Adipose-rich microenvironment in breast cancer
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Non-technical overview of the research topic and relevance to breast cancer: Increasing evidence
 supports the concept that cancer cells cannot develop into a lethal tumor without the cooperation of other
 neighboring cells. Of the many cell types that make up the so-called breast microenvironment, some have been
 under intense study for their role in breast cancer development and growth while little is known about others. A
 cell type that is abundant in human breast tissue, and even more so in obesity, is the fat cell, also known as the
 adipocyte and is located in the adipose tissue (fat tissue) in the breast. While fat cells are best known as energy
 storage cells, they also secrete many molecules and factors that can influence the behavior of other cells.
 Despite this, the contribution of fat cells and the local fat tissue in the breast microenvironment to breast cancer
 growth is largely unexplored. In this project, we focus on Triple Negative Breast Cancer (TNBC), an aggressive
 cancer for which the cause is unknown, and, therefore currently there is no treatment for TNBC. Chemotherapy
 remains the only option for these patients. Our overarching goal is to evaluate the role of fat cells and other
 cells in the fat tissue [(also known as stromal vascular fraction (SVF) cells] near the tumor in TNBC and identify
 the mechanisms by which they may be contributing to cancer growth.
 
 
 The question(s) or central hypotheses of the research: We have developed a mouse model to study
 interactions between cells in the fat tissue and breast cancer cells. To study the distinct effects of fat in a
 controlled manner, we set up an experiment using a fat cell line called F442A that is widely used to study
 obesity in mice. When F442A cells are injected into mice, they develop into a regular fat tissue with all the
 properties associated with fat. Our preliminary data show that when we inject these fat cells together with TNBC
 cells in mice, tumors grew faster, compared with mice that were injected with only the tumor cells. We can also
 show that when F442A fat cells are cultured in the lab, they release small vesicles which are known as
 extracellular vesicles (EV). These EVs can carry messages and signals from their cell of origin, and in this way,
 communicate with neighboring cells. We observed that when we treat TNBC cells with EVs that are isolated
 from F442A fat cells, tumor growth was increased. Another key observation we made is that fat tissue/cells
 from high fat diet-fed obese mice released more EVs that fat tissue from lean mice. Moreover, the EVs released
 from the fat tissue from obese mice expressed very high levels of a protein called Milk fat globulin E8 (MFGE8),
 and this protein is known to be associated with TNBC in humans. Guided by these preliminary data our central
 hypothesis is that EVs secreted by fat cells and other cells in the fat tissue in the breast drives TNBC.
 
 
 The general methodology: We will initially characterize the role of adipocyte/SVF-derived EV in breast cancer
 in vitro (i.e. in a culture dish). EVs will be generated from F442A fat cells and from fat cells and the SVF cells
 from fat tissues from obese and lean mice. We will then determine the extent to which these EVs promote
 TNBC using a panel of human TNBC cell lines. Reagents that will inhibit/neutralize MFGE8 will be used to
 determine the role of fat cell derived MFGE8 to tumor growth. Next, we will provide “Proof of concept” that
 adipose-derived EVs contribute to TNBC in vivo, i.e. in mice. Here, we will use our already established mouse
 model to determine whether fat cells derived from lean and obese mice, as well as their EVs supports tumor
 growth when injected in mice. We will also use reagents that block MFGE8 to test whether tumor growth is
 supported by MFGE8 that is present in EVs secreted from the fat tissue.
 
 
 Innovative elements of the project and potential impact: First, we are proposing to our knowledge the first
 animal model to study interactions between fat cells and breast cancer cells. This model has great potential to
 become a powerful tool for the identification of specific factors and pathways by which local fat cells drive
 breast cancer. Second, we are proposing a unique role for fat-tissue derived EVs and specifically for MFGE8
 secreted in EVs as a mechanism that supports TNBC, and, also contribute to understanding the connection
 between obesity and breast cancer. These studies could lead to the potential use of fat-derived EV-MFGE8 as
 a biomarker to identify subsets of patients (e.g. obese/overweight) that could benefit from anti-MFGE8
 therapies to not only reduce the risk of developing TNBC, but also decrease tumor growth in those already
 diagnosed with TNBC.