Tianqi Chen

All Publications

• Direct measurement of engineered cancer mutations and their transcriptional phenotypes in single cells. Nature biotechnology Kim, H. S., Grimes, S. M., Chen, T., Sathe, A., Lau, B. T., Hwang, G. H., Bae, S., Ji, H. P. 2023

  Abstract

  Genome sequencing studies have identified numerous cancer mutations across a wide spectrum of tumor types, but determining the phenotypic consequence of these mutations remains a challenge. Here, we developed a high-throughput, multiplexed single-cell technology called TISCC-seq to engineer predesignated mutations in cells using CRISPR base editors, directly delineate their genotype among individual cells and determine each mutation's transcriptional phenotype. Long-read sequencing of the target gene's transcript identifies the engineered mutations, and the transcriptome profile from the same set of cells is simultaneously analyzed by short-read sequencing. Through integration, we determine the mutations' genotype and expression phenotype at single-cell resolution. Using cell lines, we engineer and evaluate the impact of >100 TP53 mutations on gene expression. Based on the single-cell gene expression, we classify the mutations as having a functionally significant phenotype.

  View details for DOI 10.1038/s41587-023-01949-8

  View details for PubMedID 37697151

  View details for PubMedCentralID 8018281

• Follicular lymphoma evolves with a surmountable dependency on acquired glycosylation motifs in the B cell receptor. Blood Haebe, S. E., Day, G., Czerwinski, D. K., Sathe, A., Grimes, S. M., Chen, T., Long, S. R., Martin, B. A., Ozawa, M. G., Ji, H. P., Shree, T., Levy, R. 2023

  Abstract

  An early event in the genesis of follicular lymphoma (FL) is the acquisition of new glycosylation motifs in the B cell receptor (BCR) due to gene rearrangement and/or somatic hypermutation. These N-linked glycosylation motifs (N-motifs) contain mannose-terminated glycans and can interact with lectins in the tumor microenvironment, activating the tumor BCR pathway. N-motifs are stable during FL evolution suggesting that FL tumor cells are dependent on them for their survival. Here, we investigated the dynamics and potential impact of N-motif prevalence in FL at the single cell level across distinct tumor sites and over time in 17 patients. While most patients had acquired at least one N-motif as an early event, we also found (i) cases without N-motifs in the heavy or light chains at any tumor site or timepoint and (ii) cases with discordant N-motif patterns across different tumor sites. Inferring phylogenetic trees for the patients with discordant patterns, we observed that both N-motif-positive and N-motif-negative tumor subclones could be selected and expanded during tumor evolution. Comparing N-motif-positive to N-motif-negative tumor cells within a patient revealed higher expression of genes involved in the BCR pathway and inflammatory response, while tumor cells without N-motifs had higher activity of pathways involved in energy metabolism. In conclusion, while acquired N-motifs likely support FL pathogenesis through antigen-independent BCR signaling in most FL patients, N-motif-negative tumor cells can also be selected and expanded and may depend more heavily on altered metabolism for competitive survival.

  View details for DOI 10.1182/blood.2023020360

  View details for PubMedID 37683139