Abstract
Multicellular dynamics, including neoadjuvant treatment–associated changes, were uncovered in PDAC.
Major Finding: Multicellular dynamics, including neoadjuvant treatment–associated changes, were uncovered in PDAC.
Approach: Single-nucleus RNA sequencing and whole-transcriptome spatial profiling were performed on differentially treated frozen tumors.
Impact: This refined molecular taxonomy can improve therapeutic targeting in this treatment-refractory disease.
Two subtypes of pancreatic ductal adenocarcinoma (PDAC), classical and basal, have been defined by bulk RNA profiling; however, additional subtypes that reflect features of the tumor microenvironment and their association with patient outcomes remains limited. Using single-nucleus RNA sequencing (snRNAseq) and spatial transcriptomics on 43 frozen primary PDAC tumors from either treatment-naïve or neoadjuvant therapy–treated patients, Hwang, Jagadeesh, Guo, Hoffman, and colleagues constructed a high-resolution molecular landscape of cellular subtypes and spatial communities that exist within PDAC and defined 14 malignant cell programs and four cancer-associated fibroblast (CAF) programs. Evaluation of the CAF programs revealed overlap of the neurotropic, immunomodulatory, and adhesive programs with the inflammatory CAF (iCAF) signature but not the myofibroblast CAF signature, suggesting they represent iCAF subsets with specific gene enrichment patterns that reflect the annotated phenotype. Further refinement of the malignant cell classification revealed three programs that correspond to squamoid, basaloid, and mesenchymal states as well as acinar-like and neuroendocrine-like programs that were ascribed to nonmalignant cells in previous studies. Additionally, a neural-like progenitor (NRP) malignant cell program was discovered, featuring pathways and genes involved in neuronal development/migration that was significantly enriched in the surviving cancer cells after chemo- and radiotherapy. Investigation into a relationship between expression of these programs and clinical response demonstrated that the NRP and squamoid programs were associated with reduced time to progression (TTP), while the immunomodulatory program increased the TTP. Furthermore, spatial organization of these multicellular communities led to the definition of three multicellular communities, which included treatment-enriched, squamoid–basaloid, and classical. Overall, this study uncovered a high-resolution molecular and cellular classification of PDAC tumor composition and supports that treatment-associated enrichment of specific intercellular interactions can provide clues into mechanisms of therapeutic resistance that may be harnessed to guide more effective therapeutic strategies.
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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