Clinical, genomic, and spatial transcriptomic features of pancreatic adenosquamous carcinoma support subtype-specific therapeutic strategies

PURPOSE: Pancreatic adenosquamous carcinoma (ASQ) is a rare variant with poorly defined clinical and molecular features compared to 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 clinicopathologic features, treatment patterns, and survival of ASQ patients treated at Johns Hopkins from 2013-2023 (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 8 patients) were analyzed using Visium spatial transcriptomics with a comparator PDAC dataset (n=4). RESULTS: ASQ patients 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 (MSI-high, PD-L1+, TMB ³10 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, while 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.

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Publication Details

Journal
Clinical Cancer Research
Published
2026-08-14
DOI
https://doi.org/10.1158/1078-0432.ccr-25-2699
Primary Topic
Pancreatic and Hepatic Oncology Research
Type
article
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article

Clinical, genomic, and spatial transcriptomic features of pancreatic adenosquamous carcinoma support subtype-specific therapeutic strategies

Jerry W. Mitchell, Jae W. Lee, Ryon P. Graf, Elana J. Fertig et al.
Clinical Cancer Research
Pancreatic and Hepatic Oncology Research
article

Clinical, genomic, and spatial transcriptomic features of pancreatic adenosquamous carcinoma support subtype-specific therapeutic strategies

Jerry W. Mitchell, Jae W. Lee, Ryon P. Graf, Elana J. Fertig, Dean C. Pavlick, Daniel A. Laheru, Hassan Sinan, Richard A. Burkhart, Gerald Li, Anirban Maitra, Elizabeth M. Jaffee, Dimitrios N. Sidiropoulos, Milind M. Javle, Saurav D. Haldar, Jiayun Lu, Nilofer S. Azad, Júlia C.F. Quintanilha, Fen Saj, Elizabeth D. Thompson, Luciane T. Kagohara, Shubham Pant, Jeffrey S. Ross, Christopher Jakubowski, Hao Wang, Meredith Wetzel
article en

Abstract

PURPOSE: Pancreatic adenosquamous carcinoma (ASQ) is a rare variant with poorly defined clinical and molecular features compared to 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 clinicopathologic features, treatment patterns, and survival of ASQ patients treated at Johns Hopkins from 2013-2023 (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 8 patients) were analyzed using Visium spatial transcriptomics with a comparator PDAC dataset (n=4). RESULTS: ASQ patients 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 (MSI-high, PD-L1+, TMB ³10 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, while 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.

Clinical Cancer Research
University of Maryland, Baltimore (US), Montefiore Medical Center (US), The University of Texas MD Anderson Cancer Center (US), Johns Hopkins University (US), SUNY Upstate Medical University (US), Johns Hopkins Medicine (US), Boston Foundation (US), Johns Hopkins University Applied Physics Laboratory (US), NYU Langone Health (US), PHG Foundation (GB), Johns Hopkins Hospital (US), Veterans Medical Research Foundation of San Diego (US), Sidney Kimmel Comprehensive Cancer Center (US), University of Baltimore (US), Icahn School of Medicine at Mount Sinai (US)
No poverty
Openalex Percentile: Top 12%
Pancreatic and Hepatic Oncology Research
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