Marker-free lineage tracing reveals an environment-instructed clonogenic hierarchy in pancreatic cancer.

Autor:	Lodestijn SC; Amsterdam UMC, University of Amsterdam, LEXOR, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands; Oncode Institute, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands., Miedema DM; Amsterdam UMC, University of Amsterdam, LEXOR, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands; Oncode Institute, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands., Lenos KJ; Amsterdam UMC, University of Amsterdam, LEXOR, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands; Oncode Institute, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands., Nijman LE; Amsterdam UMC, University of Amsterdam, LEXOR, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands; Oncode Institute, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands., Belt SC; Amsterdam UMC, University of Amsterdam, LEXOR, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands; Oncode Institute, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands., El Makrini K; Amsterdam UMC, University of Amsterdam, LEXOR, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands; Oncode Institute, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands., Lecca MC; Amsterdam UMC, University of Amsterdam, LEXOR, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands; Oncode Institute, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands., Waasdorp C; Amsterdam UMC, University of Amsterdam, LEXOR, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands; Oncode Institute, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands., van den Bosch T; Amsterdam UMC, University of Amsterdam, LEXOR, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands; Oncode Institute, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands., Bijlsma MF; Amsterdam UMC, University of Amsterdam, LEXOR, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands; Oncode Institute, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands. Electronic address: m.f.bijlsma@amsterdamumc.nl., Vermeulen L; Amsterdam UMC, University of Amsterdam, LEXOR, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands; Oncode Institute, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands. Electronic address: l.vermeulen@amsterdamumc.nl.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2021 Oct 19; Vol. 37 (3), pp. 109852.
DOI:	10.1016/j.celrep.2021.109852
Abstrakt:	Effective treatments for pancreatic ductal adenocarcinoma (PDAC) are lacking, and targeted agents have demonstrated limited efficacy. It has been speculated that a rare population of cancer stem cells (CSCs) drives growth, therapy resistance, and rapid metastatic progression in PDAC. These CSCs demonstrate high clonogenicity in vitro and tumorigenic potential in vivo. However, their relevance in established PDAC tissue has not been determined. Here, we use marker-independent stochastic clonal labeling, combined with quantitative modeling of tumor expansion, to uncover PDAC tissue growth dynamics. We find that in contrast to the CSC model, all PDAC cells display clonogenic potential in situ. Furthermore, the proximity to activated cancer-associated fibroblasts determines tumor cell clonogenicity. This means that the microenvironment is dominant in defining the clonogenic activity of PDAC cells. Indeed, manipulating the stroma by Hedgehog pathway inhibition alters the tumor growth mode, revealing that tumor-stroma crosstalk shapes tumor growth dynamics and clonal architecture. Competing Interests: Declaration of interests M.F.B. has received research funding from Celgene and acted as a consultant to Servier. L.V. has received speaker and consultancy fees from Genentech. The remaining authors declare no competing interests in the context of this publication. (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu