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.

Dr. Liu is combining single-molecule fluorescence and force spectroscopy to study dynamic interactions between meiotic double-strand break (DSB) proteins and DNA. Meiotic recombination initiates with DSBs that are generated by the protein Spo11. Spo11 and its partner proteins ensure that DSBs occur at the right chromosome sites and at the right time. Dysregulated DSBs lead to chromosome instability, a hallmark of cancer cells. Dr. Liu’s study will elucidate the dynamics of DSB formation during meiosis, which will shed light on cancer formation and pave the way for new therapeutic alternatives.

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.

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.

Dr. McClune [HHMI Fellow] investigates plant biosynthesis of therapeutic compounds. Approximately half of FDA-approved chemotherapeutics, including first line drugs like paclitaxel (Taxol) and vinblastine (Velban), derive from the arsenal of defensive chemicals that plants synthesize. Unfortunately, both the discovery of new plant-derived therapies and their scalable production are limited by intrinsic challenges of plant biology and genomics. Dr. McClune is developing systematic methods for identifying the biosynthetic pathways plants use to produce defensive molecules. Using single-cell technology, he will characterize rare cells responsible for synthesizing potentially beneficial chemicals and identify the enzymes they use to produce such molecules.

Dr. McGinn studies how bacterial pathogens sense and manipulate their human hosts. Dr. McGinn is focusing on the tick-borne bacterial pathogen Rickettsia parkeri, which can only survive within eukaryotic host cells. By uncovering novel interactions between host and pathogen, his work may reveal new insights into how human cells work and what goes awry in disease states. He is also developing tools to manipulate key virulence pathways in Rickettsia parkeri that can be used to transform the bacteria into a vehicle for delivering antigens or new drugs directly to cancer cells.

Dr. McLaughlin [HHMI Fellow] is using the developing nervous system to study metastasis, the primary cause of cancer-related fatalities. In metastasis, cell surface and secreted molecules enable cells to travel through diverse environments and invade distant tissues. Likewise, growing axons in the developing nervous system use similar sets of cell surface proteins to traverse long distances to form precise connections with their synaptic partner cells. Dr. McLaughlin aims to define the mechanisms used by cell surface proteins to promote axon targeting, which will provide critical insight into how these molecules are harnessed by malignant cells during metastasis.