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.

To power directional movement, cells build dynamic sheet-like protrusions at their leading edge. How individual molecules are coordinated to produce these changes in cell morphology is poorly appreciated. Dr. Sim [Connie and Bob Lurie Fellow] uses immune cell migration as a model system to investigate the self-organization of a protein assembly known as the WAVE complex, which facilitates the formation of these protrusions in migratory cells. Her work will harness recent advances in electron microscopy and protein prediction and design to study the mechanism of the WAVE complex. As a critical player in cell migration, the dysregulation of the WAVE complex is associated with tumor cell invasion and metastasis in several cancer types. This aberrant migration enables cancer cells to travel to and infiltrate adjacent tissue sites. Understanding the fundamental mechanisms of cell migration can thus better inform the development of therapeutics that limit the progression of cancer. Dr. Sim received her PhD from the University of California, Berkeley and her BA from Bowdoin College, Brunswick.

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.

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.

Many types of cancer, chemotherapy, and numerous other underlying conditions can leave patients vulnerable to infection by bacteria that would normally be unable to survive in the body. These opportunistic infections are challenging to treat, as antibiotics are often ineffective against these pathogens or have serious side effects not well-tolerated by individuals with underlying conditions. Dr. Sullivan studies how opportunistic infections occur, with a particular focus on lung infection. His ongoing work is centered on identifying bacterial adaptations that enable pathogens to survive both the host defense systems present in the lung as well as antibiotic treatment. His work will help deepen our understanding of opportunistic infection and may provide novel avenues for more effective and tolerable treatment of these pathogens.

Antimicrobial resistance is a growing crisis that imperils our ability to protect patients immunocompromised by cancer treatment. Despite this, the few new antibiotics currently in clinical trials primarily use established mechanisms of action. Identification of new targets for antimicrobial drugs is thus an urgent clinical need. Recent work has shown that bacteria can tolerate substantial inhibition of many proteins thought to be essential for growth, rendering them poor drug targets. The mechanisms that cause this robustness are poorly understood. By combining cutting-edge microfluidic technologies with methods for controlled gene repression, Dr. Taggart will systematically identify mechanisms that allow bacterial cells to tolerate inhibition of genes critical for cellular growth. This work will guide the selection of targets for future antibiotic development and may reveal mechanisms by which to sensitize bacterial cells to existing drugs. Dr. Taggart received his PhD from Massachusetts Institute of Technology, Cambridge and his BS from Haverford College, Haverford.

Dr. Thawani studies how so-called “selfish DNA” elements copy and paste themselves within the human genome. Using advanced methods such as cryo-electron microscopy to reveal the atomic structures of various molecules associated with these selfish elements, she aims to delineate their mechanism of mobility. She is also interested in understanding how selfish DNA elements are recognized and silenced within the human genome. Dr. Thawani plans to harness these discoveries to engineer new genome editing technologies to precisely insert large genes at user-specified sites in a variety of human cell types. This general technology will translate directly into new gene therapy tools that will enable treatment of loss-of-function genetic diseases, including many cancer types, and provide a path to improving CAR-T therapies for blood cancers.