Molecular Mechanisms of Human TNBC Metastasis in Vivo
Abstract
This project will address the Department of Defense Breast Cancer Research Program s Overarching Challenge: Eliminate the mortality associated with metastatic breast cancer. Breast cancer is a malicious disease, with a long and oftentimes devastating course and, all too often, a poor outcome. This is especially true of triple-negative breast cancer (TNBC), a particularly aggressive form of breast cancer that does not respond to many of the most potent treatments available to oncologists. While some TNBC patients do initially respond to conventional therapies, nearly 50% of them will experience recurrence and metastasis within 2 to 3 years. Almost 90% of deaths due to breast cancer are attributed to metastatic disease (cancer cells spreading to distant organs), and treatments used to shrink or slow metastatic tumors provide only temporary relief; there is no cure for metastatic breast cancer. Understanding the underlying mechanisms that control metastasis is of critical importance for the discovery and development of new, targeted treatments and for the increased survival of TNBC cancer patients. One promising entry point for understanding progression to metastasis -- and determining how to prevent it -- is to focus on the interplay between the immune system and cancer cells. However, studying the interplay between the immune system and metastatic cancer cells has been a significant challenge. This is because researchers often use mouse models as surrogates for human disease, and the mouse immune system is sufficiently different from the human immune system that few correlates comparing the immune response to cancer cells have been defined. This creates a need for animal models that can faithfully and consistently replicate the complexity of the human immune system to better understand its effect on the tumor microenvironment, cancer cell longevity, and metastatic spread to other organs. To address this challenge, we developed a humanized mouse model to study the immune response to TNBC cancer cells. This mouse model is unique because it expresses many human immune cell types not present in other models. In our preliminary results, we discovered that the presence of human cytokines (proteins that stimulate immune cells) in humanized mice are sufficient to induce cancer cells to spread to distant organs, thus mirroring the cancer progression seen in almost 50% of TNBC patients. Importantly, we measured no metastatic disease in humanized mice that lacked human cytokines. This distinction will allow us to precisely define immune cells or signals that drive cancer cells to spread -- signals that could represent promising therapeutic targets for intervention. Aims, goals, and deliverables of the project: The goal of this proposal is to identify immune mechanisms that promote metastasis of human breast cancer, specifically TNBC tumors. We will study the behavior of complex human tumors, in the humanized mouse model because this model reflects the actual complexity of cancer-immune system interactions better than most other mouse models that are currently available. In addition to defining the immune cells and signals that stimulate metastasis, we also aim to identify genomic biomarkers of metastasis within TNBC tumors. We will use a novel approach that integrates two high-throughput gene-sequencing techniques to address which genes are activated in metastasis-promoting immune cells. This precise definition of activated genes will allow for a clearer picture of the genomic basis underlying the progression and dissemination of breast cancer. Ultimately, key metastasis-promoting genes could then be pharmacologically targeted to suppress metastasis before it has a chance to occur. Ultimate applicability of the research: We anticipate that the proposed work will pinpoint the immune mechanisms that incite metastasis in some TNBC tumors. These combined experiments, using a novel mouse model and high-through
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1710010
Entities
People
- Anna Palucka
Organizations
- Jackson Laboratory
- United States Army