Research Spotlight: Learning More About Treatment Resistance in A Highly Fatal Form of Pancreatic Cancer

William L. Hwang, MD, PhD, a physician-scientist in the Department of Radiation Oncology at Mass General, was the lead author of a recent study in Nature Genetics, Single-nucleus and Spatial Transcriptome Profiling of Pancreatic Cancer Identifies Multicellular Dynamics Associated with Neoadjuvant Treatment.

What was the question you set out to answer with this study?

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and treatment-refractory cancer. Using high-resolution single-nucleus and spatial transcriptomic approaches, we set out to identify cancer cell and fibroblast states that mediate resistance to chemotherapy and radiotherapy in pancreatic cancer and elucidate how treatment remodels the tumor microenvironment.

What are two or three key takeaways?

1) We developed a single-nucleus RNA-sequencing approach for banked frozen patient pancreatic cancer and identified a novel neural-like progenitor subtype that is associated with resistance to chemotherapy and radiotherapy, and poor clinical outcomes.

(2) Whole-transcriptome digital spatial profiling revealed three multicellular communities with distinct contributions from malignant, fibroblast, and immune subtypes: classical, squamoid-basaloid, and treatment-enriched.

(3) Spatially-defined receptor-ligand interactions, especially those that are differentially correlated between untreated and treated tumors, may functionally underpin these communities.

What were your conclusions?

Our high-resolution molecular framework sheds light on the inter- and intratumoral diversity of pancreatic cancer, spatial organization into discrete communities, treatment-associated remodeling and clinically relevant prognostication.

These findings can be harnessed to augment precision oncology efforts in pancreatic cancer.

About the Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In July 2022, Mass General was named #8 in the U.S. News & World Report list of "America’s Best Hospitals." MGH is a founding member of the Mass General Brigham healthcare system.