Clinical cancer research : an official journal of the American Association for Cancer Research · 2026
Clinical, Genomic, and Spatial Transcriptomic Features of Pancreatic Adenosquamous Carcinoma Support Subtype-Specific Therapeutic Strategies.
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Haldar S Daniel, Wetzel Meredith, Lu Jiayun, Lee Jae W, Sinan Hassan, Jakubowski Christopher D, Saj Fen, Pavlick Dean, Graf Ryon P, Quintanilha Julia, Li Gerald, Mitchell Jerry, Ross Jeffrey S, Maitra Anirban, Javle Milind, Pant Shubham, Wang Hao, Burkhart Richard, Laheru Daniel A, Jaffee Elizabeth M, Fertig Elana J, Thompson Elizabeth D, Sidiropoulos Dimitrios N, Kagohara Luciane T, Azad Nilofer S
Аннотация
PURPOSE: Pancreatic adenosquamous carcinoma (ASQ) is a rare variant with poorly defined clinical and molecular features compared with conventional pancreatic ductal adenocarcinoma (PDAC). This study aimed to characterize the clinical outcomes, genomic landscape, and spatial transcriptomic architecture of ASQ.
EXPERIMENTAL DESIGN: We retrospectively evaluated the clinicopathologic features, treatment patterns, and survival of patients with ASQ treated at Johns Hopkins from 2013 to 2023 (n = 178). Genomic landscapes of ASQ (n = 244) versus PDAC (n = 29,021) were compared using the FoundationCore database. Surgically resected ASQ tumors (n = 11 from eight patients) were analyzed using Visium spatial transcriptomics with a comparator PDAC dataset (n = 4).
RESULTS: Patients with ASQ had poor outcomes in both resected and advanced disease. FoundationCore analysis revealed similar KRAS mutation frequency, higher MTAP loss, and enrichment of low-frequency immune biomarkers (microsatellite instability-high, PD-L1+, TMB ≥10 muts/Mb) in ASQ compared with PDAC. Spatial transcriptomics revealed broadly similar immune cell proportions across subtypes, with higher regulatory T-cell abundance observed in ASQ in the context of sparse detection in PDAC. Differences in spatial co-localization patterns of immune populations were observed between ASQ and PDAC, whereas distance analyses within ASQ showed immune infiltrates closest to squamous regions and farthest from glandular regions. Furthermore, ASQ showed increased squamous/basal lineage expression compared with PDAC, with intratumoral squamous regions enriched for epithelial-mesenchymal transition, apical junction, inflammatory, and stress response pathways relative to the glandular niche.
CONCLUSIONS: Despite shared genomic drivers with PDAC, ASQ exhibits transcriptionally distinct features with spatially organized tumor and immune heterogeneity, supporting the need for subtype-specific therapeutic strategies.
EXPERIMENTAL DESIGN: We retrospectively evaluated the clinicopathologic features, treatment patterns, and survival of patients with ASQ treated at Johns Hopkins from 2013 to 2023 (n = 178). Genomic landscapes of ASQ (n = 244) versus PDAC (n = 29,021) were compared using the FoundationCore database. Surgically resected ASQ tumors (n = 11 from eight patients) were analyzed using Visium spatial transcriptomics with a comparator PDAC dataset (n = 4).
RESULTS: Patients with ASQ had poor outcomes in both resected and advanced disease. FoundationCore analysis revealed similar KRAS mutation frequency, higher MTAP loss, and enrichment of low-frequency immune biomarkers (microsatellite instability-high, PD-L1+, TMB ≥10 muts/Mb) in ASQ compared with PDAC. Spatial transcriptomics revealed broadly similar immune cell proportions across subtypes, with higher regulatory T-cell abundance observed in ASQ in the context of sparse detection in PDAC. Differences in spatial co-localization patterns of immune populations were observed between ASQ and PDAC, whereas distance analyses within ASQ showed immune infiltrates closest to squamous regions and farthest from glandular regions. Furthermore, ASQ showed increased squamous/basal lineage expression compared with PDAC, with intratumoral squamous regions enriched for epithelial-mesenchymal transition, apical junction, inflammatory, and stress response pathways relative to the glandular niche.
CONCLUSIONS: Despite shared genomic drivers with PDAC, ASQ exhibits transcriptionally distinct features with spatially organized tumor and immune heterogeneity, supporting the need for subtype-specific therapeutic strategies.