题 目:Unrevealing heterogeneity in signaling networks through single-cell and single-molecule technologies
报告人: Dr. Xiaokang Lun（伦小康）
Wyss Institute，Harvard University
时 间: 11月26日（周四）9:00-10:00
地 点: Online (Zoom会议)
会议 ID：690 589 7825
主持人: 林一瀚 研究员
Signaling networks are key regulators of cellular function. Although the concentrations of signaling proteins are perturbed in disease states, and are modulated by drug therapies, our understanding of how such changes shape the properties of signaling networks is limited. In Dr. Bernd Bodenmiller’s lab, I used mass cytometry-based high-dimensional analysis to simultaneously assess over 40 phosphorylation sites at single-cell resolution and to comprehensive characterize the signaling network modulations induced by differential protein abundances. I discovered that overexpression of MAP kinases lead to heterogeneous signaling dynamics and complex signaling behaviors that are different from direct kinase activation. To systematically and quantitatively characterize such unprecedented signaling effects in the human genome, I analyzed the network responses to 649 human kinases and phosphatases that were expressed over an abundance range of four orders of magnitudes at single-cell resolution. Based on these data I expanded the functional classification of human kinases and phosphatases and detected 208 novel signaling relationships and a phosphatase-driven mechanism in cancer progression. I identified 54 proteins that caused ligand-independent ERK activation. These proteins were confirmed as potential biomarkers for drug resistance in cells carrying BRAF mutations. In a parallel study, I developed an experimental and computational toolbox, named CellCycleTRACER that addressed the impact of cell cycle and cell size effects in single-cell signaling network analysis.
Biological organisms are fundamentally complex molecular systems and the composition and interaction of biomolecules determine cell state and function. In Dr. Peng Yin’s lab, I developed a novel DNA technology-based quantitative imaging method for single-molecule proteomics. By using a pool of barcoded short DNA strands to chemically label specific amino acid residues in a denatured protein, and by counting the number of labeled residues with DNA exchange-based multiplexed imaging, the composition signatures of examined single proteins can be generated. This information can be mapped to the human proteome database for protein identification. In a separate study, I established a hypothesis-free and single-molecule system to record protein-protein interactions into DNA sequences that are readout via next generation sequencing.
Xiaokang earned his Bachelor’s degree in biology at Wuhan University in 2011. He received a Huygens Full Scholarship to pursue a Master’s degree in biomedical sciences at the University of Amterdam. In early 2014, he joined Dr. Bernd Bodenmiller’s lab at the University of Zurich and started his PhD research in single-cell systems biology. He graduated in 2018 with a distinctive PhD thesis awarded by the University of Zurich. Currently, Xiaokang is supported by the Swiss National Science Foundation with a postdoctoral fellowship to continue his research at Harvard University. In Dr. Peng Yin’s lab, Xiaokang is working on developing novel DNA nanotechnologies for protein detection, identification, and characterization.