Revealing and Targeting the Many Pathways of Metastasis in Breast Cancer
Abstract
Currently, there is no cure for metastasis. Treatments may temporarily control disease progression, but metastasis often leads to death in breast cancer patients. While a large tumor size is sometimes indicative of advanced breast cancer, in reality, metastatic spread involves cellular processes that are fundamentally distinct from tumor growth. For example, cancer cells that are more invasive or survive longer when traveling in bloodstream are often more metastatic. Thus, limiting the growth of the tumor may postpone but will not abrogate metastatic relapse. This distinction is important and should be considered when searching for effective drugs for reducing mortality among the breast cancer patient population. However, candidate drugs are often evaluated based on their capacity to reduce tumor size and not their impact on metastatic progression. Our proposal aims to develop a rigorous platform to identify new vulnerabilities in the metastatic cascade. We have brought together an impressive team of world-class scientists and oncologists to tackle this critical problem. Metastasis is a complex and multistep process. In order to metastasize, cancer cells need to adapt to an ever-changing environment as they traverse the bloodstream and invade a new organ. Throughout this journey they also need to interact with other cells in distal tissues and evade immune cells. Therefore, a comprehensive and holistic understanding of breast cancer metastasis requires (i) identifying the internal adaptations that cancer cells need to achieve to become metastatic, (ii) discovering the restrictions imposed by the microenvironment and the immune system that shapes metastatic tumor evolution, and (iii) better understanding the cell-to-cell communication strategies that cancer cells adopt to make the metastatic environment more hospitable. These challenges inform the aims of our proposal as we seek to develop novel systems biological approaches that not only provide much needed insights into the biology of metastasis, but also rapidly translate these findings into actionable steps in the clinic that can immediately benefit breast cancer patients. In our first aim, we propose a concerted effort to collect data on all aspects of gene expression in models of metastasis. The goal is to compare genetically matched poorly and highly metastatic cell lines and patient-derived xenografts (PDXs) by measuring changes in DNA, RNA, and protein levels. We will also measure changes in metabolism associated with higher metastatic capacity. We will then build computational tools that can integrate these multifaceted datasets into the knowledge of regulatory pathways that are responsible for the observed changes in highly metastatic cells. These identified pathways will be functionally validated using CRISPR-Cas9-based gene perturbation strategies in xenograft mouse models. The gene signatures associated with those pathways that are functionally implicated in metastasis will be carefully tested against data from clinical samples comparing metastases to primary tumors in patients or relapse-free survival data from large, publicly available datasets. While Aim 1 is focused on identifying pathways that increase metastatic capacity of cancer cells, our second aim seeks to elucidate the role of microenvironment in shaping metastatic disease. For this, we are leveraging state-of-the-art single-cell genomic strategies that not only reveal the heterogeneity of cancer cells but also capture their phylogenic relationships. We are especially interested in revealing a comprehensive map of metastatic tumor evolution in the lung, bone, and brain. More importantly, we have devised an experimental model that measure the impact of adaptive immunity, such as T cells and natural killer cells, on the evolution of metastatic tumors in distal organs. We posit that identifying pathways that are co-opted by cancer cells to bypass immune cells form the basis of rational combination t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210121
Entities
People
- Hani Goodarzi
Organizations
- United States Army
- University of California, San Francisco