Improved personalized medicine by drug partner discovery via a novel proteome-wide gene overexpression perturbation platform
Throughout my career, I have focused on the generation and integration of high-throughput data to propose novel hypotheses for experimental validation or new clinical biomarkers. In the Kim lab at McGill University, we have a broad research interest in developing and utilizing novel platforms to generate various omics data to solve clinical problems, such as drug resistance in cancer chemotherapy.
Our lab adapts two state-of-the-art tools to perform high-throughput overexpression screens to look for novel players in human disease. The ORFeome library, constructed by Drs. David E. Hill, Marc Vidal, and Frederick P. Roth’s group is a collection of barcoded ORFs that are cloned into a Gateway-compatible system. The newest version hOFReome 9.1 (Collaboration and The ORFeome Collaboration, 2016; Luck et al., 2020) includes ~90% of all human protein-coding genes, allowing for an unbiased proteome-wide screening for searching candidate biomarkers and therapeutic targets.
The second system, the Bxb-landing pad system (Matreyek et al., 2017, 2020), was constructed by Dr. Doug Fowler’s lab (Matreyek et al., 2017, 2020) and improved by Dr. Frederick P. Roth’s group to deliver exogenous DNA to a designated safe harbor locus in transfectable mammalian cell lines. Bxb landing pad system enables us to select gene-inserted cells with FACS for making every cell in the recombined pool express a single gene. Therefore, when we do an en masse transfection of our ORFeome collection, we are able to express “one gene per cell” with an artificial promoter to achieve “homogenous gene expression”.
Current projects at the Kim lab
Using gene overexpression phenotypes to discover drug partners that eliminate therapeutic resistance
Mechanisms for therapeutic resistance often depend on the regulation of gene overexpression. The current "One Treatment Fits All" approach has limitations due to cancer heterogeneity and does not address an individual's distinct response to therapy (Hamburg and Collins, 2010). Combinatorial drug use is limited in current personalized medicine approaches, but the combinatorial space is much larger, and each patient may be treated with a ‘unique fingerprint' of drug combinations to overcome resistance.
We use our overexpression screening platform to discover novel pathways whose upregulation induces anti-cancer drug resistance in various cancer types. By identifying the ORFeome gene whose overexpression alters sensitivity to a particular drug, we can find causal genes for therapeutic resistance. We can propose a novel combinatorial therapy using a second drug that can suppress resistance, or induce toxicity. Moreover, we are interested in the application of an overexpression perturbation system to find novel developmental drivers or regulators of extracellular vesicles’ biogenesis.
Please see the details on the paper published.
https://www.biorxiv.org/content/10.1101/2025.09.02.673780
Decoding Parkinson’s Disease from a Drop of Blood and Integrated Analysis with Functional Genomics on Alpha-Synuclein Uptake: A New Era of Precision Medicine
Parkinson’s disease (PD) treatment has long been hindered by the difficulty of monitoring disease progression without relying on subjective observation or invasive procedures. To overcome this, our latest research introduces a breakthrough in "deep plasma proteomics," utilizing a specialized technique to filter blood plasma and detect over 6,400 proteins—an unprecedented depth that allows us to see molecular details that were previously hidden. By analyzing these comprehensive protein signatures, we successfully solved a critical clinical puzzle: distinguishing the biological "footprint" of the disease’s natural progression from the changes merely caused by dopaminergic medications. We took this a step further by integrating our findings with functional genomic screens, linking these blood-based signals directly to the cellular mechanisms driving neurodegeneration in the brain. This systems-level approach not only validated robust biomarkers for tracking patient health but also identified "druggable" targets that are already addressed by existing medications, paving the way for a new era of precision medicine where a simple blood draw can guide personalized therapeutic strategies.
Mapping the Hidden "Postal System" of Cellular Communication via Applying Functional Genomics on Extracellular Vesicles (EVs)
Cellular communication relies heavily on the exchange of extracellular vesicles (EVs)—tiny biological packages that ferry information between cells—but this process is frequently exploited by cancers to drive tumor progression. To decipher the genetic rules governing this hidden communication network, we developed a trio of novel functional genomics platforms: BOGO-EV and CIRCUS to track how vesicles are manufactured, and a "Trojan horse" system called TAMER to determine how they are absorbed. By identifying these specific bottlenecks, our study establishes a new blueprint for precision medicine, demonstrating that pharmacological inhibitors can target these proteins to break the pathological communication loops that fuel disease.
Exploring disease mutants that cause a gain of protein-protein interactions
Mutations rewiring PPI networks are known to be important in cancer(Bowler et al., 2015)and other diseases. Comprehensively investigating mutations in PPI-mediating domains may be a new approach to finding treatments for cancers and rare diseases. We are interested in applying proteomics approaches to detect changes in PPIs of selected human disease variants to address how these variants alter the interactome of the protein. We seek to explore phenotypic effects caused by novel gain-of-interactions, and ultimately discover drugs that can inhibit the interaction.