Dr. Caldas is investigating the mechanisms by which RNA interference (RNAi) related pathways, implicated in cancer primarily through their role in regulating gene expression, contribute to the fidelity of cell division. In addition to major changes in gene expression, a hallmark of many cancers is genome instability and chromosome loss, processes highly related to inaccurate cell division. Using C. elegans as a model system, her goal is to identify new aspects of cell division control that can be targeted for cancer therapy.

Dr. Cambier [HHMI Fellow] studies the role of cells called macrophages in mediating inflammation in immune responses to cancer. He is using the Mycobacterium marinum/zebrafish model of infection to examine misguided immune responses, many of which are shared with cancer. In particular, he proposes to study the distribution of a mycobacterial glycolipid molecule that is associated with driving macrophage activation and death, and will visualize the interactions of these glycolipids with macrophages in a living system. This new imaging approach along with the ability to manipulate host and pathogen genetics in a controlled setting will shed light on the inflammatory mechanisms driving disease. He hopes these findings will lead to new cancer therapies that modulate macrophages.

Dr. Case is establishing an in vitro experimental system to study the formation of integrin signaling complexes on model membranes. Integrins form multiprotein signaling complexes that are essential for the survival, growth, and migration of tumor cells; integrins and their associated proteins are commonly mutated or misregulated in diverse cancer types. She will elucidate the molecular interactions and physical mechanisms that regulate the assembly of  integrin complexes to potentially reveal novel strategies for disrupting integrin signaling in cancer.

Dr. Chakravarty [HHMI Fellow] is investigating heritable physical structures, called higher order assemblies, formed upon overexpression of RNA binding proteins. RNA binding proteins are consistently overexpressed in multiple cancers. His research will illuminate the mechanism of assembly formation and its role in altering gene regulation, thereby suggesting novel avenues to potential therapeutic intervention.

Dr. Chung is focusing on the biology of fat storage organelles called lipid droplets (LDs). Many cancer cells are characterized by an increased number of LDs, and this accumulation has been proposed to be pathogenic. Key questions of LD biology remain unanswered, limiting the potential for therapeutic intervention. She will combine various imaging technologies and biochemical approaches to elucidate the molecular architecture of initial LD formation and its regulation.

Dr. Crickard [The Mark Foundation for Cancer Research Fellow] is using high-throughput single molecule imaging to rebuild and visualize the process of homologous recombination (HR) in real time. DNA is subjected to many insults leading to damage. This DNA damage leads to a loss in genomic integrity, resulting in the formation and metastasis of many types of cancer. To guard against DNA damage, cells have developed several complex regulatory networks devoted to repair of damaged DNA, including HR. HR involves the search and pairing of one damaged piece of DNA to similar or identical DNA sequences to promote repair of the damaged piece, thus maintaining genome integrity. He seeks to understand, at the most basic biochemical level, how two of the key protein components in HR, Rad51 and Rad54, function to find and repair damaged DNA. His findings will give new insights into how cells fix damaged DNA, which may be key to the development of novel treatments and therapeutic options for all types of cancer.

We share our bodies with trillions of microorganisms: the microbiota. The microbiota interacts with our bodies to affect health and disease, including cancer development and response to therapies. For example, in patients receiving hematopoietic stem cell transplantation as treatment for leukemias, lymphomas, and other blood cancers, disruptions in the microbiota have been linked to disease relapse, infections, treatment complications, and survival. Given these serious effects, it is important to understand how to manipulate the microbiota through therapies like prebiotics: carbohydrates that can be ingested to stimulate the growth and maintenance of various bacteria. The challenge is that different people have different microbiotas and therefore may respond differently to the same prebiotic. To address this challenge, Drs. David and Sung have developed a novel microfluidic platform to isolate individual bacteria from a patient’s stool sample and grow them against selected prebiotics, allowing an understanding of how a given patient’s microbiota may respond to different prebiotics. To do this using conventional techniques would take a stack of petri dishes as tall as the Empire State Building and months of work; their innovative system can do it in a single day. They believe that by using this novel system, they will be able to predict the best prebiotic for a given patient, thereby manipulating their microbiota and improving cancer outcomes. They will test this strategy using patient samples in their artificial gut “bioreactor” as well as in mouse models. The success of this project would lead to clinical trials of personalized prebiotics.

Dr. Dixon aims to determine whether the altered metabolism of cancer cells creates new vulnerabilities that can exploited therapeutically. “Reductive stress” is a cellular concept in which too much glutathione could lead to cell growth arrest and death. He is investigating how a gene called NRF2 balances the demand for new glutathione synthesis with the need to avoid glutathione-mediated reductive stress. Reductive stress-mediated protein unfolding and aggregation may burden the protein folding and stress response machineries and explain, in part, the heightened sensitivity of cancer cells to inhibitors of these pathways. Thus, his work could also suggest new approaches to selectively eliminate cancers with mutations that lead to high NRF2 expression, using agents that enhance reductive stress. His central goal is to characterize cell-specific metabolic alterations and seek new ways to exploit these differences therapeutically.

Dr. Dodson is investigating how defects that are not strictly based on DNA mutations can be passed from parent to progeny for multiple generations. Germ cells, the producers of eggs and sperm in animals, normally transmit the blueprint for life from parent to progeny. When germ cells acquire defects, however, these defects may also pass from parent to progeny. These underexplored defects may contribute to the onset and inheritance of familial cancer syndromes, and a better understanding of them could result in new cancer therapies.