TY - JOUR
T1 - MMP9 modulates the metastatic cascade and immune landscape for breast cancer anti-metastatic therapy
AU - Owyong, Mark
AU - Chou, Jonathan
AU - van den Bijgaart, Renske J.E.
AU - Kong, Niwen
AU - Efe, Gizem
AU - Maynard, Carrie
AU - Talmi-Frank, Dalit
AU - Solomonov, Inna
AU - Koopman, Charlotte
AU - Hadler-Olsen, Elin
AU - Headley, Mark
AU - Lin, Charlene
AU - Wang, Chih Yang
AU - Sagi, Irit
AU - Werb, Zena
AU - Plaks, Vicki
N1 - Funding Information:
We thank members of the Werb laboratory for helpful discussions. We specifically thank Elena Atamaniuc, Ying Yu, Kiarash Salari, Ankitha Nanjaraj, and Helen Capili for technical assistance; Caroline Bonnans for immunofluorescence advice; Nguyen H Nguyen and Vaishnavi Sitarama for their assistance with therapeutic experiments; and Catharina Hagerling and the University of California, San Francisco Flow Cytometry Core for advice with flow cytometry. This work was supported by a Department of Defense Postdoctoral Fellowship (W81XWH-11-01-0139) to V Plaks, Department of Defense Predoctoral Fellowship (W81XWH-10-1-0168) to J Chou, grants from the National Cancer Institute (R01 CA057621, U01 CA199315, CA180039, and CA190851) and the Parker Institute for Cancer Immunotherapy to Z Werb, grants from the California Breast Cancer Research Program (23IB-001) and Cancer League Award to Z Werb and V Plaks, and funds from the Israel Science Foundation (1800/19), the USA-Israel Binational Science Foundation (712506-01), the European Union’s Horizon 2020 research and innovation program (grants agreement No [801126] and [695437]), and The Thompson Family Foundation, Inc. to I Sagi.
Funding Information:
We thank members of the Werb laboratory for helpful discussions. We specifically thank Elena Atamaniuc, Ying Yu, Kiarash Salari, Ankitha Nanjaraj, and Helen Capili for technical assistance; Caroline Bonnans for immuno-fluorescence advice; Nguyen H Nguyen and Vaishnavi Sitarama for their assistance with therapeutic experiments; and Catharina Hagerling and the University of California, San Francisco Flow Cytometry Core for advice with flow cytometry. This work was supported by a Department of Defense Postdoctoral Fellowship (W81XWH-11-01-0139) to V Plaks, Department of Defense Predoctoral Fellowship (W81XWH-10-1-0168) to J Chou, grants from the National Cancer Institute (R01 CA057621, U01 CA199315, CA180039, and CA190851) and the Parker Institute for Cancer Immunotherapy to Z Werb, grants from the California Breast Cancer Research Program (23IB-001) and Cancer League Award to Z Werb and V Plaks, and funds from the Israel Science Foundation (1800/19), the USA-Israel Binational Science Foundation (712506-01), the European Union’s Horizon 2020 research and innovation program (grants agreement No [801126] and [695437]), and The Thompson Family Foundation, Inc. to I Sagi.
Publisher Copyright:
© 2019 Owyong et al.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85075115088&partnerID=8YFLogxK
U2 - 10.26508/lsa.201800226
DO - 10.26508/lsa.201800226
M3 - Article
C2 - 31727800
AN - SCOPUS:85075115088
SN - 2575-1077
VL - 2
JO - Life Science Alliance
JF - Life Science Alliance
IS - 6
M1 - e201800226
ER -
