Post-translational modification of the membrane type 1 matrix metalloproteinase (MT1-MMP) cytoplasmic tail impacts ovarian cancer multicellular aggregate dynamics.

Published on Aug 11, 2017in Journal of Biological Chemistry4.238
· DOI :10.1074/JBC.M117.800904
Jing Yang6
Estimated H-index: 6
(ND: University of Notre Dame),
William C. Kasberg1
Estimated H-index: 1
(ND: University of Notre Dame)
+ 3 AuthorsM. Sharon Stack17
Estimated H-index: 17
(ND: University of Notre Dame)
Sources
Abstract
: Membrane type 1 matrix metalloproteinase (MT1-MMP, MMP-14) is a transmembrane collagenase highly expressed in metastatic ovarian cancer and correlates with poor survival. Accumulating evidence shows that the cytoplasmic tail of MT1-MMP is subjected to phosphorylation, and this post-translational modification regulates enzymatic activity at the cell surface. To investigate the potential role of MT1-MMP cytoplasmic residue Thr567 phosphorylation in regulation of metastasis-associated behaviors, ovarian cancer cells that express low endogenous levels of MT1-MMP were engineered to express wild-type MT1-MMP, a phosphomimetic mutant (T567E), or a phosphodeficient mutant (T567A). Results show that Thr567 modulation influences behavior of both individual cells and multicellular aggregates (MCAs). The acquisition of either wild-type or mutant MT1-MMP expression results in altered cohesion of epithelial sheets and the formation of more compact MCAs relative to parental cells. Cells expressing MT1-MMP-T567E phosphomimetic mutants exhibit enhanced cell migration. Furthermore, MCAs formed from MT1-MMP-T567E-expressing cells adhere avidly to both intact ex vivo peritoneal explants and three-dimensional collagen gels. Interaction of these MCAs with peritoneal mesothelium disrupts mesothelial integrity, exposing the submesothelial collagen matrix on which MT1-MMP-T567E MCAs rapidly disperse. Together, these findings suggest that post-translational regulation of the Thr567 in the MT1-MMP cytoplasmic tail may function as a regulatory mechanism to impact ovarian cancer metastatic success.
📖 Papers frequently viewed together
12 Authors (Kaori Taniwaki, ..., Ikuo Yana)
108 Citations
20112.74PLOS ONE
6 Authors (Olga Tatti, ..., Kaisa Lehti)
30 Citations
2 Authors (Jian Cao, ..., Pallavi Kozarekar)
1 Citations
References49
Newest
#1Yuliya Klymenko (ND: University of Notre Dame)H-Index: 8
#2Jeffrey Johnson (ND: University of Notre Dame)H-Index: 17
Last. M. Sharon Stack (ND: University of Notre Dame)H-Index: 17
view all 7 authors...
Abstract Epithelial ovarian carcinoma spreads via shedding of cells and multicellular aggregates (MCAs) from the primary tumor into peritoneal cavity, with subsequent intraperitoneal tumor cell:mesothelial cell adhesion as a key early event in metastatic seeding. Evaluation of human tumor extracts and tissues confirms that well-differentiated ovarian tumors express abundant E-cadherin (Ecad), whereas advanced lesions exhibit upregulated N-cadherin (Ncad). Two expression patterns are observed: "m...
32 CitationsSource
#1Lan G. Coffman (UM: University of Michigan)H-Index: 15
#2Daniela Burgos-Ojeda (UM: University of Michigan)H-Index: 5
Last. Ronald J. Buckanovich (UM: University of Michigan)H-Index: 42
view all 6 authors...
Emerging evidence suggest that many high-grade serous "ovarian" cancers (HGSOC) start in the fallopian tube. Cancer cells are then recruited to the ovary and then spread diffusely through the abdomen. The mechanism of ovarian cancer spread was thought to be largely due to direct shedding of tumor cells into the peritoneal cavity with vascular spread being of limited importance. Recent work challenges this dogma, suggesting hematogenous spread of ovarian cancer may play a larger role in ovarian c...
41 CitationsSource
#1Lana Bruney (MU: University of Missouri)H-Index: 1
#2Yueying Liu (ND: University of Notre Dame)H-Index: 16
Last. M. Sharon Stack (MU: University of Missouri)H-Index: 59
view all 5 authors...
Epithelial ovarian cancer (EOC) is the most fatal gynecologic cancer in the U.S., resulting in >14,000 deaths/year. Most women are diagnosed at late stage with widely disseminated intra-peritoneal metastatic disease, resulting in a 5-year survival rate of <30%. EOCs spread via direct extension and exfoliation into the peritoneal cavity, adhesion to peritoneal mesothelial cells, mesothelial cell retraction to expose sub-mseothelial matrix and anchoring in the type I collagen-rich matrix to genera...
13 CitationsSource
#1Rebecca L. Siegel (ACS: American Cancer Society)H-Index: 67
#2Kimberly D. Miller (ACS: American Cancer Society)H-Index: 28
Last. Ahmedin Jemal (ACS: American Cancer Society)H-Index: 140
view all 3 authors...
Abstract Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the National Cancer Institute (Surveillance, Epidemiology, and End Results [SEER] Program), the Centers for Disease Control and Prevention (National Program of Cancer Registries), and the North American Association of Central Can...
10.8k CitationsSource
#1Yueying Liu (ND: University of Notre Dame)H-Index: 16
#2Matthew N. Metzinger (ND: University of Notre Dame)H-Index: 3
Last. M. Sharon Stack (ND: University of Notre Dame)H-Index: 17
view all 22 authors...
Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy, with high mortality attributable to widespread intraperitoneal metastases. Recent meta-analyses report an association between obesity, ovarian cancer incidence, and ovarian cancer survival, but the effect of obesity on metastasis has not been evaluated. The objective of this study was to use an integrative approach combining in vitro , ex vivo , and in vivo studies to test the hypothesis that obesity contr...
48 CitationsSource
#1Sarah Heerboth (BU: Boston University)H-Index: 10
#2Genevieve Housman (ASU: Arizona State University)H-Index: 11
Last. Sibaji Sarkar (BU: Boston University)H-Index: 15
view all 8 authors...
EMT and MET comprise the processes by which cells transit between epithelial and mesenchymal states, and they play integral roles in both normal development and cancer metastasis. This article reviews these processes and the molecular pathways that contribute to them. First, we compare embryogenesis and development with cancer metastasis. We then discuss the signaling pathways and the differential expression and down-regulation of receptors in both tumor cells and stromal cells, which play a rol...
376 CitationsSource
#1Lana BruneyH-Index: 3
#2Kaitlynn C. ConleyH-Index: 1
Last. M. Sharon Stack (ND: University of Notre Dame)H-Index: 17
view all 5 authors...
Mucin16 (MUC16/cancer antigen 125 (CA-125)), a high-molecular-weight glycoprotein expressed on the ovarian tumor cell surface, potentiates metastasis via selective binding to mesothelin on peritoneal mesothelial cells. Shed MUC16/CA-125 is detectable in sera from ovar - ian cancer patients. We investigated the potential role of membrane type 1 matrix metalloproteinase (MT1-MMP, MMP-14), a transmembrane collagenase highly expressed in ovarian cancer cells, in MUC16/CA-125 ectodomain shedding. An ...
22 CitationsSource
#1Sunila Pradeep (University of Texas MD Anderson Cancer Center)H-Index: 30
#2Seung W. Kim (University of Texas MD Anderson Cancer Center)H-Index: 2
Last. Anil K. Sood (University of Texas MD Anderson Cancer Center)H-Index: 132
view all 32 authors...
Ovarian cancer has a clear predilection for metastasis to the omentum, but the underlying mechanisms involved in ovarian cancer spread are not well understood. Here, we used a parabiosis model that demonstrates preferential hematogenous metastasis of ovarian cancer to the omentum. Our studies revealed that the ErbB3-neuregulin 1 (NRG1) axis is a dominant pathway responsible for hematogenous omental metastasis. Elevated levels of ErbB3 in ovarian cancer cells and NRG1 in the omentum allowed for t...
172 CitationsSource
#1Ernst Lengyel (U of C: University of Chicago)H-Index: 66
#2Joanna E. Burdette (UIC: University of Illinois at Chicago)H-Index: 29
Last. M. Stack (ND: University of Notre Dame)H-Index: 2
view all 9 authors...
Epithelial ovarian cancer (OvCa) is associated with high mortality and, as the majority (>75%) of women with OvCa have metastatic disease at the time of diagnosis, rates of survival have not changed appreciably over 30 years. A mechanistic understanding of OvCa initiation and progression is hindered by the complexity of genetic and/or environmental initiating events and lack of clarity regarding the cell(s) or tissue(s) of origin. Metastasis of OvCa involves direct extension or exfoliation of ce...
132 CitationsSource
#1Rachel A. Davidowitz (Harvard University)H-Index: 4
#2Laura M. Selfors (Harvard University)H-Index: 24
Last. Joan S. Brugge (Harvard University)H-Index: 122
view all 15 authors...
Metastatic dissemination of ovarian tumors involves the invasion of tumor cell clusters into the mesothelial cell lining of peritoneal cavity organs; however, the tumor-specific factors that allow ovarian cancer cells to spread are unclear. We used an in vitro assay that models the initial step of ovarian cancer metastasis, clearance of the mesothelial cell layer, to examine the clearance ability of a large panel of both established and primary ovarian tumor cells. Comparison of the gene and pro...
83 CitationsSource
Cited By10
Newest
Proteases play a crucial role in the progression and metastasis of ovarian cancer. Pericellular protein degradation and fragmentation along with remodeling of the extracellular matrix (ECM) is accomplished by numerous proteases that are present in the ovarian tumor microenvironment. Several proteolytic processes have been linked to cancer progression, particularly those facilitated by the matrix metalloproteinase (MMP) family. These proteases have been linked to enhanced migratory ability, extra...
Source
#1Ilenia MasiH-Index: 1
#2Valentina CapraraH-Index: 11
Last. Laura Rosanò (National Research Council)H-Index: 37
view all 9 authors...
Summary Cancer cells use actin-based membrane protrusions, invadopodia, to degrade stroma and invade. In serous ovarian cancer (SOC), the endothelin A receptor (ETAR) drives invadopodia by a not fully explored coordinated function of β-arrestin1 (β-arr1). Here, we report that β-arr1 links the integrin-linked kinase (ILK)/βPIX complex to activate Rac3 GTPase, acting as a central node in the adhesion-based extracellular matrix (ECM) sensing and degradation. Downstream, Rac3 phosphorylates PAK1 and...
Source
#1Charles Marusak (UM: University of Miami)H-Index: 1
#2Varsha Thakur (UM: University of Miami)H-Index: 1
Last. Barbara Bedogni (UM: University of Miami)H-Index: 4
view all 21 authors...
Purpose: The extracellular matrix (ECM) is an intriguing, yet understudied component of therapy resistance. Here, we investigated the role of ECM remodeling by the collagenase, MT1-MMP, in conferring resistance of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutant melanoma to BRAF inhibitor (BRAFi) therapy. Experimental Design: Publicly available RNA-sequencing data and reverse phase protein array were used to determine the relevance of MT1-MMP upregulation in BRAFi-resistant melanoma ...
Source
#1Yuliya Klymenko (IU: Indiana University)H-Index: 8
#2Brandi Bos (ND: University of Notre Dame)H-Index: 1
Last. M. Sharon Stack (ND: University of Notre Dame)H-Index: 17
view all 8 authors...
Epithelial ovarian cancer (EOC) metastasis occurs by exfoliation of cells and multicellular aggregates (MCAs) from the tumor into the peritoneal cavity, adhesion to and retraction of peritoneal mesothelial cells and subsequent anchoring. Elevated levels of lysophosphatidic acid (LPA) have been linked to aberrant cell proliferation, oncogenesis, and metastasis. LPA disrupts junctional integrity and epithelial cohesion in vitro however, the fate of free-floating cells/MCAs and the response of host...
1 CitationsSource
#1Elizabeta Madzharova (DTU: Technical University of Denmark)H-Index: 2
#2Philipp Kastl (DTU: Technical University of Denmark)H-Index: 2
Last. Ulrich auf dem Keller (DTU: Technical University of Denmark)H-Index: 35
view all 4 authors...
Due to their capacity to process different proteins of the extracellular matrix (ECM), matrix metalloproteinases (MMPs) were initially described as a family of secreted proteases, functioning as main ECM regulators. However, through proteolytic processing of various biomolecules, MMPs also modulate intra- and extracellular pathways and networks. Thereby, they are functionally implicated in the regulation of multiple physiological and pathological processes. Consequently, MMP activity is tightly ...
17 CitationsSource
#1Anna M. Knapinska (FAU: Florida Atlantic University)H-Index: 10
#2Gregg B. Fields (FAU: Florida Atlantic University)H-Index: 74
For over 20 years, membrane type 1 matrix metalloproteinase (MT1-MMP) has been recognized as a key component in cancer progression. Initially, the primary roles assigned to MT1-MMP were the activation of proMMP-2 and degradation of fibrillar collagen. Proteomics has revealed a great array of MT1-MMP substrates, and MT1-MMP selective inhibitors have allowed for a more complete mapping of MT1-MMP biological functions. MT1-MMP has extensive sheddase activities, is both a positive and negative regul...
13 CitationsSource
#1Sarah Nersesian (Queen's University)H-Index: 7
#2Rodette Williams (Queen's University)H-Index: 2
Last. Andrew W.B. Craig (Queen's University)H-Index: 27
view all 8 authors...
Amplification of HER2 leads to development of HER2-positive (HER2+) cancers with high rates of metastasis compared to other cancer subtypes. The goal of this study was to probe the vulnerability of HER2+ cancer cells to a filamentous actin (F-actin) severing and capping toxin. The growth and viability of human HER2+ breast cancer (HCC1954) and ovarian cancer (SKOV3) cell lines were significantly impaired upon treatment with the marine macrolide mycalolide B (Myc B) at doses above 100 nanomolar. ...
8 CitationsSource
#1Wenzheng Bao (Tongji University)H-Index: 11
#2Chang-An YuanH-Index: 3
Last. De-Shuang Huang (Tongji University)H-Index: 72
view all 7 authors...
Post translational modification plays a significiant role in the biological processing. The potential post translational modification is composed of the center sites and the adjacent amino acid residues which are fundamental protein sequence residues. It can be helpful to perform their biological functions and contribute to understanding the molecular mechanisms that are the foundations of protein design and drug design. The existing algorithms of predicting modified sites often have some shortc...
21 CitationsSource
#1Neri AmaraH-Index: 10
#2Martina TholenH-Index: 6
Last. Matthew BogyoH-Index: 89
view all 3 authors...
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 coval...
5 CitationsSource
#1Ruth M. Escalona (University of Melbourne)H-Index: 13
#2Emily Chan (University of Melbourne)H-Index: 4
Last. Nuzhat AhmedH-Index: 39
view all 5 authors...
Approximately sixty per cent of ovarian cancer patients die within the first five years of diagnosis due to recurrence associated with chemoresistance. The metzincin family of metalloproteinases is enzymes involved in matrix remodeling in response to normal physiological changes and diseased states. Recently, there has been a mounting awareness of these proteinases and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), as superb modulators of cellular communication...
3 CitationsSource