RT Journal Article
SR Electronic
T1 Obesity-driven changes in ECM composition promote local invasion and metastasis of breast tumors
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.01.29.924431
DO 10.1101/2020.01.29.924431
A1 Andrew Wishart
A1 Yifan Peng
A1 Sydney Conner
A1 Justinne Guarin
A1 Rebecca Crews
A1 Jackson Fatherree
A1 Andrew S. Greenberg
A1 Madeleine J. Oudin
YR 2020
UL http://biorxiv.org/content/early/2020/01/30/2020.01.29.924431.abstract
AB The extracellular matrix (ECM) is a major component of the tumor microenvironment that supports cellular growth, promotes local invasion from the primary tumor, and contributes to metastatic outgrowth in sites of colonization. Obesity is a systemic disease that causes chronic inflammation which can lead to ECM deposition and ultimately fibrosis in adipose tissues such as the mammary gland. Overweight breast cancer patients have increased metastasis to the lung and liver, exhibit resistance to chemotherapy and have worse outcomes. We found that ECM isolated from the mammary gland of both tumor-bearing and obese mice increased invasion of breast cancer cells and set out to investigate whether obesity-driven changes in ECM could identify novel drivers of invasion and metastasis in breast cancer. We performed proteomics of the mammary fat pads of both lean and obese mice and identified the entire landscape of obesity-driven ECM changes. In particular, we focused on Collagen VI, an ECM protein secreted by adipocytes in mammary tissues. Collagen VI is upregulated in the ECM of obese and tumor-bearing mice and is associated with poor outcome in human breast cancer. We found that Collagen VI drives adhesion, migration and invasion of several human breast cancer cell lines via crosstalk between the adhesion receptor NG2 and the receptor tyrosine kinase EGFR, and activation of MAPK signaling. Overall, these studies demonstrate that obesity can have profound effects on the ECM composition of tissues, which in turn can promote local invasion and metastasis.