Molecular Determinants of Normal and Malignant Mammary Stem Cell Function and Heterogeneity
Abstract
Breast cancer is expected to surpass lung cancer as the most commonly diagnosed malignancy in the United States this year, with an estimated 252,710 new cases according to the American Cancer Society. The primary reason for death in breast cancer patients is tumor spread (metastasis) and drug resistance. Both of these phenomena can be attributed to the presence of tumor-initiating cells (TICs), which have many similarities to normal mammary stem cells (MaSCs). Like any stem cell, MaSCs and TICs have the ability to generate copies of themselves and produce all the different cells within a tissue. In the normal mammary gland, MaSCs routinely replace lost cells and expand during pregnancy and lactation to generate cells that produce milk. TICs make up a small fraction of cells within a breast tumor, but since they have the same capabilities of normal MaSCs, TICs are the main contributors to cancer growth and tumor initiation at distant sites. Since stem cells and TICs also tend to be resistant to drugs, they are typically left behind after treatment only to repopulate the tumor once again. Therefore, in order to prevent tumor growth, metastases, and drug resistance, it will be critical to understand the biology of TICs so they can be specifically targeted for elimination. In this research proposal, I address the question of how TICs function from multiple angles: normal vs. cancer stem cells, stem cells vs. microenvironment, and candidate-based vs. unbiased approaches. Using this comprehensive strategy,I hope to identify genes within stem cells or the cells they interact with that are critical for their function. By focusing on normal and cancerous mammary stem cells, this proposal addresses the overarching challenge of what drives breast cancer growth and how to stop it. The primary goal of this basic research proposal is to identify specific genes and proteins that are required for MaSC/TIC function with the hope that this new knowledge will allow future researchers to target TICs therapeutically. In combination with conventional therapy, eliminating TICs would represent a significant advance in treating breast tumors and metastases that are not eligible for surgery, as well as recurrent and drug-resistant tumors. My ultimate career goal is to run a breast cancer research laboratory focused on stem cells in metastasis and drug resistance, as these are the main causes of treatment failure. I first became interested in the role of stem cells in cancer during my PhD training, which touched on both developmental and cancer biology. Therefore, I chose to join the laboratory of Dr. Yibin Kang, a leading expert in mammary stem cells and breast cancer, at Princeton University for my postdoctoral training. The researcher development plan designed by Dr. Kang will prepare me for an independent research career by developing my technical, mentoring, writing, and presentation skills. It calls for regular presentations in lab meetings, department meetings, and internal and external conferences as well as one-on-one sessions between Dr. Kang and myself to discuss progress and future directions. The plan also ensures that I will attend a course on Advanced Genomics and Bioinformatics as well as grant and manuscript writing workshops at Princeton and the Cancer Institute of New Jersey. I will also have the opportunity to mentor undergraduate and graduate students in the lab and in the classroom as a teaching assistant for the cancer biology course taught by Dr. Kang. By the end of my postdoctoral training, I will be a well-rounded scientist prepared to take on the many responsibilities of an independent researcher. The proposed research plan will help me reach my career goals by giving me a solid foundation in breast cancer biology. In implementing this proposal, I will also gain experience in cutting-edge experimental approaches (CRISPR, single cell sequencing) as well as techniques specific to the mammary gland (ma
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810010
Entities
People
- Nicole Aiello
Organizations
- Princeton University
- United States Army