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This week we profile a recent publication in Nature Communications from the lab of Dr. Andrew Weng (pictured, right) at BC Cancer with first authors Dr. Xuehai Wang (second from right) and Michael Nissen.

Can you provide a brief overview of your lab’s current research focus?

My lab’s current research focus is on defining genetic and epigenetic drivers of T-cell leukemogenesis and B-cell lymphomagenesis. To study T-cell leukemia development, we devised a synthetic biology approach in which genetic and/or epigenetic variables are introduced into normal human cord blood cells, and we see what the effects are on cells as they grow and differentiate in vitro and after injection in vivo into immunodeficient mice. To study B-cell lymphoma development, we first describe genetic/epigenetic/phenotypic variables present in primary patient lymphoma biopsy specimens, often at single cell resolution using techniques like mass cytometry (CyTOF), single cell RNA-seq, single cell ATAC-seq, single cell targeted sequencing (Tapestri), and single cell whole genome sequencing. Then we model those genetic/epigenetic variables by gene transduction/editing of normal and malignant human lymph node cells and assess their effects on cell growth, survival, and important developmental events like class switch recombination. For B-cell work, we typically use either 2-dimensional feeder co-cultures or 3-dimensional organoid cultures.

What is the significance of the findings in this publication?

The study we just published in Nature Communications describes phenotypic variation within and between individual patient follicular lymphoma (FL) biopsy samples. We assembled an unusually large cohort of 155 patient FL samples and characterized cellular phenotypes at single cell resolution using complementary B- and T-cell directed, 39-marker antibody panels. We defined for the first time an alternate, but prevalent subtype of cells which resemble normal memory B-cells (MB). This result was striking in that FL is conventionally regarded to resemble normal germinal center B-cells (GCB) and that this newly discovered MB type is more likely to undergo transformation to more aggressive disease than GCB type. Further, we also found that phenotypic diversity within a tumor was also a strong predictor of risk of transformation.

What are the next steps for this research?

The next steps for this research project are to identify the underlying molecular determinants that drive phenotypic diversity within individual FL tumors and which lead FL tumor cells to adopt MB vs. GCB phenotypes. To address these questions, we are deploying simultaneous assessment of surface phenotypes, transcriptomes, genomes, epigenomes, and spatial interactions, all performed at single cell resolution, using a combination of CITE-seq, scRNA-seq, scRNA/ATAC-seq, Tapestri, scWGS, and imaging mass cytometry (Hyperion). This descriptive multi-omics work will be performed on patient FL biopsy samples accrued and tracked clinically through the Departments of Pathology and Medical Oncology at BC Cancer, with research endeavors supported within the Centre for Lymphoid Cancers and Terry Fox Laboratory at the BC Cancer Research Institute. Importantly, we will be able to perform functional validation of these findings using gene transduction and gene editing of primary human B-cells obtained from patient samples and cultured in our 2-D and 3-D in vitro culture models.

If you’d like to mention your funding sources, please list them.

The follicular lymphoma work was supported by an operating grant from the Cancer Research Society and a recently renewed program project grant from the Terry Fox Research Institute. The project has also been enabled by infrastructural funds from the BC Cancer Foundation. The lymphoma functional modeling work currently receives support from the Leukemia and Lymphoma Society of Canada and the BC Cancer Foundation.

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