Normally, epithelial tissues, which cover all external body surfaces and line internal cavities, expel unwanted cells to maintain health in a process known as cell extrusion. However, some cancer cells, particularly those with the common RasV12 mutation, manage to avoid extrusion. Using Drosophila (fruit flies) as a model, Dr. Sakai [Rhee Family Fellow] will explore how RasV12-mutant cells manipulate neighboring cells to avoid extrusion. Understanding this process could lead to new ways to prevent cancer cells from escaping the epithelial defense, offering potential new treatments. Dr. Sakai received his PhD and BS from Nagoya University, Nagoya.

An organism’s life experiences, such as exposure to bacterial pathogens, can cause sustained changes in its physiology and behavior. How these experiences are encoded in heritable RNA and DNA-associated proteins (called chromatin), and how these in turn affect the physiology of the organism itself and its progeny, are not well understood. Previous research has shown that the roundworm C. elegans can “read” small non-coding RNAs from the pathogenic bacterium Pseudomonas aeruginosa and learn and teach its progeny to avoid this bacterium. Dr. Sengupta’s [Rebecca Ridley Kry Fellow] research investigates how bacterial small RNAs taken up in the intestine can result in lifelong, multigenerational, and organism-wide changes at the epigenetic (RNA and chromatin) level to regulate brain function and behavior. She will investigate which small RNA and chromatin-associated genes are required for the learned response, where these genes function, and what changes at the epigenetic and gene expression level underlie this response. This will inform principles of epigenetic regulation of gene expression following diverse environmental stimuli, and stimuli within tissue environments, including tumor microenvironments. Dr. Sengupta received her PhD from Yale University and her MS and BS from the Indian Institute of Science Education and Research.

Cancer cells adapt their metabolism to achieve rapid growth and proliferation. Much of their metabolic malleability hinges on mitochondria, subcellular hubs for energy transformation and biosynthesis. As a key means to control mitochondrial composition and meet metabolic demands, cells mark mitochondrial proteins for degradation by a process called ubiquitylation. How both cancerous and healthy cells direct and monitor mitochondrial ubiquitylation remains poorly understood. Dr. Sheetz [HHMI Fellow] aims to dissect the cellular machinery that performs mitochondrial ubiquitylation and determine how this process promotes metabolic adaptability in cancer cells. A major translational goal is to identify approaches for tuning the levels of mitochondrial ubiquitylation in tumors and in metabolic disorders that put patients at risk for cancer. Dr. Sheetz received his PhD from Yale University, New Haven and his BS from the University of North Carolina, Chapel Hill. 

Cells in our body communicate with each other in a highly selective manner. These cell-cell interactions form the basis of numerous physiological functions, such as neuronal wiring and immune recognition. Dr. Shin plans to explore the general principles of cell-cell communication by constructing a synthetic synapse and studying its organization and functional diversity. His findings will elucidate the mechanisms that organize cell-cell interfaces involved in immune cell recognition of cancer and in the cell-type transitions associated with cancer and metastasis. This work will also provide a platform for engineering highly customized cell-cell interfaces, which may prove useful in engineering immune cell therapeutics.

This project employs the stickers-and-spacers model adapted from polymer physics. Macromolecules such as proteins and nucleic acids are described as a sequence of attractive domains called "stickers" and flexible, non-interacting domains called "spacers." Dr. Shin will  use his lab's Monte Carlo simulation engine LaSSI (Lattice simulation engine for Sticker and Spacer Interactions) to calculate the average interactions between macromolecules and analyze their mesoscopic organization and phase properties.

Neutrophils are important anti-microbial cells within the innate immune system. Recently, it has been shown that neutrophils can perform diverse functions, taking on both pro-inflammatory and pro-healing roles in response to tissue injury or insult. Dr. Siwicki's [Dale F. and Betty Ann Frey Fellow] goal is to understand how different neutrophil subtypes or states function to balance inflammatory versus regenerative processes, ultimately influencing tissue health and cancer. This work has the potential to uncover the basis of neutrophils' pro-tumor versus anti-tumor functions and could open the door to therapeutic targeting of specific neutrophil behaviors in order to improve clinical outcomes in cancer. Dr. Siwicki received her PhD from Harvard Medical School, Boston and ScB from Brown University, Providence.

The interaction between cancer cells and their non-malignant neighbors in the tumor microenvironment is critical for cancer progression. While certain types of cellular crosstalk within the tissue safeguard against malignancy, cancer cells are often able to exploit nearby cells to fuel tumor growth. Dr. Song [HHMI Fellow] is interested in understanding how the complex cellular communication network in the skin, namely its sensory and immunological components, contributes to the development of cutaneous squamous cell carcinoma, one of the most common skin cancers. Identifying novel neuronal and immunological interactions within the tumor microenvironment has the potential to uncover pathways regulating cancer progression and anti-tumor immunity. Dr. Song received her PhD from Yale University, New Haven and her AB from Bryn Mawr College, Bryn Mawr.

Groundbreaking advances in immunotherapy have revolutionized the treatment of cancer. In particular, new antibody drugs that block immunosuppressive pathways have achieved remarkable success in reawakening the immune system to clear tumor cells, leading to lasting cures in patients whose cancers do not respond to any other therapies. Unfortunately, the majority of patients (>70%) do not respond to immunotherapy treatment. It is difficult to predict which patients will benefit, creating an urgent demand for novel immunotherapy drugs that act through alternative mechanisms. Dr. Spangler is working to develop a class of antibody therapeutics that target cancer-promoting pathways in a different way than all current immunotherapies, with the goal of drastically expanding the percentage of cancer patients who benefit from them.

Dr. Squyres [National Mah Jongg League Fellow] is using quantitative microscopy and cell biology approaches to study how bacteria in biofilms coordinate their behavior in space and time. Biofilms are dense, multicellular communities of bacteria embedded in an extracellular matrix. Biofilms often form during bacterial infections, resulting in infections that are difficult to treat and resist antibiotics; cancer patients are at particular risk for these types of infections. Dr. Squyres is currently investigating how the release of extracellular DNA, a key component of the biofilm matrix, is coordinated during biofilm development. Greater understanding of how bacteria function in biofilms can lead to new approaches to target these treatment-resistant infections.

More than one third of all people will receive a cancer diagnosis at some point in their lifetime. Dr. Sretenovic [Connie and Bob Lurie Fellow] is using both yeast and human cell lines to model various properties of cancerous cells as complex genetic traits. Combining novel CRISPR genome editing approaches with next-generation sequencing technology, he aims to dissect the intricate relationships between genetic variants, chemical and physical environmental factors, and phenotypic outcomes (i.e., observable characteristics). The goal of his project is to understand the genetic basis for a panel of cancer-related traits to inform the development of anti-cancer treatments. Dr. Sretenovic received his PhD from the University of Maryland, College Park, and his MS and BS from University of Ljubljana, Ljubljana.

Our DNA is constantly subjected to damage, and our cells must repair this damage to ensure survival. Breaks in DNA that completely sever DNA molecules are particularly toxic, and failure to repair these breaks can lead to genetic alterations that drive cancer initiation and progression. Dr. Stinson studies the two main cellular pathways that repair these DNA breaks: non-homologous end joining (NHEJ) and homologous recombination (HR). Defects in these pathways are linked to predisposition to many cancers, including leukemia, breast, ovarian, and prostate cancers. His prior work has demonstrated how NHEJ minimizes genetic alterations during DNA break repair. Ongoing work will elucidate fundamental mechanisms of HR that suppress cancer and seek to identify new HR factors. This work has important clinical implications for identifying patients that may benefit from treatments that target HR-defective tumors and for discovering potential mechanisms of resistance to treatment.