TY - JOUR
T1 - Evaluation of Extracellular Matrix Composition to Improve Breast Cancer Modeling
AU - Byrne, Charles Ethan
AU - Decombe, Jean Baptiste
AU - Bingham, Grace C.
AU - Remont, Jordan
AU - Miller, Lindsay G.
AU - Khalif, Layah
AU - King, Connor T.
AU - Hamel, Katie
AU - Bunnell, Bruce A.
AU - Burow, Matthew E.
AU - Martin, Elizabeth C.
N1 - Funding Information:
Supported in part by U54 GM104940 from the National Institute of General Medical Sciences of the National Institutes of Health, which funds the Louisiana Clinical and Translational Science Center.
Publisher Copyright:
© Mary Ann Liebert, Inc., publishers 2021.
PY - 2021/4
Y1 - 2021/4
N2 - The development of resistance to therapy is a significant obstacle to effective therapeutic regimens. Evaluating the effects of oncology drugs in the laboratory setting is limited by the lack of translational models that accurately recapitulate cell-microenvironment interactions present in tumors. Acquisition of resistance to therapy is facilitated, in part, by the composition of the tumor extracellular matrix (ECM), with the primary current in vitro model using collagen I (COL I). Here we seek to identify the prevalence of COL I-enhanced expression in the triple-negative breast cancer (TNBC) subtype. Furthermore, we identify if methods of response to therapy are altered depending on matrix composition. We demonstrated that collagen content varies in patient tumor samples across subtypes, with COL I expression dramatically increased in typically less aggressive estrogen receptor (ER)-positive(ER+)/progesterone receptor (PGR)-positive (PGR+) cancers irrespective of patient age or race. These findings are of significance considering how frequently COL I is implicated in tumor progression. In vitro analyses of ER+ and ER-negative (ER-) cell lines were used to determine the effects of ECM content (collagen I, collagen IV, fibronectin, and laminin) on proliferation, cellular phenotype, and survival. Neither ER+ nor ER- cells demonstrated significant increases in proliferation when cultured on these ECM substrates. ER- cells cultured on these substrates were sensitized to both chemotherapy and targeted therapy. In addition, MDA-MB-231 cells expressed different morphologies, binding affinities, and stiffness across these substrates. We also demonstrated that ECM composition significantly alters transcription of senescence-associated pathways across ER+ and ER- cell lines. Together, these results suggest that complex matrix composites should be incorporated into in vitro tumor models, especially for the drug-resistant TNBC subtype. The importance of tumor extracellular matrix (ECM) in disease progression is often inadequately represented in models of breast cancer that rely heavily on collagen I and Matrigel. Through immunohistochemistry analysis of patient breast tumors, we show a wide variation in collagen content based on subtype, specifically a repression of fibril collagens in the receptor negative subtype, irrespective of age and race. We also demonstrated that tumor ECM composition alters cellular elasticity and oncogenic pathway activation demonstrating that physiologically relevant three-dimensional models of breast cancer should include an ECM that is subtype specific.
AB - The development of resistance to therapy is a significant obstacle to effective therapeutic regimens. Evaluating the effects of oncology drugs in the laboratory setting is limited by the lack of translational models that accurately recapitulate cell-microenvironment interactions present in tumors. Acquisition of resistance to therapy is facilitated, in part, by the composition of the tumor extracellular matrix (ECM), with the primary current in vitro model using collagen I (COL I). Here we seek to identify the prevalence of COL I-enhanced expression in the triple-negative breast cancer (TNBC) subtype. Furthermore, we identify if methods of response to therapy are altered depending on matrix composition. We demonstrated that collagen content varies in patient tumor samples across subtypes, with COL I expression dramatically increased in typically less aggressive estrogen receptor (ER)-positive(ER+)/progesterone receptor (PGR)-positive (PGR+) cancers irrespective of patient age or race. These findings are of significance considering how frequently COL I is implicated in tumor progression. In vitro analyses of ER+ and ER-negative (ER-) cell lines were used to determine the effects of ECM content (collagen I, collagen IV, fibronectin, and laminin) on proliferation, cellular phenotype, and survival. Neither ER+ nor ER- cells demonstrated significant increases in proliferation when cultured on these ECM substrates. ER- cells cultured on these substrates were sensitized to both chemotherapy and targeted therapy. In addition, MDA-MB-231 cells expressed different morphologies, binding affinities, and stiffness across these substrates. We also demonstrated that ECM composition significantly alters transcription of senescence-associated pathways across ER+ and ER- cell lines. Together, these results suggest that complex matrix composites should be incorporated into in vitro tumor models, especially for the drug-resistant TNBC subtype. The importance of tumor extracellular matrix (ECM) in disease progression is often inadequately represented in models of breast cancer that rely heavily on collagen I and Matrigel. Through immunohistochemistry analysis of patient breast tumors, we show a wide variation in collagen content based on subtype, specifically a repression of fibril collagens in the receptor negative subtype, irrespective of age and race. We also demonstrated that tumor ECM composition alters cellular elasticity and oncogenic pathway activation demonstrating that physiologically relevant three-dimensional models of breast cancer should include an ECM that is subtype specific.
KW - breast cancer
KW - extracellular matrix
KW - optical tweezers
KW - tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85104843064&partnerID=8YFLogxK
U2 - 10.1089/ten.tea.2020.0364
DO - 10.1089/ten.tea.2020.0364
M3 - Article
C2 - 33797977
AN - SCOPUS:85104843064
SN - 1937-3341
VL - 27
SP - 500
EP - 511
JO - Tissue Engineering - Part A
JF - Tissue Engineering - Part A
IS - 7-8
ER -