|WISHART, ANDREW - Tufts University|
|CONNER, SYDNEY - Tufts University|
|GUARIN, JUSTINNE - Tufts University|
|FATHERREE, JACKSON - Tufts University|
|PANG, YIFAN - Tufts University|
|MCGINN, RACHEL - Tufts University|
|CREWS, REBECCA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
|NABER, STEPHEN - Tufts Medical Center|
|HUNTER, MARTIN - Tufts University|
|GREENBERG, ANDREW - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
|OUDIN, MADELEINE - Tufts University|
Submitted to: Science Advances
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/8/2020
Publication Date: 10/21/2020
Citation: Wishart, A., Conner, S., Guarin, J., Fatherree, J., Pang, Y., McGinn, R., Crews, R., Naber, S., Hunter, M., Greenberg, A.S., Oudin, M.J. 2020. Decellularized extracellular matrix scaffolds identify full-length collagen VI as a driver of breast cancer cell invasion in obesity and metastasis. Science Advances. https://doi.org/10.1126/sciadv.abc3175.
Interpretive Summary: As women age, they accumulate increased levels of fat within the mammary gland. This has been demonstrated to promote the development of breast cancer and the metastasis of the breast cancer to different organs in the body such as bone. In collaboration with the laboratory of Dr. Madeleine Oudin in the Bioengineering Department at Tufts University, we investigated the pattern of proteins that surround fat cells in mammary gland tissue of obese mice. We identified a number of proteins in mammary gland tissue which were increased with obesity. When we isolated these proteins and then cultured breast cancer cells on these proteins, we observed that the breast cancer cells were found to move in a manner consistent with increased ability to metastasize/spread to other tissues. These studies will facilitate future investigation at delineating diets that would prevent the increase in the deleterious proteins in the mammary gland that promote breast cancer metastasis.
Technical Abstract: The extracellular matrix (ECM), a major component of the tumor microenvironment, promotes local invasion to drive metastasis. Here, we describe a method to study whole-tissue ECM effects from disease states associated with metastasis on tumor cell phenotypes and identify the individual ECM proteins and signaling pathways that are driving these effects. We show that decellularized ECM from tumor-bearing and obese mammary glands drives TNBC cell invasion. Proteomics of the ECM from the obese mammary gland led us to identify full-length collagen VI as a novel driver of TNBC cell invasion whose abundance in tumor stroma increases with body mass index in human TNBC patients. Last, we describe the mechanism by which collagen VI contributes to TNBC cell invasion via NG2-EGFR cross-talk and MAPK signaling. Overall, these studies demonstrate the value of decellularized ECM scaffolds obtained from tissues to identify novel functions of the ECM.