Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis.
Obesity and extracellular matrix (ECM) density are considered independent risk and prognostic factors for breast cancer. Whether they are functionally linked is uncertain. We investigated the hypothesis that obesity enhances local myofibroblast content in mammary adipose tissue and that these stromal changes increase malignant potential by enhancing interstitial ECM stiffness. Indeed, mammary fat of both diet- and genetically induced mouse models of obesity were enriched for myofibroblasts and stiffness-promoting ECM components. These differences were related to varied adipose stromal cell (ASC) characteristics because ASCs isolated from obese mice contained more myofibroblasts and deposited denser and stiffer ECMs relative to ASCs from lean control mice. Accordingly, decellularized matrices from obese ASCs stimulated mechanosignaling and thereby the malignant potential of breast cancer cells. Finally, the clinical relevance and translational potential of our findings were supported by analysis of patient specimens and the observation that caloric restriction in a mouse model reduces myofibroblast content in mammary fat. Collectively, these findings suggest that obesity-induced interstitial fibrosis promotes breast tumorigenesis by altering mammary ECM mechanics with important potential implications for anticancer therapies.
Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
Bo Ri
BR
Seo
Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
Priya
P
Bhardwaj
Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
Siyoung
S
Choi
Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
Jacqueline
J
Gonzalez
Department of Materials Science and Engineering, Cornell University, Ithaca, NY 14853, USA.
Roberto C
RC
Andresen Eguiluz
Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. Department of Materials Science and Engineering, Cornell University, Ithaca, NY 14853, USA.
Karin
K
Wang
Department of Biological and Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA.
Sunish
S
Mohanan
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Patrick G
PG
Morris
Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
Baoheng
B
Du
Department of Healthcare Policy and Research, Weill Cornell Medical College, New York, NY 10065, USA.
Xi K
XK
Zhou
Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
Linda T
LT
Vahdat
Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10065, USA.
Akanksha
A
Verma
Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10065, USA.
Olivier
O
Elemento
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Clifford A
CA
Hudis
Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
Rebecca M
RM
Williams
Department of Materials Science and Engineering, Cornell University, Ithaca, NY 14853, USA.
Delphine
D
Gourdon
Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
Andrew J
AJ
Dannenberg
Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. Kavli Institute at Cornell for Nanoscale Science, Cornell University, Ithaca, NY 14853, USA. cf99@cornell.edu.
Claudia
C
Fischbach
D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000209:etiology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000150:complications / Q000378:metabolism*