Dr. Adams [Marion Abbe Fellow] studies a specialized subset of immune cells that secrete potent antitumor cytokines called type I interferons (IFN-I). Within a tumor, these cells, called plasmacytoid dendritic cells (pDCs), are impaired, which contributes to an immunosuppressive state and cancer progression. Dr. Adams aims to uncover the molecular mechanisms that govern IFN-I production and pDC dysfunction in cancer. As dendritic cells are a promising cell therapy for cancer, understanding the regulation of pDC-IFN-I production can guide strategies to harness and integrate their anti-tumor function in new immunotherap

Dr. Andreeva investigates the role of a molecule called NLRP3 in the assembly of inflammasommes, multiprotein complexes that form in response to cellular infection or stress. NLRP3 acts as a sensor inside the cell that detects danger signals and activates the inflammasome complex to trigger inflammation and cell death. Dr. Andreeva aims to uncover the step-by-step mechanism of NLRP3 activation and regulation to understand how to prevent "false alarms" that cause disease. This research has the potential to aid the development of drugs that specifically turn off the NLRP3 inflammasome and treat a variety of inflammatory disorders, from osteoarthritis to Alzheimer's disease and cancer.

Dr. Ardy [Robert Black Fellow] is investigating the genetic determinants that govern the behavior of fibroblasts, a type of connective tissue cell that has been implicated in arthritis, heart disease, and cancer. Activated fibroblasts can exacerbate disease through various mechanisms, including remodeling tissue architecture and modulating the immune system. Dr. Ardy plans on using state-of-the-art genetic tools, including CRISPR inhibition and activation coupled with single-cell RNA sequencing technology, to uncover the proteins and pathways that regulate fibroblast behavior and thereby inform the development of new targeted cancer treatments. Dr. Ardy received his PhD from the Medical University of Vienna and his BS from the University of California, Los Angeles.

The connection between cardiovascular disease and cancer, the two leading causes of death in the United States, extends beyond cancer treatment’s impact on the cardiovascular system. These complex diseases share several important risk factors and aspects of disease progression. In the development of atherosclerosis, a build-up of fatty material in the arterial walls, vascular smooth muscle cells can change their roles and influence the progression of disease. Dr. Bell aims to determine if the same dynamic activity of smooth muscle cells occurs in the environment of a tumor, and whether these cells influence disease progression or response to therapies. Preclinical data suggests a significant role for these cells in the tumor environment for multiple solid tumor types, such as melanoma, breast cancer, and colon cancer. These findings could represent a new pharmacologic target for multiple cancers.

Evidence that aging is driven by defined, regulated processes (rather than simple “wear and tear”) has sparked hope that we might target these processes to fight age-related diseases. A particularly exciting example is the regulation of protein homeostasis, or the balance between protein synthesis, folding, and degradation. Protein homeostasis is deregulated in both cancer and normal aging, but the underlying mechanisms remain elusive. Dr. Boos will use the short-lived African turquoise killifish as a new model organism to study how different cells and tissues respond to protein misfolding, how they coordinate their responses, and how aging influences these pathways. This research will not only unravel fundamental mechanisms of aging, but also inform new strategies to fight multiple types of cancer. Dr. Boos received his PhD and his B.Ed. from the University of Kaiserslautern.

Dr. Bridges studies how bacterial cells form communities called biofilms that have particular three-dimensional architectures. He is investigating how the bacterial cell-cell communication process called quorum sensing drives the spatio-temporal gene expression patterns that govern biofilm formation. Biofilm bacteria are implicated as causal in various cancers and, furthermore, cancer patients receiving chemotherapy frequently suffer from infections caused by bacteria that rely fundamentally on biofilm formation for pathogenesis. By discovering the quorum-sensing program that bacteria execute to sculpt biofilm architectures, he hopes to contribute to the development of new strategies to interfere with formation of these bacterial communities.

Dr. Catipovic [HHMI Fellow] focuses on the mechanisms governing the resolution of errors that arise during RNA translation in mammals. Ribosomes translating the same message can collide if they are damaged or encounter blockages much like cars involved in a traffic accident. While cells can tolerate small numbers of these incidents, pervasive collisions overwhelm the cell and force it to make crucial decisions regarding long-term viability. Dr. Catipovic investigates the biochemical mechanisms governing this determination. He uses reconstituted translation systems, consisting of purified translation factors in vitro, as a tool to study the signaling pathways initiated by ribosomal collisions that effect the life-death decisions of severely stressed cells. Perturbation of these pathways can cause premature cell death or unregulated cellular proliferation, which is found in almost all cancers.

Dr. Chang is studying protamines—short, positively-charged proteins that condense DNA into chromatin and regulate gene expression in sperm nuclei. While eukaryotic cells use histones to package genomes in a way that allows access for transcription and replication, sperm cells must package their genomes more tightly. For this, many animals deploy protamines instead of histones. Despite sharing certain functions with highly conserved histones, protamines have independently arisen in evolution multiple times and are continuing to rapidly evolution. Using Drosophila fruit fly species as a model, Dr. Chang studies how sperm chromatin regulates gene expression and reproductive fitness. Additionally, although protamine expression is typically limited to testes, their misexpression has been observed in many cancers, indicating an opportunity for therapeutic intervention.

Dr. Chen is developing platforms to conduct high-throughput screens of protein-based fluorescent biosensors. Biosensors allow visualization of otherwise invisible biological processes such as communication between cells. Cells use diverse peptides to send messages to each other, and this has important implications for tumor growth and side effects of cancer treatments. This project will increase understanding of the complex signaling networks among cells and may lead to rational design of new cancer therapies targeting faulty cellular communication.

Cancers originating from different tissue types harbor distinct genetic mutations. Using molecular and systematic approaches in genetics, Dr. Chiba will dissect the mechanisms of how distinct combinations of oncogenic mutations drive tumors from different tissue origins. Due to the differing genetic background of these tumors, the efficacy of therapies that target the same oncogenic mutations varies between tumor types. Thus, understanding multiple different mutations in a tissue-specific context is critical for effective precision therapies.