All Cancers

Current Projects
Cayla E. Jewett, PhD

Every cell contains specialized compartments called organelles that perform distinct functions, and cells employ counting mechanisms to finely tune organelle population. Centrioles are one type of organelle required for proper cell division and mammalian development. Cells normally contain two or four centrioles, depending on cell cycle state, and centriole gains or losses result in cancer. One exception to this rule are the cells that line our airways, brain ventricles, and reproductive tracts. These cells contain hundreds of centrioles-yet how these specialized cells break the rules of conventional cell cycle-regulated counting mechanisms remains a mystery. Dr. Jewett's [Merck Fellow] work utilizes primary cell culture and in vivo models to understand the molecular framework that allows increased numbers of centrioles in certain cell types. This work will advance our understanding of how defects in centriole growth cause human diseases such as cancer. Dr. Jewett received her PhD from the University of Colorado School of Medicine and her BS from the University of Denver. 

Project title: "Mechanisms of centriole number control in multiciliated cells"
Institution: The Johns Hopkins University School of Medicine
Named Award: Merck Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Andrew J. Holland, PhD
Cancer Type: All Cancers
Research Area: Cell Biology
Grace E. Johnson, PhD

Dr. Johnson [HHMI Fellow] studies the role that a particular type of cell-cell communication, known as quorum sensing, plays in the development of spatially structured bacterial communities called biofilms. Biofilm formation promotes disease in many clinically relevant bacterial species, and infections caused by them pose severe risks for patients receiving chemotherapy. Dr. Johnson is currently investigating how quorum sensing within biofilms establishes patterns of gene expression, and in turn, how these patterns drive biofilm development and dictate biofilm architectural features. By defining mechanisms underlying biofilm formation and biofilm architecture, Dr. Johnson hopes to contribute to the generation of new approaches for disrupting quorum-sensing-controlled bacterial community interactions as a means of combating bacterial pathogens. Dr. Johnson received her PhD from MIT and her BS from Yale University.

Project title: "Defining quorum-sensing signaling patterns and their effects on gene expression and morphology in V. cholerae biofilms at the single-cell and community levels"
Institution: Princeton University
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Bonnie L. Bassler, PhD
Cancer Type: All Cancers
Research Area: Microbiology
Henry R. Kilgore, PhD

Cells are compartmentalized into membrane-bound and membrane-less organelles, providing spatial structure to the cell’s concentration of proteins and nucleic acids. Dr. Kilgore’s research aims to understand the environment inside different organelles and apply this knowledge to the development of targeted cancer therapies, as better targeting within the cell will improve drug efficacy, increase potency, and decrease side effects. Using both live cells and reductionist models, he will investigate how molecules distribute themselves within the cell as a function of their chemical properties. Learning and applying the chemical grammar of this spatial partitioning will enable the design and preparation of molecular probes and drugs that synergize with the chemistry of the cell as a mechanism of treating all cancers. Dr. Kilgore received his PhD from Massachusetts Institute of Technology and his BS from the University of California, Berkeley.

Project title: "Subcellular pharmacokinetics"
Institution: Whitehead Institute for Biomedical Research
Award Program: Fellow
Sponsor(s) / Mentor(s): Richard A. Young, PhD
Cancer Type: All Cancers
Research Area: Drug Discovery
Seungsoo Kim, PhD

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.

Project title: "Transcription factor cooperation shaping TWIST1 multifunctionality across craniofacial development and cancer metastasis"
Institution: Stanford University
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Joanna K. Wysocka, PhD
Cancer Type: All Cancers
Research Area: Chromatin Biology
Grant A. King, PhD

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.

Project title: "How do host cells engage with extrachromosomal DNA?"
Institution: Fred Hutchinson Cancer Research Center
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Harmit S. Malik, PhD
Cancer Type: All Cancers
Research Area: Cell Biology
Heidi E. Klumpe, PhD

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.

Project title: "The design principles of stable aggregation"
Institution: Boston University
Named Award: Merck Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Ahmad S. Khalil, PhD, and Mary Dunlop, PhD
Cancer Type: All Cancers
Research Area: Systems Biology
Nora Kory, PhD

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.

Project title: "Targeting mitochondrial transporters in cancer"
Institution: Harvard T.H. Chan School of Public Health
Award Program: Innovator
Cancer Type: Blood, Gynecological, All Cancers
Research Area: Biochemistry
Archana Krishnamoorthy, PhD

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. 

 

Project title: "Mechanisms of chromosome fragmentation generating chromothripsis"
Institution: Dana-Farber Cancer Institute / Harvard Medical School
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): David S. Pellman, MD, and Johannes Walter, PhD
Cancer Type: All Cancers
Research Area: Genome Maintenance
Jean-Benoît Lalanne, PhD

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.

Project title: "At-scale dissection of developmental enhancers with single-cell reporters"
Institution: University of Washington
Award Program: Fellow
Sponsor(s) / Mentor(s): Jay A. Shendure, MD, PhD
Cancer Type: All Cancers
Research Area: Genomics
Nicholas C. Lammers, PhD

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.

Project title: "A computational platform for predicting whole-embryo morphologies from single-cell transcriptomes"
Institution: University of Washington
Award Program: Quantitative Biology Fellow
Sponsor(s) / Mentor(s): Cole Trapnell, PhD, and David Kimelman, PhD
Cancer Type: All Cancers
Research Area: Quantitative Biology
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