Dr. Luo [HHMI Fellow] is focusing on the interplay between energy-producing mitochondria and the nucleus inside mammalian cells. Mitochondria contain their own small genome that encodes some proteins, but the vast majority are encoded in the cell's nucleus. The communication between mitochondria and the nucleus to produce the proteins necessary to properly function is tightly controlled, and its dysregulation has been implicated in human diseases including cancer. Dr. Luo is using ribosome profiling in parallel with CRISPR to quantitatively monitor translation (the process of protein production from RNA) on the mitochondrial surface and identify key regulators of this process. She hopes gaining an understanding of the underlying mechanism will yield fundamental insights into mitochondrial biology and its role in disease.

Metastatic cancers exploit cellular machinery to increase their proliferative potential and direct invasive cell migration. Specifically, cancer cells can adjust the translation of RNA into proteins to keep up with the demands of growth and metastasis. An important way that cells fine-tune their translation and quickly modulate cellular responses is through localized translation, or the translation of proteins in other areas of the cell further from the nucleus. To study the scope of localized translation, Dr. Luo has developed a highly sensitive, spatially-specific, and optically-controlled technique, which enables the quantification of translation at any given subcellular location. She will focus on understanding mechanisms of localized translation by identifying which genes are locally translated, how they are regulated, and why this process is important. Understanding the molecular mechanism of local protein synthesis could yield invaluable insights into the basis of cancer metastasis and inform therapeutic strategies. 

Patients with the same cancer diagnosis may experience very distinct disease progressions and treatment responses. These differences between patients have been associated with their degree of intra-tumor heterogeneity-the genetic, epigenetic, spatial, and environmental differences between the tumor cells. Characterizing the genetic and epigenetic states of different tumor cells is key to understanding how intra-tumor heterogeneity influences tumor progression, expansion, metastasis, and treatment response. Recent advances in single-cell RNA sequencing and spatial transcriptomics (which shows the spatial distribution of RNA molecules within a tissue sample) provide new opportunities to study intra-tumor heterogeneity in higher resolution. Dr. Ma's research aims to characterize intra-tumor heterogeneity in terms of specific genetic and epigenetic measures, and eventually develop 3D tumor models that capture this heterogeneity across multiple cancer types. Dr. Ma received her BS from Zhejiang University and her PhD in computational biology from Carnegie Mellon University.

The proposed computational methods will be based on previous methods developed in the group. Dr. Ma will develop a better method for identifying tumor clones for spatially resolved transcriptomics (SRT) data using both copy number and allele information using HMM and HMRF. She will adapt optimal transport frameworks and include biological networks as prior knowledge for integrating epigenetic data with SRT and between SRT slices to construct 3D spatial tumor multi-omics models.

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.

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.

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.

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.

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.

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.

Dr. Owens [Suzanne and Bob Wright Fellow] focuses on heat shock proteins (HSPs) and their “master regulator” called heat shock transcription factor 1 (HSF1). The transformation and growth of cancers causes a wide array of cellular stresses including metabolic changes, genomic instability, and protein misfolding that would halt the growth of a normal cell. Tumor cells, however, depend on cellular stress response machinery, like HSPs, for their survival. HSF1 is critical to tumor development and progression, and HSF1 activity is strongly correlated with poor prognosis in many common cancers. For decades, efforts to develop cancer therapies targeting HSPs have failed. Dr. Owens aims to understand how HSPs and HSF1 interact to regulate activity, and how this regulation is co-opted to promote tumor growth and progression.