# Function of Membrane Type Matrix Metalloproteinase

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $370,500

## Abstract

Abstract
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.

## Key facts

- **NIH application ID:** 9896984
- **Project number:** 2R01CA071699-21A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** STEPHEN J WEISS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $370,500
- **Award type:** 2
- **Project period:** 1997-06-11 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896984

## Citation

> US National Institutes of Health, RePORTER application 9896984, Function of Membrane Type Matrix Metalloproteinase (2R01CA071699-21A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9896984. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*