GATA6 and CK5 Stratify the Survival of Patients With Pancreatic Cancer Undergoing Neoadjuvant Chemotherapy

Kokumai, Takashi; Omori, Yuko; Ishida, Masaharu; Ohtsuka, Hideo; Mizuma, Masamichi; Nakagawa, Kei; Maeda, Chiho; Ono, Yoshio; Mizukami, Yusuke; Miura, Shin; Kume, Kiyoshi; Masamune, Atsushi; Morikawa, Takanori; Unno, Michiaki; Furukawa, Toru

doi:10.1016/j.modpat.2023.100102

Cited by 8 publications

(9 citation statements)

References 38 publications

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“…Independent studies have shown that a limited number of markers can approximate subtype identity on a single-cell level in situ 24,25 . Here, we used multiplex IHC with a panel of six markers, two classical (caudal type homeobox 2 [CDX2], mucin 5 subtypes A and C [MUC5AC]), and four basal markers (Cytokeratin (CK)5, high mobility group AT-hook 2 [HMGA2], Carbohydrate antigen (CA)125/MUC16, and CK17) to approximate subtype identity of tumor in_lobules and tumor in_stroma ( Figure 2a ).…”

Section: Resultsmentioning

confidence: 99%

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A distinctive tumor compartment in pancreatic lobules defined by nascent stroma and classical tumor cell phenotype

Söderqvist,

Viljamaa,

Geyer

et al. 2024

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor type characterized by a particularly extensive stroma. While different types of cancer-associated fibroblasts (CAFs) in this desmoplastic stroma have been described, areas of early invasion and nascent stroma are understudied. Here, we identify a distinctive PDAC niche within the pancreatic lobules, a compartment dominated by pancreatic exocrine cells and slender stroma. Cellular interaction profiling using machine learning on whole slide images of human PDAC reveals that the tumor invasion front in the lobules is dominated by specific interactions of tumor cells and exocrine cells that have undergone acinar-to-ductal metaplasia (ADM). Multiplex protein and mRNA stains confirm that tumor growth in the lobules is closely linked to ADM in the lobules, and reveal stromal protein gradients from the gracile lobular stroma to the characteristic desmoplastic stroma. We identify nascent CAFs (nCAFs), co-expressing expressing nerve growth factor receptor (NGFR) and platelet-derived growth factor receptor alpha (PDGFRa) that are absent in the mature, desmoplastic stroma. Lobular invasion and nCAFs are intertwined with phenotypic changes of the cancer cells, such that tumor cells in lobules express classical subtype markers, while those embedded in the desmoplastic are on the basal end of the phenotypic continuum. In mice, the PDAC subtype – basal or classical – similarly depends on tissue location, suggesting microenvironmental factors rather than clonal selection as important drivers of tumor phenotype identity. Clinically, our results mandate factoring in tumor tissue location when calling PDAC subtypes. Biologically, they identify pancreatic lobules as a distinctive tissue niche associated with nascent stroma, and they suggest that lobular colonization by tumor cells is a significant route of PDAC progression.

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Section: Resultsmentioning

confidence: 99%

Section: The Classical Pdac Cell Subtype Dominates In Pancreatic Lobulesmentioning

confidence: 99%

A distinctive tumor compartment in pancreatic lobules defined by nascent stroma and classical tumor cell phenotype

Söderqvist,

Viljamaa,

Geyer

et al. 2024

Preprint

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“…indicating that molecular PDAC subtypes could differentiate patient survival following neoadjuvant chemotherapy rather than chemoradiotherapy. 32 …”

Section: Discussionmentioning

confidence: 99%

GATA6 identifies an immune-enriched phenotype linked to favorable outcomes in patients with pancreatic cancer undergoing upfront surgery

van Eijck,

Real,

Malats

et al. 2024

Cell Reports Medicine

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“…Phenotype classification by RNA signatures may not be clinically relevant because of the high cost and difficulty in analyzing heterogeneous tumors. However, immunohistochemical analysis has several advantages in overcoming this issue; GATA6, CK5, and Vimentin may serve as relevant markers for defining the differential expression profile of heterogeneous tumors [ 64 ]. Like GATA6, GATA4 maintains the classical phenotype in cooperation with GATA6 [ 65 ].…”

Section: Precancerous Lesions and Gene Alterationsmentioning

confidence: 99%

Current status of molecular diagnostic approaches using liquid biopsy

et al. 2023

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers, and developing an efficient and reliable approach for its early-stage diagnosis is urgently needed. Precancerous lesions of PDAC, such as pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasms (IPMN), arise through multiple steps of driver gene alterations in KRAS, TP53, CDKN2A, SMAD4, or GNAS. Hallmark mutations play a role in tumor initiation and progression, and their detection in bodily fluids is crucial for diagnosis. Recently, liquid biopsy has gained attention as an approach to complement pathological diagnosis, and in addition to mutation signatures in cell-free DNA, cell-free RNA, and extracellular vesicles have been investigated as potential diagnostic and prognostic markers. Integrating such molecular information to revise the diagnostic criteria for pancreatic cancer can enable a better understanding of the pathogenesis underlying inter-patient heterogeneity, such as sensitivity to chemotherapy and disease outcomes. This review discusses the current diagnostic approaches and clinical applications of genetic analysis in pancreatic cancer and diagnostic attempts by liquid biopsy and molecular analyses using pancreatic juice, duodenal fluid, and blood samples. Emerging knowledge in the rapidly advancing liquid biopsy field is promising for molecular profiling and diagnosing pancreatic diseases with significant diversity.

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GATA6 and CK5 Stratify the Survival of Patients With Pancreatic Cancer Undergoing Neoadjuvant Chemotherapy

Cited by 8 publications

References 38 publications

A distinctive tumor compartment in pancreatic lobules defined by nascent stroma and classical tumor cell phenotype

A distinctive tumor compartment in pancreatic lobules defined by nascent stroma and classical tumor cell phenotype

GATA6 identifies an immune-enriched phenotype linked to favorable outcomes in patients with pancreatic cancer undergoing upfront surgery

Current status of molecular diagnostic approaches using liquid biopsy

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