Dr. Kim [HHMI Fellow] is studying the molecular links between cancer cells undergoing metastasis and formation of the face during development (known as craniofacial development). Both craniofacial and cancer cells must enter a migratory state triggered by certain key transcription factors including TWIST1. However, the exact role of TWIST1 appears to vary across cell types, which might explain some of the differences between cells found in various cancers and in normal craniofacial development. Dr. Kim is using genomic tools to dissect how transcription factor cooperation may toggle TWIST1 function across cell types, with potential implications for all cancers.

Like changes in key genes that control the cell cycle, changes to chromosomes can result in abnormal cell function and sometimes even cancer. Recently, a new type of genetic change has been linked to diverse cancers: the formation of circular DNA molecules from chromosomes. These molecules, known as extrachromosomal DNA or ecDNA, are dangerous because they do not follow the same rules of inheritance as normal chromosomes. Understanding the behavior of ecDNA within cells may uncover strategies to eliminate ecDNA and restore cellular health. Using a model ecDNA in budding yeast, Dr. King [HHMI Fellow] will identify and characterize pathways that either limit or enhance ecDNA propagation. He will then determine whether these pathways play a consistent role in human cancer cells, with the goal of identifying novel therapeutic vulnerabilities in treatment-resistant ecDNA-driven cancers. Dr. King received his PhD from the University of California, Berkeley and his BA from Columbia University, New York.

Cells living in aggregates can perform more complex tasks than individual cells, but they also face key challenges as they have less access to space and nutrients. Tumors, like the healthy tissues they disrupt, must balance these physical forces and effectively distribute metabolites to continue to grow. Dr. Klumpe [Merck Fellow] will use yeast as a simplified model of cell aggregation to engineer diverse aggregates and observe their growth and maintenance over many generations. Understanding how certain properties of an aggregate affect its long-term stability can shed light on "design principles" that underlie the persistence of tumors, as well as what stabilizes other multicellular structures, such as healthy tissue and biomaterials. Dr. Klumpe received her PhD from the California Institute of Technology and her BS/BA from North Carolina State University.

Cancer cells rely on efficient uptake, conversion, and exchange of nutrients and vitamins to support their rapid growth and survival. The molecular transport channels that allow passage of nutrients between the different cellular compartments are critical for the survival of cancer cells and are thus promising as potential drug targets. However, drug discovery efforts are hampered by a lack of basic understanding of these channels' identities, functions, and regulation inside cancer cells. Dr. Kory's research aims to identify transporters central to cancer cell nutrient supply and detoxification pathways and determine their role in the emergence, survival, and aggressiveness of cancer. Her research is relevant to all cancers, but particularly pediatric, blood, and breast cancers.

Cancer initiation and progression stems from cell division errors that promote chromosome breakage and accumulation of mutations. Dr. Krishnamoorthy [HHMI Fellow] will use cutting-edge, cross-disciplinary approaches to provide insights into the fundamental question of how cell division shapes the cancer genome. Understanding the mechanisms of cancer genome complexity will help identify better diagnostics and treatments for cancers linked with high levels of genome alterations. Dr. Krishnamoorthy received her PhD from Vanderbilt University, Nashville and her MS from Middle Tennessee State University, Murfreesboro and her BS from PES Institute of Technology, Bangalore. 

Dr. Lalanne investigates the biophysical determinants of gene expression. Dysregulation of the expression of select oncogenes and tumor suppressors in specific tissues is sufficient to initiate tumorigenesis. Such dysregulation can arise from small-scale genetic changes that alter the binding sites of transcription factors in otherwise inactive enhancers (the short, non-coding regions of DNA to which transcription factors bind, activating gene expression). Despite substantial efforts in functional genomics, the quantitative connection between DNA sequence and expression remains largely elusive. Using a combination of single-cell transcriptomics and reporter assays, Dr. Lalanne plans to decipher the underlying sequence determinants of cell type-specific gene regulation. His goal is to formulate predictive models of which mutations in the non-coding genome can perturb the gene expression program and ultimately lead to cancer development.

In both embryonic development and disease, the same genetic mutation can lead to highly variable outcomes in different individuals. Dr. Lammers aims to shed light on the drivers of this nongenetic variability using the developing zebrafish embryo as a model system. By combining fluorescence microscopy and single-cell sequencing, he will test whether subtle differences in gene expression within individual cells can explain why some embryos with a given genetic mutation survive to adulthood, while others perish within the first 24 hours of their development. His findings will provide a quantitative foundation for understanding the genetic and molecular basis of cancer outcomes in human patients where, for instance, tumors with the same underlying mutations often exhibit dramatically different disease courses.

Dr. Lammers will train Variational Autoencoders to learn low-dimensional latent space representations of whole-embryo transcriptomes and grayscale images depicting embryonic morphology. He will then train a third neural network to translate from transcriptional latent space to morphological latent space. Together, these three networks will comprise a new computational method, morphSeq, that takes single-cell transcriptomes of mutant and wildtype embryos as input and produces predictions for corresponding embryo morphologies as its output.

Dr. Lapointe examines how the synthesis of proteins (translation) is controlled, as dysregulated translation is a ubiquitous feature of cancer. He is focused on a key challenge: how regulation that originates at the end of a messenger RNA (mRNA, a genetic molecule that encodes a protein) impacts the start of translation, which occurs near the beginning of the mRNA. His goal is to reveal and analyze dynamic pathways that underlie this fundamental mechanism to control gene expression. Using an integrated approach of single-molecule fluorescence microscopy, structural, and biochemical strategies, this research should yield generalizable insights into how translation is precisely regulated and how it is disrupted in a wide array of cancers.

Dr. Li [The Mark Foundation for Cancer Research Fellow] is mapping the positions of the amino acid cysteine in cancer-relevant proteins. He will perform functional screens that reveal the cysteine residues that are essential to the progression of cancer. Since the unique chemistry of cysteine makes it an attractive target for therapeutic development, this map can guide the discovery and optimization of drugs that can bind to and inhibit cancer-promoting proteins. His research has the potential to greatly accelerate the discovery of new cancer targets and their corresponding therapeutics. 

Stable levels of ions (such as sodium or potassium) are critical for human health. Imbalanced ion concentrations indicate a metabolic disorder and are related to the process of metastasis. Dr. Liu aims to develop small molecule therapies that target proteins involved in metabolic disorders. To this end, she is developing computational methods to screen billions of compounds and identify potential drug candidates. With this project she hopes to not only meet an urgent therapeutic need but also improve the computational-based drug discovery pipeline.