William L. Hwang, MD, PhD: Precision Oncology in Pancreatic Cancer through Single-Cell and Spatial Omics

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer mortality in the United States by 2030. Given that resistance to cytotoxic therapy is pervasive, there is a critical need to elucidate clinically-relevant gene expression programs and spatial relationships among malignant and stromal cells in the tumor microenvironment (TME), particularly in residual disease. Development and application of a single-nucleus RNA-seq (snRNA-seq) technique to banked frozen primary PDAC specimens that either received neoadjuvant therapy or were treatment-naïve, led to the discovery of expression programs across malignant cell and fibroblast profiles that formed the basis for a refined molecular taxonomy.

To further uncover how neoadjuvant treatment and cancer cell- and fibroblast-intrinsic programs modulate the composition of multicellular neighborhoods, spatial profiling was performed with the GeoMx[1] platform (NanoString) formalin-fixed paraffin-embedded sections using human whole transcriptome atlas (WTA). WTA data along with the snRNA-seq cell type signatures were deconvolved to map expression programs onto the tumor architecture revealing three distinct multicellular neighborhoods, annotated as classical, squamoid-basaloid, and treatment-enriched.

Speaker’s Bio

William L. Hwang, MD, PhD is a clinician-investigator and radiation oncologist at the Massachusetts General Hospital Cancer Center. As a physician-scientist, he specializes in the treatment of gastrointestinal cancers and his research program is focused on the development and application of single-cell and spatial biology methods, genetically-engineered mouse models, and pooled genetic screens in organoids to study the tumor-stroma interactions in pancreatic cancer (and other GI malignancies) at unprecedented resolution. He is particularly interested in studying the (1) cell state plasticity involved in early tumorigenesis and therapeutic resistance; (2) tumor-nerve crosstalk, and (3) mechanisms by which radiotherapy and systemic therapies reprogram the tumor immune microenvironment and how these changes may be harnessed to improve immunotherapeutic strategies.

For Research Use Only.  Not for Use in Diagnostic Procedures.