High‐resolution and quantitative spatial analysis reveal intra‐ductal phenotypic and functional diversification in pancreatic cancer
The Journal of Pathology, vol. 262, pp. 76–89
Abstract
Abstract A ‘classical’ and a ‘basal‐like’ subtype of pancreatic cancer have been reported, with differential expression of GATA6 and different dosages of mutant KRAS . We established in situ detection of KRAS point mutations and mRNA panels for the consensus subtypes aiming to project these findings to paraffin‐embedded clinical tumour samples for spatial quantitative analysis. We unveiled that, next to inter‐patient and intra‐patient inter‐ductal heterogeneity, intraductal spatial phenotypes exist with anti‐correlating expression levels of GATA6 and KRAS G12D . The basal‐like mRNA panel better captured the basal‐like cell states than widely used protein markers. The panels corroborated the co‐existence of the classical and basal‐like cell states in a single tumour duct with functional diversification, i.e. proliferation and epithelial‐to‐mesenchymal transition respectively. Mutant KRAS G12D detection ascertained an epithelial origin of vimentin‐positive cells in the tumour. Uneven spatial distribution of cancer‐associated fibroblasts could recreate similar intra‐organoid diversification. This extensive heterogeneity with functional cooperation of plastic tumour cells poses extra challenges to therapeutic approaches. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Authors 19
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Affiliation as printed
Laboratory of Medical & Molecular Oncology (LMMO) Vrije Universiteit Brussel (VUB) Brussels Belgium
Laboratory of Medical & Molecular Oncology (LMMO) Vrije Universiteit Brussel (VUB) Brussels Belgium
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Affiliation as printed
Laboratory of Medical & Molecular Oncology (LMMO) Vrije Universiteit Brussel (VUB) Brussels Belgium
Equal contibutions
Laboratory of Medical & Molecular Oncology (LMMO) Vrije Universiteit Brussel (VUB) Brussels Belgium
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Affiliation as printed
Laboratory of Medical & Molecular Oncology (LMMO) Vrije Universiteit Brussel (VUB) Brussels Belgium
Equal contibutions
Laboratory of Medical & Molecular Oncology (LMMO) Vrije Universiteit Brussel (VUB) Brussels Belgium
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Vrije Universiteit Brussel · Universitair Ziekenhuis Brussel
Affiliation as printed
Department of Surgery, Department of Gastroenterology‐Hepatology, Department of Advanced Interventional Endoscopy Universitair Ziekenhuis Brussel (UZB), Vrije Universiteit Brussel (VUB) Brussels Belgium
Department of Surgery, Department of Gastroenterology-Hepatology, Department of Advanced Interventional Endoscopy, Universitair Ziekenhuis Brussel (UZB), Vrije Universiteit Brussel (VUB), Brussels, Belgium
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Vrije Universiteit Brussel · Universitair Ziekenhuis Brussel
Affiliation as printed
Department of Surgery, Department of Gastroenterology‐Hepatology, Department of Advanced Interventional Endoscopy Universitair Ziekenhuis Brussel (UZB), Vrije Universiteit Brussel (VUB) Brussels Belgium
Department of Surgery, Department of Gastroenterology-Hepatology, Department of Advanced Interventional Endoscopy, Universitair Ziekenhuis Brussel (UZB), Vrije Universiteit Brussel (VUB), Brussels, Belgium
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Vrije Universiteit Brussel · Hasselt University
Affiliation as printed
Department of Cardio and Organ Systems, Biomedical Research Institute Hasselt University Diepenbeek Belgium
Laboratory of Medical & Molecular Oncology (LMMO) Vrije Universiteit Brussel (VUB) Brussels Belgium
Department of Cardio and Organ Systems, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
Laboratory of Medical & Molecular Oncology (LMMO) Vrije Universiteit Brussel (VUB) Brussels Belgium
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Vrije Universiteit Brussel · Universitair Ziekenhuis Brussel
Affiliation as printed
Centre for Medical Genetics, Clinical Sciences, Reproduction and Genetics Research Group Universitair Ziekenhuis Brussel (UZB), Vrije Universiteit Brussel (VUB) Brussels Belgium
Centre for Medical Genetics, Clinical Sciences, Reproduction and Genetics Research Group, Universitair Ziekenhuis Brussel (UZB), Vrije Universiteit Brussel (VUB), Brussels, Belgium
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Vrije Universiteit Brussel · Universitair Ziekenhuis Brussel
Affiliation as printed
Centre for Medical Genetics, Clinical Sciences, Reproduction and Genetics Research Group Universitair Ziekenhuis Brussel (UZB), Vrije Universiteit Brussel (VUB) Brussels Belgium
Centre for Medical Genetics, Clinical Sciences, Reproduction and Genetics Research Group, Universitair Ziekenhuis Brussel (UZB), Vrije Universiteit Brussel (VUB), Brussels, Belgium
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Universitair Ziekenhuis Brussel
Affiliation as printed
Department of Anatomo‐Pathology Universitair Ziekenhuis Brussel (UZB) Brussels Belgium
Department of Anatomo-Pathology, Universitair Ziekenhuis Brussel (UZB), Brussels, Belgium
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Centre National de la Recherche Scientifique · Inserm · Aix-Marseille Université · Centre de Recherche en Cancérologie de Marseille · Institut Paoli-Calmettes
Affiliation as printed
Cancer Research Center of Marseille (CRCM), INSERM, CNRS, Institut Paoli‐Calmettes, Aix‐Marseille Marseille University Marseille France
Cancer Research Center of Marseille (CRCM), INSERM, CNRS, Institut Paoli-Calmettes, Aix-Marseille, Marseille University, Marseille, France
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Centre National de la Recherche Scientifique · Inserm · Aix-Marseille Université · Centre de Recherche en Cancérologie de Marseille · Institut Paoli-Calmettes
Affiliation as printed
Cancer Research Center of Marseille (CRCM), INSERM, CNRS, Institut Paoli‐Calmettes, Aix‐Marseille Marseille University Marseille France
Cancer Research Center of Marseille (CRCM), INSERM, CNRS, Institut Paoli-Calmettes, Aix-Marseille, Marseille University, Marseille, France
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Centre National de la Recherche Scientifique · Inserm · Aix-Marseille Université · Centre de Recherche en Cancérologie de Marseille · Institut Paoli-Calmettes
Affiliation as printed
Cancer Research Center of Marseille (CRCM), INSERM, CNRS, Institut Paoli‐Calmettes, Aix‐Marseille Marseille University Marseille France
Cancer Research Center of Marseille (CRCM), INSERM, CNRS, Institut Paoli-Calmettes, Aix-Marseille, Marseille University, Marseille, France
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Lukas J.A.C. Hawinkels Aachen Department of Gastroenterology and Hepatology Leiden University Medical Center Leiden The Netherlands Department of Gastroenterology and Hepatology
Leiden University Medical Center
Affiliation as printed
Department of Gastroenterology and Hepatology Leiden University Medical Center (LUMC) Leiden The Netherlands
Department of Gastroenterology and Hepatology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
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Vrije Universiteit Brussel · Universitair Ziekenhuis Brussel
Affiliation as printed
Department of Surgery, Department of Gastroenterology‐Hepatology, Department of Advanced Interventional Endoscopy Universitair Ziekenhuis Brussel (UZB), Vrije Universiteit Brussel (VUB) Brussels Belgium
Department of Surgery, Department of Gastroenterology-Hepatology, Department of Advanced Interventional Endoscopy, Universitair Ziekenhuis Brussel (UZB), Vrije Universiteit Brussel (VUB), Brussels, Belgium
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Inserm · Centre de Recherche sur l'Inflammation
Affiliation as printed
Centre de Recherche sur l'inflammation (CRI) INSERM Paris France
Centre de Recherche sur l'inflammation (CRI), INSERM, Paris, France
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Université Libre de Bruxelles · Erasmus Hospital
Affiliation as printed
Department of Gastroenterology, Hepatology and Digestive Oncology, HUB Bordet Erasme Hospital Université Libre de Bruxelles Brussels Belgium
Laboratory of Experimental Gastroenterology, Faculty of Medicine Université Libre de Bruxelles (ULB) Bruxelles Belgium
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Université Libre de Bruxelles · Institut Jules Bordet
Affiliation as printed
Department of Radiation‐Oncology Université Libre de Bruxelles (ULB), Hospital Universitaire de Bruxelles (HUB) Institut Jules Bordet Brussels Belgium
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Université Libre de Bruxelles · Erasmus Hospital
Affiliation as printed
Department of Gastroenterology, Hepatology and Digestive Oncology, HUB Bordet Erasme Hospital Université Libre de Bruxelles Brussels Belgium
Laboratory of Experimental Gastroenterology, Faculty of Medicine Université Libre de Bruxelles (ULB) Bruxelles Belgium
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Ilse Rooman corresponding
Affiliation as printed
Laboratory of Medical & Molecular Oncology (LMMO) Vrije Universiteit Brussel (VUB) Brussels Belgium
Laboratory of Medical & Molecular Oncology (LMMO) Vrije Universiteit Brussel (VUB) Brussels Belgium
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