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. Gill [HHMI Fellow] is studying cell-cell communication via quorum sensing in developing biofilms. Biofilms are communities of bacteria that take on a three-dimensional structure and often develop striking visual features like wrinkles. Resident bacteria exploit this complexity to resist antimicrobial treatments and cause disease, particularly in healthcare settings, where biofilms pose serious threats to immunocompromised chemotherapy patients. Quorum sensing is the process by which bacteria orchestrate collective behaviors, including the assembly and dissolution of biofilm communities. Using quantitative microscopy at single-cell resolution, Dr. Gill is investigating how these signals between bacteria result in the construction of spectacular 3D biofilms at the air-liquid interface. A deeper understanding of how bacteria thrive in dynamic environments will contribute to new strategies to combat infections, which will positively impact treatments for all cancer types. Dr. Gill received her PhD from Harvard University, Cambridge and her BS from Drexel University, Philadelphia.

Successful immune responses against cancer require immune cells of various types to control each other’s proliferation, differentiation, and death. These interactions collectively constitute a set of intercellular signaling circuits. A fundamental challenge in cancer research is to understand the relationship between the architecture and functions of these circuits. Dr. Indana will quantitatively model and synthetically construct intercellular circuits with immune-like functions to understand how circuit architectures empower immune behaviors such as threat detection and cancer elimination while maintaining the ability to return to a non-inflammatory state. This work promises to uncover the “design principles” underlying various immune functions, providing a foundation for engineering novel immunotherapies. Dr. Dhiraj received his PhD and MS from Stanford University, Stanford and his BTech from Indian Institute of Technology, Roorkee.

T lymphocytes, an important component of the immune system, recognize infected or cancerous cells with great specificity, ensuring targeted elimination. These potent cells are kept in check by regulatory T cells, the guardians of the immune system. While essential for curtailing excessive inflammation and preventing autoimmunity, their immunosuppressive properties can promote the development and progression of cancer. Regulatory T cells are distinguished by the presence of a protein called Foxp3, which plays a critical role in their differentiation, function and fitness. Foxp3 deficiency results in fatal autoimmune inflammatory disease, underscoring its importance for maintaining organismal health. Despite its significance, however, the reliance of regulatory T cells on Foxp3 in disease contexts like infection and cancer remains incompletely understood. Dr. Schiepers [HHMI Fellow] will study the fate and function of regulatory T cells in these settings using mouse genetics approaches and disease models of melanoma and colorectal cancer. Dr. Schiepers received his PhD from The Rockefeller University, New York and his MS and BS from Utrecht University, Utrecht.

Sugar molecules on the surface of cells can be arranged in many different patterns, and it is the exact structure of a sugar that gives it its unique function. In sugars on the surface of cancer cells, the location of sulfate (SO4-) groups changes as the tumor grows and spreads. The study of sulfated sugars has been stymied, however, by the difficulty of synthesizing them in the laboratory. Dr. LaPorte’s research aims to remove this roadblock by developing a chemical reaction that easily constructs biologically important sugars with a sulfate group bound to them. These sulfated sugars will then be used to test how specific sulfation patterns affect their interaction with other biological proteins. The results of these experiments will lay the groundwork for new cancer treatments that use complicated sugar structures to selectively target cancer cells without harming healthy cells. Dr. LaPorte received his PhD from University of Illinois, Urbana-Champaign, Champaign and his BS from North Central College, Naperville.

Dr. Cuevas-Navarro’s [Berger Foundation Fellow] research project focuses on targeting mutations in the RAS genes (HRAS, NRAS, and KRAS), present in about 30% of cancer patients and notorious for driving aggressive tumor growth. Dr. Cuevas-Navarro aims to mitigate these mutations’ effects by using pharmacological agents to enhance a biochemical process that regulates RAS proteins. His project will investigate the mechanism of action of these compounds and assess their effectiveness in patient-derived cancer models. This research has the potential to expand treatment options across various cancer types, including those where current treatments are limited. Dr. Cuevas-Navarro received his PhD from University of California, San Francisco and his BS from University of California, Davis.

Leukemia is a cancer of the immune system and is a major cause of death from cancer in children and young adults. Chimeric antigen receptor (CAR) T cell therapy, which involves genetic engineering of a cancer patient’s own immune system cells to fight cancer, has demonstrated curative potential. Despite excellent initial responses to treatment, however, leukemia recurs in up to half of pediatric leukemia patients after CAR T treatment. A major cause of treatment failure is that CAR T cells do not attach to cancer cells as strongly as natural T cells do to their targets, and this limits their ability to find and kill cancer cells. Dr. Pauerstein’s research is attempting to improve CAR T cell sensitivity to cancer cells using synthetic cell adhesion molecules, a type of molecular glue between two cells. Engineering adhesion into CAR T cells should build a synthetic immune synapse that can help improve cell-based treatments for leukemia and eventually other cancers.  Dr. Pauerstein received his MD, PhD from Stanford University, Stanford and his BA from Rice University, Houston.

Peptide drugs, which mimic the function of natural peptides such as hormones or growth factors, have emerged as a promising strategy for the treatment of cancer. Despite their potential, however, very few have reached the clinic in the past decade, primarily due to their off-target toxicity. The design of a suitable system to deliver peptides in a site-specific manner would address a major challenge in the development of anticancer peptide drugs. De novo protein design, or building proteins “from scratch,” has allowed for the engineering of functional proteins for a broad range of applications, from catalysis to pharmaceuticals. Dr. Bhattacharya [Connie and Bob Lurie Fellow] aims to design proteins from scratch that can “mask” a peptide of interest for systemic delivery to the desired location. This project will initially target pediatric sarcomas, but eventually extend to other cancers like glioblastoma and breast cancer. Dr. Bhattacharya received his PhD from Syracuse University, Syracuse and his MS and BS from University of Calcutta, Kolkata.

To prevent autoimmune attacks, T cells are screened in the thymus to ensure they do not react to self-derived antigens. Dr. Huisman [National Mah Jongg League Fellow] studies the thymus and, specifically, a population of cells called “thymic mimetic cells” that mimic other tissues, such as muscle or gut, and assist T cells in developing tolerance to diverse cell types. Dr. Huisman’s research focuses on understanding how thymic mimetic cells develop. This work may lead to improved understanding of thymus-mediated tolerance to tumors, novel therapeutic opportunities for manipulating mimetic cells to induce anti-tumor responses, and increased understanding of thymic tumors. Dr. Huisman received her PhD from Massachusetts Institute of Technology, Cambridge and her BS from University of Michigan, Ann Arbor.

Genome rearrangements have been widely observed in human cancers. Recent whole-genome sequencing data has identified chromothripsis, an event that introduces massive genome rearrangements in only one or a few chromosomes through catastrophic shattering and random reattachment, as one of the most frequent genome rearrangements. Chromothripsis has been associated with poor clinical outcomes in multiple cancers, but the shattering mechanisms that induce chromosome fragmentation remain uncharacterized. Dr. Wu [Marion Abbe Fellow] aims to determine the role of cytoplasmic nucleases (enzymes that cleave DNA) in chromosome shattering and genome rearrangement, which will contribute to our understanding of chromothripsis in all cancers. She will extend this project to a mouse model of glioma to determine the effects of candidate nucleases on cancer progression. Dr. Wu received her PhD and BS from Peking University, Beijing.