TY - UNPB
T1 - Tumor-restrictive type III collagen in the breast cancer microenvironment: prognostic and therapeutic implications
AU - Volk, Susan
AU - Brisson, Becky K.
AU - Dekky, Basil
AU - Berger, Ashton C.
AU - Mauldin, Elizabeth A.
AU - Loebel, Claudia
AU - Yen, William
AU - Stewart, Daniel C.
AU - Gillette, Deborah
AU - Assenmacher, Charles Antoine
AU - Cukierman, E.
AU - Burdick, Jason A.
AU - Borges, Virginia F.
N1 - Brisson, Becky K Dekky, Bassil Berger, Ashton C Mauldin, Elizabeth A Loebel, Claudia Yen, William Stewart, Daniel C Gillette, Deborah Assenmacher, Charles-Antoine Cukierman, Edna Burdick, Jason A Borges, Virginia F Volk, Susan W Orcid: 0000-0003-3993-4145 S10 OD023666/OD/NIH HHS/United States T35 OD010919/OD/NIH HHS/United States Preprint United States 2023/04/24 Res Sq. 2023 Apr 12. doi: 10.21203/rs.3.rs-2631314/v1.
PY - 2023
Y1 - 2023
N2 - Collagen plays a critical role in regulating breast cancer progression and therapeutic resistance. An improved understanding of both the features and drivers of tumor-permissive and -restrictive collagen matrices are critical to improve prognostication and develop more effective therapeutic strategies. In this study, using a combination of in vitro, in vivo and in silico experiments, we show that type III collagen (Col3) plays a tumor-restrictive role in human breast cancer. We demonstrate that Col3-deficient, human fibroblasts produce tumor- permissive collagen matrices that drive cell proliferation and suppress apoptosis in noninvasive and invasive breast cancer cell lines. In human TNBC biopsy samples, we demonstrate elevated deposition of Col3 relative to type I collagen (Col1) in noninvasive compared to invasive regions. Similarly, in silico analyses of over 1000 breast cancer patient biopsies from The Cancer Genome Atlas BRCA cohort revealed that patients with higher Col3:Col1 bulk tumor expression had improved overall, disease-free and progression-free survival relative to those with higher Col1:Col3 expression. Using an established 3D culture model, we show that Col3 increases spheroid formation and induces formation of lumen-like structures that resemble non-neoplastic mammary acini. Finally, our in vivo study shows co-injection of murine breast cancer cells (4T1) with rhCol3-supplemented hydrogels limits tumor growth and decreases pulmonary metastatic burden compared to controls. Taken together, these data collectively support a tumor-suppressive role for Col3 in human breast cancer and suggest that strategies that increase Col3 may provide a safe and effective modality to limit recurrence in breast cancer patients.
AB - Collagen plays a critical role in regulating breast cancer progression and therapeutic resistance. An improved understanding of both the features and drivers of tumor-permissive and -restrictive collagen matrices are critical to improve prognostication and develop more effective therapeutic strategies. In this study, using a combination of in vitro, in vivo and in silico experiments, we show that type III collagen (Col3) plays a tumor-restrictive role in human breast cancer. We demonstrate that Col3-deficient, human fibroblasts produce tumor- permissive collagen matrices that drive cell proliferation and suppress apoptosis in noninvasive and invasive breast cancer cell lines. In human TNBC biopsy samples, we demonstrate elevated deposition of Col3 relative to type I collagen (Col1) in noninvasive compared to invasive regions. Similarly, in silico analyses of over 1000 breast cancer patient biopsies from The Cancer Genome Atlas BRCA cohort revealed that patients with higher Col3:Col1 bulk tumor expression had improved overall, disease-free and progression-free survival relative to those with higher Col1:Col3 expression. Using an established 3D culture model, we show that Col3 increases spheroid formation and induces formation of lumen-like structures that resemble non-neoplastic mammary acini. Finally, our in vivo study shows co-injection of murine breast cancer cells (4T1) with rhCol3-supplemented hydrogels limits tumor growth and decreases pulmonary metastatic burden compared to controls. Taken together, these data collectively support a tumor-suppressive role for Col3 in human breast cancer and suggest that strategies that increase Col3 may provide a safe and effective modality to limit recurrence in breast cancer patients.
KW - Brca Tnbc breast cancer collagen mammary tumors metastasis tumor microenvironment tumor stroma type III collagen
U2 - 10.21203/rs.3.rs-2631314/v1
DO - 10.21203/rs.3.rs-2631314/v1
M3 - Preprint
C2 - 37090621
T3 - Research square
BT - Tumor-restrictive type III collagen in the breast cancer microenvironment: prognostic and therapeutic implications
ER -