Table 2.

Molecular subtyping of pancreatic cancer

Study	Histopathology and methodology	Subtypes	Biological insight	Clinical relevance
Moffitt et al.67	(n = 206; 145 primary PDAC and 61 metastatic PDAC) mRNA expression microarray (n = 206; 134 normal sites) and RNAseq in 15 primary samples, 37 PDXs, 3 cell lines, and 6 CAFs	Epithelial: Basal-like Classical Stromal: Activated Normal	•Different stromal subtypes may explain differences in stromal therapy observed in preclinical models •Metastases retain subtype signature •Basal-like subtype in majority of metastases •Lung metastases associated with classical subtype	•Poor survival in basal-like subtype and activated stroma in classical subtype •Basal-like subtype benefits from adjuvant chemotherapy •Stroma-targeted therapies might need to be subtype directed
Collisson et al.65	n = 85 primary untreated PDAC Microdissected (n = 27), whole PDAC (n = 39), and PDCLs (n = 19) Non-negative matrix factorization and consensus clustering	Classical Quasi-mesenchymal Exocrine-like	•Absence of exocrine-like subtype in ATCC PDAC cell lines •Subtype-specific function for GATA6 and KRAS addiction in classical subtype	•Poor survival for quasi-mesenchymal subtype, better for classical subtype •Quasi-mesenchymal subtype more sensitive to gemcitabine •Classical subtype •More sensitive to erlotinib
Bailey et al.54	n = 266 primary untreated PDAC Consensus clustering to subtypes according to signatures defined by Moffitt et al.67 and Collisson et al.65 RNAseq (n = 96) and expression array (n = 266)	Squamous Immunogenic Pancreatic progenitor ADEX	•Squamous subtype enriched for inflammation, metabolic reprogramming, cell proliferation, and epigenetic downregulation of endodermal genes •Squamous and immunogenic subtypes enriched for immune signalling including macrophages and T-cell subpopulations, respectively •Squamous subtype associated with adenosquamous histology; pancreatic progenitor associated with colloid and IPMN	•Poor survival in squamous subtype •Subtype-specific therapeutic targets including metabolic and cell cycle inhibitors and immunomodulation •Myeloid depletion in squamous subtype and immune evasion in immunogenic subtype

ADEX: aberrantly differentiated endocrine exocrine; ATCC: American Type Culture Collection; CAF: cancer-associated fibroblast; IPMN: intraductal papillary mucinous neoplasm; PDAC: pancreatic ductal adenocarcinoma; PDCL: patient-derived cell line; PDX: patient-derived xenograft; RNAseq: RNA sequencing; TCGA: The Cancer Genome Atlas.

Adapted from Collisson EA, Bailey P, Chang DK, Biankin AV. Molecular subtypes of pancreatic cancer. Nat Rev Gastroenterol Hepatol 2019; 16: 207-220,⁶⁴ with permission from Springer Nature Limited. Copyright © 2019.