TY - JOUR
T1 - Breast Cancer-Secreted Factors Promote Lung Metastasis by Signaling Systemically to Induce a Fibrotic Premetastatic Niche
AU - Cohen, Noam
AU - Mundhe, Dhanashree
AU - Deasy, Sarah K.
AU - Adler, Omer
AU - Ershaid, Nour
AU - Shami, Tamar
AU - Levi-Galibov, Oshrat
AU - Wassermann, Rina
AU - Scherz-Shouval, Ruth
AU - Erez, Neta
N1 - Publisher Copyright: ©2023 American Association for Cancer Research.
PY - 2023/10/13
Y1 - 2023/10/13
N2 - Metastatic cancer is largely incurable and is the main cause of cancer-related deaths. The metastatic microenvironment facilitates formation of metastases. Cancer-associated fibroblasts (CAF) are crucial players in generating a hospitable metastatic niche by mediating an inflammatory microenvironment. Fibroblasts also play a central role in modifying the architecture and stiffness of the extracellular matrix (ECM). Resolving the early changes in the metastatic niche could help identify approaches to inhibit metastatic progression. Here, we demonstrate in mouse models of spontaneous breast cancer pulmonary metastasis that fibrotic changes and rewiring of lung fibroblasts occurred at premetastatic stages, suggesting systemic influence by the primary tumor. Activin A (ActA), a TGFβ superfamily member, was secreted from breast tumors and its levels in the blood were highly elevated in tumor-bearing mice. ActA upregulated the expression of profibrotic factors in lung fibroblasts, leading to enhanced collagen deposition in the lung premetastatic niche. ActA signaling was functionally important for lung metastasis, as genetic targeting of ActA in breast cancer cells significantly attenuated lung metastasis and improved survival. Moreover, high levels of ActA in human patients with breast cancer were associated with lung metastatic relapse and poor survival. This study uncovers a novel mechanism by which breast cancer cells systemically rewire the stromal microenvironment in the metastatic niche to facilitate pulmonary metastasis. SIGNIFICANCE: ActA mediates cross-talk between breast cancer cells and cancer-associated fibroblasts in the lung metastatic niche that enhances fibrosis and metastasis, implicating ActA as a potential therapeutic target to inhibit metastatic relapse.
AB - Metastatic cancer is largely incurable and is the main cause of cancer-related deaths. The metastatic microenvironment facilitates formation of metastases. Cancer-associated fibroblasts (CAF) are crucial players in generating a hospitable metastatic niche by mediating an inflammatory microenvironment. Fibroblasts also play a central role in modifying the architecture and stiffness of the extracellular matrix (ECM). Resolving the early changes in the metastatic niche could help identify approaches to inhibit metastatic progression. Here, we demonstrate in mouse models of spontaneous breast cancer pulmonary metastasis that fibrotic changes and rewiring of lung fibroblasts occurred at premetastatic stages, suggesting systemic influence by the primary tumor. Activin A (ActA), a TGFβ superfamily member, was secreted from breast tumors and its levels in the blood were highly elevated in tumor-bearing mice. ActA upregulated the expression of profibrotic factors in lung fibroblasts, leading to enhanced collagen deposition in the lung premetastatic niche. ActA signaling was functionally important for lung metastasis, as genetic targeting of ActA in breast cancer cells significantly attenuated lung metastasis and improved survival. Moreover, high levels of ActA in human patients with breast cancer were associated with lung metastatic relapse and poor survival. This study uncovers a novel mechanism by which breast cancer cells systemically rewire the stromal microenvironment in the metastatic niche to facilitate pulmonary metastasis. SIGNIFICANCE: ActA mediates cross-talk between breast cancer cells and cancer-associated fibroblasts in the lung metastatic niche that enhances fibrosis and metastasis, implicating ActA as a potential therapeutic target to inhibit metastatic relapse.
UR - http://www.scopus.com/inward/record.url?scp=85179467105&partnerID=8YFLogxK
U2 - https://doi.org/10.1158/0008-5472.CAN-22-3707
DO - https://doi.org/10.1158/0008-5472.CAN-22-3707
M3 - مقالة
C2 - 37548552
SN - 0008-5472
VL - 83
SP - 3354
EP - 3367
JO - Cancer Research
JF - Cancer Research
IS - 20
ER -