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Chemical Tools for Selective Activity Profiling of Endogenously Expressed MMP-14 in Multicellular Models
journal contribution
posted on 2018-08-30, 00:00 authored by Neri Amara, Martina Tholen, Matthew BogyoMatrix
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. 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 demonstrate the applicability of
this approach for studies of MMP function in whole organisms and identify
important regulatory mechanisms for MMP-14 activity in the tumor microenvironment.