Multiscale analysis of metabolic inflammation as a driver of breast cancer
- Multiscale analysis of metabolic inflammation as a driver of breast cancer
List of Collaborating Institutions
- Boston University
Boston Medical Center
Beth Israel Deaconess Medical Center
In this U01 project, we address an urgent and understudied problem. Breast cancer patients with co-morbid metabolic disease, such as Type 2 diabetes, are more likely to experience tumor progression, metastasis and earlier mortality than breast cancer patients with normal metabolism. Type 2 diabetes drives progression of aggressive estrogen receptor negative and triple negative breast cancer subtypes, in particular. As a chronic inflammatory disease, Type 2 diabetes features abnormal T cell polarization and a more dangerous tumor microenvironment; for example, the breast adipose tissue is inflamed/apoptotic. Published and preliminary data show abnormal expression in Type 2 diabetes of immune checkpoint receptors on T cell subsets in both periphery and tumor infiltrates. Type 2 diabetes patients lose T cell tumor surveillance, favoring escape of micrometastases from the primary tumor. Yet existing approaches to breast tumor progression and immuno-oncology therapies are built on metabolically healthier cancer patients, rather than among underserved patient populations where the prevalence of Type 2 diabetes and triple negative breast cancer is high.
We will develop computational models that consider previously unappreciated variables that may critically inform outcomes. These variables have never been inputs to systems level studies of breast cancer progression. Abundant data support a central hypothesis: Type 2 diabetes worsens the inflammatory and immune exhaustion mechanisms that promote more aggressive tumor progression in the microenvironment of estrogen receptor negative breast cancer. Yet, strikingly, existing breast co-culture and organoid models to explore microenvironment and immunotherapy have ignored the metabolic and inflammatory components of Type 2 diabetes. Models built on relatively healthy women are inappropriate to understand mechanisms that are important for the millions of Americans with Type 2 diabetes and related co-morbid metabolic conditions. Therefore, our innovative, multidisciplinary team of investigators is developing improved models to address this knowledge gap.
The crosstalk between exhausted T cells in tumor infiltrates, metabolic abnormalities and tumor aggressiveness can only be modeled with systems biology approaches that consider the microenvironment, and are informed by breast cancer epidemiological data, grounded in real clinical experience, and supported by population science. Our talented team aims to achieve exactly this goal. We drive development of multi-scale computational modeling of breast cancer progression, focusing on estrogen receptor negative/triple negative breast cancer in women with Type 2 diabetes. We are developing breast cancer organoids and exploring the function of T cell subsets in tumor cell killing, to generate and integrate metabolic, inflammatory, and immune signatures derived by multi-omic profiling, encompassing RNA-seq, quantitative (phospho)proteomics and immunophenotype, of tumors, immune cells, and organoid models to interrogate the molecular processes driving disease crosstalk at multiple levels. We are also developing new algorithms to model how Type 2 diabetes rewires immune cell signaling and metabolism in a prospective study of breast cancer patients in a safety net hospital, and testing, refining and validating these networks in organoid models. We iteratively combine computation, clinical observation and organoid experiments to develop multiscale models that reveal novel, clinically relevant immuno-oncology markers and targets.
The long term impacts of this research are important for over 100 million Americans with diabetes/pre-diabetes, who are predisposed to more aggressive cancers, compared to cancer patients who are metabolically normal, yet for whom the standard of care has not fully addressed the relevant mechanisms of progression, immune exhaustion, metastasis or chemoresistance.
Gerald Denis, PhD
Gerald Denis is Professor of Medicine and Pharmacology at Boston University School of Medicine, and co-director of the BU-Boston Medical Center Cancer Center. He focuses his work on the role of BET bromodomain proteins (BRD2, BRD3 and BRD4), which he was the first to link to human cancer, and to their functions in the adipocytes and infiltrating T cells of the breast tumor microenvironment. Cancer disparities populations, where the prevalence of obesity and metabolic co-morbidities is high, share important differences in microenvironment biology that demand new thinking.
Naomi Ko, MD, MPH
Naomi Ko is Assistant Professor of Medicine at Boston University School of Medicine and a medical oncologist at Boston Medical Center. She is actively investigating how biologic, social and treatment factors influence breast cancer outcomes in underserved, diverse breast cancer populations. She is particularly focused on mechanisms important for progression of triple negative breast cancer, and race- based cancer disparities.
Stefano Monti, PhD.
Stefano Monti is Associate Professor of Medicine at BU School of Medicine, with a joint appointment in Biostatistics at the School of Public Health. His research focuses on biological mechanisms of cancer formation and treatment, based on the analysis of genomic and genetic data. He has worked extensively with data generated from high-throughput biological assays, including expression microarrays, high-density SNP-arrays and high-throughput sequencing, and has developed new methodologies of integrative data analysis aimed at providing a holistic view of multiple data sources.
Andrew Emili, PhD
Andrew Emili is Professor of Biochemistry and Biology at Boston University, and inaugural Director of the Center for Network Systems Biology. He developed innovative proteomics, functional genomics and bioinformatics methods to investigate biological systems and molecular association networks in human cells and model organisms. In particular, his lab uses quantitative, high precision mass spectrometry to characterize protein complexes in a comprehensive, high-throughput manner. His group aims for breakthrough insights into the composition and mechanistic role of protein complexes and interaction networks in cells and tissues, and to translate this knowledge into new diagnostic/prognostic markers and therapeutic targets.
Senthil Muthuswamy, PhD
Senthil Muthuswamy is Associate Professor of Medicine at Harvard Medical School and Deputy Director of Translational Initiatives in the Cancer Research Institute of Beth Israel Deaconess Medical Center. He is a pioneer in tumor organoid biology and has developed many innovative models that capture tumor heterogeneity and complex positional information in both pancreatic and breast malignancies. He has also made major contributions to our understanding of the immune infiltrates of several tumor types.