# Local and systemic control of multiple myeloma colonization and growth by MMP-13

> **NIH NIH R01** · H. LEE MOFFITT CANCER CTR & RES INST · 2020 · $440,438

## Abstract

SUMMARY
Despite medical advances, multiple myeloma remains a fatal disease. The mechanisms underpinning how
myeloma progresses in the local bone microenvironment and through which myeloma colonizes the skeleton to
generate multiple painful osteolytic lesions needs to be addressed urgently. Matrix metalloproteinases (MMPs)
are key regulators of tumor-bone interaction via the regulation of cytokine and growth factor
bioavailability/activity. Emerging data from our group has identified that in human specimens of the disease,
MMP-13 is highly expressed by both the myeloma cells and the cells of the bone microenvironment namely,
bone building osteoblasts. In vivo analyses show that when MMP-13 is genetically ablated from the host
compartment there is a significant increase in overall survival and a concomitant decrease in myeloma induced
bone disease. We also have identified that myeloma derived exosomes can promote the skeletal colonization
of myeloma and, are rich in MMP-13. Further, preliminary data with a novel highly selective MMP-13 inhibitor
significantly limits myeloma growth in vitro and in vivo underscoring the role for MMP-13 activity in driving
multiple myeloma. Based on these preliminary findings we hypothesize that MMP-13 contributes to multiple
myeloma progression. We will test our hypothesis by; 1) Defining the role of tumor and osteoblast derived
MMP-13 in multiple myeloma progression. We will use CRISPR/cDNA overexpression approaches to
manipulate the levels of MMP-13 in myeloma cell lines while using specific Cre-recombinase driven promoters
to eliminate MMP-13 expression by osteoblasts. We will then test whether the presence or absence of MMP-13
in one or both compartments contributes to myeloma growth and associated bone disease in two separate in
vivo models (5TGM1 and U266). We will also explore MMP-13 mechanisms of action with preliminary work
pointing to regulation of transforming growth factorβ (TGFβ) activity. 2) Determining the role of myeloma
derived exosomes and specifically exosomal MMP-13 in the skeletal colonization of the disease. We will also
examine whether exosomal MMP-13, can identify smoldering multiple myeloma patients (n=200) at high-risk of
progression to active disease using proteomic techniques. 3) Identifying the efficacy of a selective MMP-13
inhibitor in limiting multiple myeloma viability using CD138 isolated myeloma cells obtained from newly
diagnosed patients in a novel ex vivo high throughput platform and clinically relevant in vivo models of the
disease. Based on the anticipated results, interrogating the role MMP-13 in multiple myeloma progression will
reveal a number of novel insights thereby providing a strong rationale for the translation of selective MMP-13
inhibitors to the clinic that we predict would have limited off-target effects due to the restricted skeletal
expression of MMP-13.

## Key facts

- **NIH application ID:** 9878083
- **Project number:** 5R01CA239214-02
- **Recipient organization:** H. LEE MOFFITT CANCER CTR & RES INST
- **Principal Investigator:** Conor C Lynch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $440,438
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878083

## Citation

> US National Institutes of Health, RePORTER application 9878083, Local and systemic control of multiple myeloma colonization and growth by MMP-13 (5R01CA239214-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9878083. Licensed CC0.

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