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.
|Feinberg, Tamar Y; Zheng, Huarui; Liu, Rui et al. (2018) Divergent Matrix-Remodeling Strategies Distinguish Developmental from Neoplastic Mammary Epithelial Cell Invasion Programs. Dev Cell 47:145-160.e6|
|Sakr, Moustafa; Li, Xiao-Yan; Sabeh, Farideh et al. (2018) Tracking the Cartoon mouse phenotype: Hemopexin domain-dependent regulation of MT1-MMP pericellular collagenolytic activity. J Biol Chem 293:8113-8127|
|Hwang, Jeongmin; Huang, Yufeng; Burwell, Timothy J et al. (2017) In Situ Imaging of Tissue Remodeling with Collagen Hybridizing Peptides. ACS Nano 11:9825-9835|
|Gómez-Escudero, Jesús; Moreno, Vanessa; Martín-Alonso, Mara et al. (2017) E-cadherin cleavage by MT2-MMP regulates apical junctional signaling and epithelial homeostasis in the intestine. J Cell Sci 130:4013-4027|
|Barnes 2nd, Richard H; Akama, Takeshi; Öhman, Miina K et al. (2017) Membrane-Tethered Metalloproteinase Expressed by Vascular Smooth Muscle Cells Limits the Progression of Proliferative Atherosclerotic Lesions. J Am Heart Assoc 6:|
|Ni, Ting; Li, Xiao-Yan; Lu, Na et al. (2016) Snail1-dependent p53 repression regulates expansion and activity of tumour-initiating cells in breast cancer. Nat Cell Biol 18:1221-1232|
|Feinberg, Tamar Y; Rowe, R Grant; Saunders, Thomas L et al. (2016) Functional roles of MMP14 and MMP15 in early postnatal mammary gland development. Development 143:3956-3968|
|Tang, Yi; Rowe, R Grant; Botvinick, Elliot L et al. (2013) MT1-MMP-dependent control of skeletal stem cell commitment via a ?1-integrin/YAP/TAZ signaling axis. Dev Cell 25:402-16|
|Willis, A L; Sabeh, F; Li, X-Y et al. (2013) Extracellular matrix determinants and the regulation of cancer cell invasion stratagems. J Microsc 251:250-60|
|Wolf, Katarina; Te Lindert, Mariska; Krause, Marina et al. (2013) Physical limits of cell migration: control by ECM space and nuclear deformation and tuning by proteolysis and traction force. J Cell Biol 201:1069-84|
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