Stabilization of the classical phenotype upon integration of pancreatic cancer cells into the duodenal epithelium

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid tumors. Based on transcriptomic classifiers, basal-like and classical PDAC subtypes have been defined that differ in prognosis. Cells of both subtypes can coexist in individual tumors; however, the contribution...

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Autores principales:	Benedek Bozóky, Carlos Fernández Moro, Carina Strell, Natalie Geyer, Rainer L. Heuchel, J. Matthias Löhr, Ingemar Ernberg, Laszlo Szekely, Marco Gerling, Béla Bozóky
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Pancreatic cancer Transcriptome subtypes Tumor microenvironment Local invasion Intestinal mimicry Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/91e8e2b3c7e24a6e950edafe3ff950a1
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spelling	oai:doaj.org-article:91e8e2b3c7e24a6e950edafe3ff950a12021-11-30T04:14:41ZStabilization of the classical phenotype upon integration of pancreatic cancer cells into the duodenal epithelium1476-558610.1016/j.neo.2021.11.007https://doaj.org/article/91e8e2b3c7e24a6e950edafe3ff950a12021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S147655862100097Xhttps://doaj.org/toc/1476-5586Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid tumors. Based on transcriptomic classifiers, basal-like and classical PDAC subtypes have been defined that differ in prognosis. Cells of both subtypes can coexist in individual tumors; however, the contribution of either clonal heterogeneity or microenvironmental cues to subtype heterogeneity is unclear. Here, we report the spatial tumor phenotype dynamics in a cohort of patients in whom PDAC infiltrated the duodenal wall, and identify the duodenal epithelium as a distinct PDAC microniche. Materials and methods: We used serial multiplex quantitative immunohistochemistry (smq-IHC) for 24 proteins to phenotypically chart PDAC tumor cells in patients whose tumors infiltrated the duodenal epithelium. Additionally, we used a genetically engineered mouse model to study the PDAC cell phenotype in the small intestinal epithelium in a controlled genetic background. Result: We show that pancreatic cancer cells revert to non-destructive growth upon integration into the duodenal epithelium, where they adopt traits of intestinal cell differentiation, associated with phenotypical stabilization of the classical subtype. The integrated tumor cells replace epithelial cells in an adenoma-like manner, as opposed to invasive growth in the submucosa. Finally, we show that this phenomenon is shared between species, by confirming duodenal integration and phenotypic switching in a genetic PDAC mouse model. Discussion: Our results identify the duodenal epithelium as a distinct PDAC microniche and tightly link microenvironmental cue to cancer transcriptional subtypes. The phenomenon of “intestinal mimicry” provides a unique opportunity for the systematic investigation of microenvironmental influences on pancreatic cancer plasticity.Benedek BozókyCarlos Fernández MoroCarina StrellNatalie GeyerRainer L. HeuchelJ. Matthias LöhrIngemar ErnbergLaszlo SzekelyMarco GerlingBéla BozókyElsevierarticlePancreatic cancerTranscriptome subtypesTumor microenvironmentLocal invasionIntestinal mimicryNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENNeoplasia: An International Journal for Oncology Research, Vol 23, Iss 12, Pp 1300-1306 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Pancreatic cancer Transcriptome subtypes Tumor microenvironment Local invasion Intestinal mimicry Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Pancreatic cancer Transcriptome subtypes Tumor microenvironment Local invasion Intestinal mimicry Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Benedek Bozóky Carlos Fernández Moro Carina Strell Natalie Geyer Rainer L. Heuchel J. Matthias Löhr Ingemar Ernberg Laszlo Szekely Marco Gerling Béla Bozóky Stabilization of the classical phenotype upon integration of pancreatic cancer cells into the duodenal epithelium
description	Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid tumors. Based on transcriptomic classifiers, basal-like and classical PDAC subtypes have been defined that differ in prognosis. Cells of both subtypes can coexist in individual tumors; however, the contribution of either clonal heterogeneity or microenvironmental cues to subtype heterogeneity is unclear. Here, we report the spatial tumor phenotype dynamics in a cohort of patients in whom PDAC infiltrated the duodenal wall, and identify the duodenal epithelium as a distinct PDAC microniche. Materials and methods: We used serial multiplex quantitative immunohistochemistry (smq-IHC) for 24 proteins to phenotypically chart PDAC tumor cells in patients whose tumors infiltrated the duodenal epithelium. Additionally, we used a genetically engineered mouse model to study the PDAC cell phenotype in the small intestinal epithelium in a controlled genetic background. Result: We show that pancreatic cancer cells revert to non-destructive growth upon integration into the duodenal epithelium, where they adopt traits of intestinal cell differentiation, associated with phenotypical stabilization of the classical subtype. The integrated tumor cells replace epithelial cells in an adenoma-like manner, as opposed to invasive growth in the submucosa. Finally, we show that this phenomenon is shared between species, by confirming duodenal integration and phenotypic switching in a genetic PDAC mouse model. Discussion: Our results identify the duodenal epithelium as a distinct PDAC microniche and tightly link microenvironmental cue to cancer transcriptional subtypes. The phenomenon of “intestinal mimicry” provides a unique opportunity for the systematic investigation of microenvironmental influences on pancreatic cancer plasticity.
format	article
author	Benedek Bozóky Carlos Fernández Moro Carina Strell Natalie Geyer Rainer L. Heuchel J. Matthias Löhr Ingemar Ernberg Laszlo Szekely Marco Gerling Béla Bozóky
author_facet	Benedek Bozóky Carlos Fernández Moro Carina Strell Natalie Geyer Rainer L. Heuchel J. Matthias Löhr Ingemar Ernberg Laszlo Szekely Marco Gerling Béla Bozóky
author_sort	Benedek Bozóky
title	Stabilization of the classical phenotype upon integration of pancreatic cancer cells into the duodenal epithelium
title_short	Stabilization of the classical phenotype upon integration of pancreatic cancer cells into the duodenal epithelium
title_full	Stabilization of the classical phenotype upon integration of pancreatic cancer cells into the duodenal epithelium
title_fullStr	Stabilization of the classical phenotype upon integration of pancreatic cancer cells into the duodenal epithelium
title_full_unstemmed	Stabilization of the classical phenotype upon integration of pancreatic cancer cells into the duodenal epithelium
title_sort	stabilization of the classical phenotype upon integration of pancreatic cancer cells into the duodenal epithelium
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/91e8e2b3c7e24a6e950edafe3ff950a1
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Stabilization of the classical phenotype upon integration of pancreatic cancer cells into the duodenal epithelium

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