All Cancers

Current Projects
J. Scott P. McCain, PhD

One of the defining features of cancerous cells is that they divide quickly. The composition of the human microbiome is also due to differences in how quickly microbes grow. How do we determine how fast cells are growing in their natural environment? Is there a way to take a ‘snapshot’ and turn it into a ‘growth rate’? This is the fundamental problem Dr. McCain is studying. He is using computational simulations, machine learning, and experiments with bacteria to determine the optimal way to use markers of gene expression to estimate these critical rates. This project will provide fundamental insights into the use of gene expression data to key processes like growth rate or metabolite secretion rate, both of which have implications for cancer biology. Dr. McCain received his MSc and PhD from Dalhousie University and his BSc from the University of Western Ontario.

Project title: "Estimating growth rates and fluxes using gene expression: Theory and applications"
Institution: Massachusetts Institute of Technology
Award Program: Fellow
Sponsor(s) / Mentor(s): Gene-Wei Li, PhD
Cancer Type: All Cancers
Research Area: Microbiology
Rebecca S. Moore, PhD

Sleep problems may be a risk factor for developing certain types of cancer—lung, colon, pancreas, and breast—and may affect the progression of these cancers and the effectiveness of their treatment. Conversely, symptoms of cancer or side effects of treatment, including restless legs and obstructive sleep apnea, may cause sleeping problems, reducing quality of life. Understanding the complex relationship between cancer and sleep creates opportunities to improve health, treatment options, and quality of life. Specifically, understanding how the peripheral nervous system and the brain regulate both the timing and rhythmicity of sleep (i.e., circadian control), and the balance between time awake and growing sleep pressure (i.e., homeostatic control), could improve survival rates and the quality of cancer treatment. To this end, Dr. Moore [HHMI Fellow] aims to identify the role of circulating dietary cholesterol on sleep and to conduct a targeted genetic screen to identify peripherally secreted proteins that affect either the circadian or the homeostatic control of sleep. These results will provide a means for therapeutic interventions to ameliorate the effects of sleep disruption. Dr. Moore received her PhD from Princeton University and her MS and BS from the City College of New York.

Project title: "Investigation of the role of peripheral secreted molecules on sleep and circadian rhythms"
Institution: University of Pennsylvania
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Amita Sehgal, PhD
Cancer Type: All Cancers
Research Area: Basic Genetics
Ryan Y. Muller, PhD

The PABPC1 protein has diverse roles in gene expression control that span functions in mRNA stability, polyA tail length control, and translation regulation. PABPC1 gene amplifications are detected in roughly 4% of cancer samples, but it is unclear how PABPC1 fits into the picture of cancer progression. Dr. Muller [HHMI Fellow] studies the sequence preferences of PABPC1 protein to understand the mechanistic details that determine which transcripts are subject to PABPC1-mediated regulation. Connecting these sequence preferences to the mis-regulation caused by excess PABPC1 may provide a therapeutic handle for cancers that contain PABPC1 gene amplifications. Dr. Muller received his PhD from the University of California, Berkeley and his BS from Arizona State University, Tempe.

Project title: "Elucidating PABPC1 sequence preferences and determining how these preferences shape gene regulation"
Institution: Whitehead Institute for Biomedical Research
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): David P. Bartel, PhD
Cancer Type: All Cancers
Research Area: Biochemistry
Stefan Niekamp, PhD

Dr. Niekamp [Dennis and Marsha Dammerman Fellow] studies how gene expression programs are regulated in normal and cancer cells. The ability to switch specific genes "on" and "off" is partly encoded by multiprotein complexes competing for access to target DNA sequences in chromatin structures. The relative distribution of these activating or repressive complexes along chromatin regulates gene expression, and a shift in the balance of these complexes is a hallmark of many cancers. Dr. Niekamp aims to determine how chromatin accessibility is achieved by the competition between activating and repressive complexes, and to understand how well-known cancer mutations disrupt the fine-tuned balance.

Project title: "Understanding the switch: Competition between chromatin remodeler and polycomb repressive complexes"
Institution: Massachusetts General Hospital
Named Award: Dennis and Marsha Dammerman Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Robert E. Kingston, PhD
Cancer Type: All Cancers
Research Area: Biophysics
Christopher Noetzel, PhD

As different tissues in the body form, cells need to undergo a complex, precisely timed series of differentiation programs to form specialized cell types. Importantly, premature or delayed initiation of these programs can contribute to cancer formation. However, how timing of cellular differentiation is encoded on a molecular level is poorly understood. Dr. Noetzel is using the protozoan parasite Cryptosporidium parvum as a simplified model of eukaryotic differentiation. After infecting the intestinal lining of a mammalian host, these single-celled parasites undergo exactly three rounds of asexual replication before collectively differentiating into gametes. These studies will investigate how this hard-wired, intrinsic developmental timer is encoded. In his project, Dr. Noetzel aims to understand how these parasites "count to three," which will inform our basic understanding of how eukaryotic cells keep track of time during development. Dr. Noetzel received his PhD from the Weill Cornell Medical College, Cornell University, New York and his MSc and BSc from Georg-August-University, Göttingen.

 

Project title: "How do eukaryotic cells count cell cycles? Intrinsic regulation of quantized asexual replication cycles and commitment to sexual differentiation in the protozoan parasite Cryptosporidium parvum"
Institution: University of Pennsylvania
Award Program: Fellow
Sponsor(s) / Mentor(s): Boris Striepen, PhD
Cancer Type: All Cancers
Research Area: Microbiology
Jeremy A. Owen, PhD

Chromatin remodelers are complex protein machines responsible for packaging DNA and regulating gene expression. Their dysfunction is strongly implicated in cancer. For example, certain types of sarcoma and ovarian cancer are driven by mutations in a chromatin remodeler called BAF. Combining experiments with theoretical work, Dr. Owen’s research aims to understand how remodelers recognize their target sites in the cell’s nucleus. By expanding our understanding of chromatin remodeling, the findings of this research will provide the groundwork for more effective cancer treatments—suggesting how drugs might target chromatin remodelers—as well as enhance our understanding of how existing drugs that target remodeler-adjacent mechanisms might work.

A central aim of this project is the development of new, quantitative models to explain the behavior of chromatin remodelers seen in experiments. Dr. Owen will achieve this by successive rounds of passing between theory and experiments repeatedly—measuring, modeling, then measuring again. For comparison to experiments, model predictions will be extracted computationally (e.g., numerically solving ODEs, or by exact stochastic simulation using Gillespie’s algorithm) or analytically (e.g., by the King-Altman procedure, and variants), as appropriate.

Project title: "The biophysics of substrate recognition in chromatin remodeling"
Institution: Princeton University
Award Program: Quantitative Biology Fellow
Sponsor(s) / Mentor(s): Tom W. Muir, PhD, and Ned S. Wingreen, PhD
Cancer Type: Gynecological, Sarcoma, All Cancers
Research Area: Chromatin Biology
Dylan M. Parker, PhD

Dr. Parker [HHMI Fellow] studies the role of molecular assemblies known as stress granules that form when cells are exposed to stressful conditions. The assembly of stress granules upon cellular insult is thought to regulate gene expression and modulate cell survival. Notably, stress granules are present in various cancers and many chemotherapeutic treatments lead to the formation of stress granules. Dr. Parker aims to determine the mechanisms regulating stress granule assembly and disassembly to understand how stress granule formation supports the development of cancer and chemotherapy-resistant tumors. This research has the potential to discover novel targets to treat cancers as well as sensitize chemotherapy-resistant cancers to existing treatments. Dr. Parker received his PhD from Colorado State University and his BS from the University of Oregon.

Project title: "Stress granule regulators and their roles in cancer progression"
Institution: University of Colorado Boulder
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Roy R. Parker, PhD
Cancer Type: All Cancers
Research Area: Biochemistry
Philip T. Pauerstein, MD, PhD

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.

Project title: "Enhancing immune synapse formation with synthetic adhesion to overcome chimeric antigen receptor-T cell resistance in pediatric B cell malignancies"
Institution: University of California San Francisco
Award Program: St. Jude Fellow
Sponsor(s) / Mentor(s): Wendell A. Lim, PhD
Cancer Type: Blood, Pediatric, All Cancers
Research Area: Immunotherapy
Fanglue Peng, PhD

Accumulating evidence shows that specialized structures of white blood cells (lymphocytes), named tertiary lymphoid organs (TLOs), can form inside tumors and play a crucial role in fighting cancer progression. Unlocking the formation and functions of TLOs holds great promise for advancing cancer immunotherapy, but studying TLOs remains challenging due to the substantial disparities between humans and animal models. To address this, Dr. Peng [Connie and Bob Lurie Fellow] will leverage single-cell sequencing data and high-throughput screening methods to investigate a key initiator of TLO formation in human tumors. He further plans to develop innovative genetic models that enable the study of TLOs in a human-specific context within living organisms. By unraveling the intricacies of TLO biology, Dr. Peng aims to uncover novel therapies that can augment cancer immunotherapy and enhance treatment outcomes across various cancer types.  Dr. Peng received his PhD from Baylor College of Medicine, Houston and his BS from Zhejiang University, Hangzhou, Zhejiang.

Project title: "Humanize CXCL13 expression in mouse to understand lymphoid neogenesis in cancer"
Institution: University of California, San Francisco
Named Award: Connie and Bob Lurie Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Jason G. Cyster, PhD
Cancer Type: All Cancers
Research Area: Basic Immunology
Titas Sengupta, PhD

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.

Project title: "Investigating bacterial small RNA-mediated regulation of host behavior"
Institution: Princeton University
Named Award: Rebecca Ridley Kry Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Coleen T. Murphy, PhD
Cancer Type: All Cancers
Research Area: Epigenetics
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