Abstract 4724: Targeting matrix metalloproteinases (MMP) for anti-metastatic therapy: Blocking active MMP9 abrogates metastatic niche formation and prevents metastatic seeding in a breast cancer model

Abstract

Abstract Currently there is no cure for a metastatic disease and it is therefore critical to target the early events that foster metastasis. It is now also recognized that a favorable microenvironment in the metastatic site, primed by the tumor, is crucial for metastasis. Our study is geared towards deciphering cellular and molecular mechanisms governing the metastatic niche that may lead to novel targeted anti-metastatic therapeutics. We utilize the multi-stage MMTV-PyMT breast cancer mouse model, which shares significant similarities with human breast cancer. By injecting a reporter metastatic cell line into hyperplasia-bearing mice, we were able to probe the susceptibility of the lung microenvironment to metastatic seeding. We demonstrate that early during mammary tumorigenesis, before metastasis has occurred, a metastatic niche is formed in the lung microenvironment. This niche is initiated in part by tumor-induced systemic pro-inflammatory factors and local extracellular matrix remodelers, as matrix metalloproteinases (MMPs). We show that the metastatic niche is associated with MMP9-expressing CD11b+Gr1+ and other lung stromal cells. MMP9, which is also expressed by tumor cells, appears as a pivotal player in the process and is therefore considered as a desirable therapeutic target. To examine the role of MMP9 activity in lung metastatic colonization, we utilized novel endogenous-like, function-specific antibodies (SDS3) that block the transiently-activated enzyme conformation of MMP9, which presumably contributes to disease progression. The therapeutic potential of SDS3 has been demonstrated in models of inflammatory bowel disease. We show that metastatic seeding within the lung microenvironment can be inhibited by SDS3, not only in experimental metastasis models but also when the lung microenvironment is primed by hyperplastic mammary tumors. Primary tumor burden was not changed with SDS3, suggesting that blocking active MMP9 is effective in preventing early metastasis rather than established tumors. To study the biodistribution and pharmacokinetics of SDS3, we utilized whole-body bioluminescence, intravital and ex-vivo live microscopy as well as flow cytometry. We show that SDS3 is retained in myeloid cells within the microenvironment of mammary tumors and lung metastatic foci. In situ zymography shows high MMP activity in premetastaic MMTV-PyMT lungs, which is reduced after SDS3. SDS3 also inhibits colony formation of cultured metastatic cells. Our results suggest that a metastatic niche is present in the lungs of hyperplastic mammary tumor-bearing mice and that it can be targeted by blocking MMP9 activity. Our study offers new insights into effectively blocking the in vivo activity of dysregulated MMPs as early anti-metastatic therapy of various cancers. Citation Format: Vicki Plaks, Jonathan Chou, Carrie Maynard, Nguyen H. Nguyen, Niwen Kong, Inna Solomonov, Dalit Talmi-Frank, Caroline Bonnans, Irit Sagi, Zena Werb. Targeting matrix metalloproteinases (MMP) for anti-metastatic therapy: Blocking active MMP9 abrogates metastatic niche formation and prevents metastatic seeding in a breast cancer model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4724. doi:10.1158/1538-7445.AM2015-4724