-14的活性在肿瘤微环境。
Matrix metalloproteases (MMPs) are a large family of zinc-dependent endopeptidases, involved in a diverse set of physiological and pathological processes, most notably in cancer. Current methods for imaging and quantifying MMP activity lack sufficient selectivity and spatiotemporal resolution to allow studies of specific MMP function in vivo. Previously, we reported a strategy for selective targeting of MMPs by engineering a functionally silent cysteine mutation that enables highly specific covalent modification by a designed activity-based probe (ABP). Here we describe the translation of that technology into a mouse model of breast cancer and subsequent demonstration of the utility of the approach for studies of MMP-14 activation in the tumor microenvironment. Using this approach, we find that MMP-14 is active in late stage tumors and is predominantly associated with stromal cell populations that have been activated by specific signaling molecules (e.g. TGFβ) produced by tumor cells. Our data demonstrates the applicability of this approach for studies of MMP function in whole organisms and identifies important regulatory mechanisms for MMP-14 activity in the tumor microenvironment.
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影响因子：
15
作者：
Morell, Montse;Thinh Nguyen Duc;Willis, Amanda L.;Syed, Salahuddin;Lee, Jiyoun;Deu, Edgar;Deng, Yang;Xiao, Junpeng;Turk, Benjamin E.;Jessen, Jason R.;Weiss, Stephen J.;Bogyo, Matthew
通讯作者：
Bogyo, Matthew
影响因子：
50.3
作者：
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通讯作者：
Coussens, Lisa M.
影响因子：
4.8
作者：
Hernandez-Barrantes, S;Toth, M;Fridman, R
通讯作者：
Fridman, R
影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS
影响因子：
7.3
作者：
Levy, DE;Lapierre, F;Galardy, RE
通讯作者：
Galardy, RE