Adipose-rich microenvironment in breast cancer

Institution: San Diego Biomedical Research Institute
Investigator(s): Fahumiya Samad, Ph.D. -
Award Cycle: 2018 (Cycle 24) Grant #: 24IB-0062 Award: $288,000
Award Type: IDEA
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (2018)

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.