Precision Oncology in Pancreatic Cancer through Single-Cell and Spatial Omics

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.