The most deadly characteristic of cancer cells is their ability to invade local tissues and metastasize. Current evidence suggests that carcinoma cell proliferative, invasive and metastatic potential are regulated in a cancer cell-autonomous fashion as well as by the surrounding cellular and acellular microenvironment. Using MT1-MMP conditional knockout mice, in combination with human patient- derived cancer xenografts, we have recently reported that carcinoma cell-derived MT1-MMP plays a dominant role in driving local tissue invasion and metastasis. Unexpectedly, however, we find that targeting carcinoma cell MT1-MMP alone in vivo triggers large scale changes in the transcriptional program of the cancer cells that extend far beyond the regulation of cell-extracellular matrix (ECM) interactions. These results suggest that MT1-MMP exerts a more global effect on carcinoma cell function than previously appreciated. Indeed, we provide new evidence that MT1-MMP controls carcinoma cell gene expression by regulating a novel mechanotransduction cascade that centers on the regulation of nuclear lamin A/C level with attendant effects on the co-transcriptional activators, YAP and TAZ and the MRTF-SRF transcriptional network. Furthermore, preliminary studies indicate that MT1-MMP exerts these effects in a proteinase-dependent fashion by effecting the remodeling of the type I collagen-rich, interstitial ECM. Finally, while monitoring the trafficking of MT1-MMP to invadopodial structures during ECM remodeling, we have uncovered a heretofore undescribed process wherein MT1-MMP translocates from promyelocytic leukemia protein (PML)-rich nuclear invaginations to ECM-degradative sites at the cell surface in association with the cytoplasmic RNA-binding protein, UNR/CSDE1. Given these findings, we outline plans for a combination of molecular and cellular studies that seek to i) define MT1-MMP as a master upstream regulator of the mechanotransduction-linked carcinoma cell transcription programs required for invasion and metastasis, ii) characterize the role of the MT1-MMP/type I collagen axis as the key determinant responsible for controlling carcinoma cell behavior in vivo and iii) establish the role of a novel, nuclear budding-initiated, MT1-MMP-PML/UNR interaction network in controlling proteinase delivery to matrix-degradative invadosomes. Together, these studies seek to identify MT1-MMP as the dominant proteolytic effector of tumor progression in vivo by virtue of its ability to control the behavior of cancer cell populations embedded within the type I collagen-rich 3D ECM encountered at primary and metastatic sites in vivo.
Carcinoma invasion and metastasis is not only regulated in a cancer cell-autonomous fashion, but also through complex interactions with surrounding stroma cells as well as the surrounding interstitial matrix itself. Herein, we outline a series of novel in vivo and ex vivo models that support a pre-eminent role for the membrane- anchored matrix metalloproteinase, MT1-MMP, in regulating tumor cell progression by unexpectedly controlling a series of mechanotransduction-linked programs that directly impact the transcriptional programs underlying invasion and metastasis. These studies should not only shed new mechanistic insights on the key proteolytic events that regulate MT1-MMP-dependent control of cancer cell invasive and metastatic activities, but also help facilitate the identification of novel targets relevant to therapeutic intervention.
Showing the most recent 10 out of 34 publications
