MMP9 modulates the metastatic cascade and immune landscape for breast cancer anti-metastatic therapy.

Mark Owyong,Jonathan Chou,Dalit Talmi-Frank,Mark Headley,Irit Sagi,Niwen Kong,Elin Hadler-Olsen,Charlene Lin,Chih-Yang Wang,Carrie Maynard,Zena Werb,Vicki Plaks,Charlotte Koopman,Inna Solomonov,Gizem Efe,Renske Je Van Den Bijgaart

doi:10.26508/lsa.201800226

Mark Owyong, Jonathan Chou + Show 14 more

Open Access

https://doi.org/10.26508/lsa.201800226

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Abstract

Metastasis, the main cause of cancer-related death, has traditionally been viewed as a late-occurring process during cancer progression. Using the MMTV-PyMT luminal B breast cancer model, we demonstrate that the lung metastatic niche is established early during tumorigenesis. We found that matrix metalloproteinase 9 (MMP9) is an important component of the metastatic niche early in tumorigenesis and promotes circulating tumor cells to colonize the lungs. Blocking active MMP9, using a monoclonal antibody specific to the active form of gelatinases, inhibited endogenous and experimental lung metastases in the MMTV-PyMT model. Mechanistically, inhibiting MMP9 attenuated migration, invasion, and colony formation and promoted CD8+ T cell infiltration and activation. Interestingly, primary tumor burden was unaffected, suggesting that inhibiting active MMP9 is primarily effective during the early metastatic cascade. These findings suggest that the early metastatic circuit can be disrupted by inhibiting active MMP9 and warrant further studies of MMP9-targeted anti-metastatic breast cancer therapy.

Highlights

IntroductionMetastasis, one of the classic “hallmarks of cancer” (Hanahan & Weinberg, 2011), is a multistage process that includes remodeling the local tumor microenvironment (TME), followed by invasion of tumor cells into the blood or lymph, survival in circulation, extravasation, and growth in a new microenvironment
Most cancer-related deaths are due to metastatic disease
We used an MMTVPyMT–derived cell line generated by Lynch and colleagues (Halpern et al, 2006) that we labeled with GFP and luciferase to mimic circulating tumor cells (CTCs) and probe their ability to colonize the lungs

Summary

Introduction

Metastasis, one of the classic “hallmarks of cancer” (Hanahan & Weinberg, 2011), is a multistage process that includes remodeling the local tumor microenvironment (TME), followed by invasion of tumor cells into the blood or lymph, survival in circulation, extravasation, and growth in a new microenvironment. The recognition that cancer is a systemic disease has been illustrated by studies showing the importance of various cell types in creating a metastatic niche (Lambert et al, 2017), and the role of the immune system in tumor growth (Aguado et al, 2017). Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, are pivotal players in ECM remodeling during cancer initiation and progression via multiple mechanisms (Kessenbrock et al, 2010; Bonnans et al, 2014). MMP9 is instrumental in establishing the metastatic niche (Hiratsuka et al, 2002; Kaplan et al, 2005) and functions as a key mediator in metastatic progression

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