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.

Dr. Stinson focuses on a cellular DNA repair process called non-homologous end joining (NHEJ), which repairs most DNA double-strand breaks (DSBs) in vertebrates. Failure to repair DSBs properly can lead to new mutations, which are a central feature of cancer initiation and progression. Dr. Stinson has discovered one way the NHEJ machinery modifies DNA at DSBs and minimizes errors when re-joining broken ends of the DNA molecule. He will further investigate the basic mechanisms of the two main DSB repair pathways, which are critical to understanding the causes of many cancers and informing therapeutic approaches.

Dr. Sullivan [Merck Fellow] studies the processes that lead to opportunistic infections affecting cancer patients. The human body, which is a hostile environment for pathogens, is well-equipped to fend off infections from most bacteria. However, cancer and chemotherapy can cause inflammation, tissue damage, and impairment of the immune system in ways that leave patients vulnerable to bacterial infection. These opportunistic infections are challenging to treat, as antibiotics often have little effect on these bacteria. Dr. Sullivan aims to identify the bacterial components that allow opportunistic pathogens to live within the lung and survive antibiotic treatment. This research will be critical to discovering more effective therapies to eradicate these infections.

Dr. Tai studies bacterial biofilms or aggregates of bacterial cells in an extracellular matrix. Biofilms play a critical role in many health and industry settings. Biofilm-forming bacteria and imbalance in patients’ gut microbiota have been found to correlate with cancer development, and cancer patients receiving therapy frequently suffer from bacterial infections. From the unique perspectives of microbiology, soft matter physics, and ecology, Dr. Tai aims to decipher how, at the single bacteria cell level, heterogeneities in cell shape, organization, and gene expression constitute the function and development of their collective communities: biofilms. His work is expected to deepen our understanding of bacterial biofilms and ultimately contribute to therapeutic strategies.

Dr. Thawani [Merck Fellow] studies selfish DNA sequences—so called because they copy and paste themselves within the human genome despite offering no specific fitness advantage. Dr. Thawani will utilize advanced methods such as cryo-electron microscopy to reveal the cellular machinery that assists these selfish elements and thus delineate their mechanism of mobility. She will use this insight 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 not only translate directly into new gene therapies, but also result in wide-ranging applications in synthetic biology. Ultimately, this work will contribute to treatment for many cancer types, including improved CAR-T therapies for blood cancers.

Dr. Tintori is studying nematode worms from Chernobyl, Ukraine, to investigate the biological effects of continuous radiation exposure. While ionizing radiation is known to cause cancer, little is known about the levels that increase health risks or how animals adapt to high radiation environments. Dr. Tintori is comparing worms from Chernobyl, the area with the highest known levels of background radiation on the planet, to similar animals that have not been exposed. This research may shed light on specific challenges presented by radiation and possible biomolecular defenses.

Chimeric antigen receptor (CAR) T cells are immune cells that have been genetically engineered to bind specific proteins on cancer cells. CARs can display exquisite sensitivity and discrimination, and CAR T cells have been deployed with spectacular success to detect and kill blood cancers. Unfortunately, they are much less effective against “solid” tumors, such as breast or kidney cancers. To address this problem, Dr. Titus [Connie and Bob Lurie Fellow] is designing T cells with membrane proteins that perform novel functions, including proteins that facilitate membrane fusion or alter the adhesion between T cells and their targets. By redesigning T cell membranes, Dr. Titus hopes to create useful cancer-fighting tools that can be deployed in conjunction with other emerging cellular therapies and immunotherapies. Dr. Titus received his MD and PhD from the University of California, San Francisco, and his AB from Harvard University.

One of the tools cancer cells employ to evade immune system detection is an increased DNA mutation rate, with some cancers mutating 100-1000 times faster than healthy tissue. Classic studies of the effects of mutations predict that most genetic changes are deleterious, yet high mutation rates appear to help cancer cells adapt and invade. Dr. Triandafillou [National Mah Jongg League Fellow] will address this paradox by using a single-cell model of cancer to measure the effects of mutations with much greater accuracy and resolution than is possible in live cancer cells. This information will help us understand how cancer cells balance deleterious mutations with the ability to adapt, and how the effects of mutations interact. She will also perform laboratory evolution experiments to track the adaptive process in different environmental conditions, mimicking the process by which cancer cells are able to colonize new micro-environments within tumors and throughout the body. This work will provide a clearer picture of how cancer cells use new mutations to proliferate. Dr. Triandafillou received her PhD from the University of Chicago and her BS from Temple University.

Dr. Unlu studies how cancer cells adapt to nutrient limitations in their environment. High metabolic demands of proliferating cancer cells create metabolic bottlenecks for in vivo growth within solid tumors. Dietary and pharmacological interventions could provide unique opportunities to target such metabolic liabilities. However, studying tumor metabolism in vivo adds many layers of biological complexity, meaning these potential targets are currently poorly characterized. Dr. Unlu plans to combine metabolomics approaches and functional CRISPR screens to systematically identify metabolites limiting for in vivo tumor growth and metastasis.

Epidemiologic studies have revealed that many cancer types display differences in incidence or outcomes between the sexes. In most cases, these differences are only partially explained by non-genetic factors such as hormonal differences, carcinogen exposure, lifestyle, and access to health care. Our understanding of how genetic factors contribute to differences in cancer incidence between the sexes remains incomplete. A fundamental genetic difference between the sexes is in chromosome composition. Relative to male somatic cells, female somatic cells have an extra X chromosome. Most genes on the second copy of chromosome X in females are inactivated via a process known as X-chromosome inactivation, which approximately equalizes the dosage of X-linked genes between males and females. Dr. Viswanathan's project tests the hypothesis that genetic alterations to the X chromosome in cancer may perturb this carefully regulated process and thereby contribute to differences in cancer incidence or pathogenic mechanisms between males and females.