Insights into the mechanisms underlying breast cancer (BCa) aggressiveness are needed, in particular for triple-negative breast cancer (TNBC). Recent studies indicate that carcinoma progression is promoted by mesenchymal stromal cells (MSC) infiltrating tumors. MSC modulate tumor matrix remodeling, immune response, vascularization, and directly stimulate cell survival and proliferation. Importantly, MSC induce the epithelial?mesenchymal transition (EMT) enabling drug resistance and motility/invasiveness of cancer cells. Accumulating data indicate that BCa is promoted by mammary white adipose tissue (WAT) surrounding the tumor. While the progression of some BCa subtypes is associated with obesity, the condition of WAT expansion, mammary WAT increases the aggressiveness of breast cancer cells irrespective of obesity. Adipose stromal cells (ASC) are MSC that serve as adipocyte progenitors and endothelium-supporting cells of WAT. Our group has discovered that ASC mobilized from WAT are recruited by tumors, where they contribute to the trophic microenvironment promoting disease progression and therapy resistance. The overarching challenge in the field is to completely understand the supportive role of ASC in cancer dissemination and to develop counter-acting approaches. Based on our preliminary data, we hypothesize that ASC from mammary WAT induce EMT and promote BCa metastasis. Currently, there are no treatment options to inactivate ASC, and the progress in the field will rely on the development of novel experimental therapeutics. Our group is a leader in the preclinical and clinical development of hunter-killer peptides that bind to selectively expressed cell surface receptors and, upon internalization, induce apoptosis in the target cell population. We previously have developed hunter-killer peptides that are selectively taken up by ASC and cause their apoptosis. Our preliminary studies in graft models indicate that inactivation of ASC with a targeted hunter-killer peptide D-CAN suppresses tumor growth and metastasis. This application is based on a collaboration of teams led by an ASC expert and a clinical oncologist. Here, we will investigate the importance of ASC in models of human TNBC and will use D-CAN to deplete ASC and to test if this can suppress TNBC progression.
In Specific Aim 1, we will use 3-dimentional co-culture of human TNBC cells and ASC, as well as mice orthotopically xenografted with human TNBC, to model the effects of ASC-cancer cell interaction. ASC-induced tumor cell proliferation and motility, desmoplasia, EMT induction, and metastasis will be measured.
In Specific Aim 2, we will use the same models and methods to test whether depletion of human ASC with D-CAN can suppress the ASC-induced TNBC growth, EMT, invasiveness and metastasis. Completing this study will establish the role of ASC in TNBC progression to metastases and outline ASC ablation, combined with conventional therapy, as a prospective approach to improve BCa treatment efficacy. Because D-CAN targets human ASC, as we reported this year, testing this new experimental adjuvant cancer treatment approach has a direct clinical relevance. Based on the results of this collaborative research program, we will plan for further development of the ASC-targeting compound. In the future, ASC targeting with drugs developed based on the prototype tested here could also be considered as an approach to treat other cancers and non-malignant fibrotic pathologies fueled by ASC recruited from WAT.

Public Health Relevance

According to our hypothesis, adipose stromal cells from tumor-adjacent adipose tissue induce the epithelial? mesenchymal transition in breast cancer cells and hence promote metastasis. We will test it in animal models of triple-negative breast cancer by using an experimental drug targeting adipose stromal cells, which will evaluate ablation of adipose stroma as a prospective approach to improve cancer treatment efficacy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA216745-02
Application #
9668100
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Arya, Suresh
Project Start
2018-04-01
Project End
2020-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77030