Marker-free lineage tracing reveals an environment-instructed clonogenic hierarchy in pancreatic cancer
Sophie C. Lodestijn,
Daniël M. Miedema,
Kristiaan J. Lenos,
Lisanne E. Nijman,
Saskia C. Belt,
Khalid El Makrini,
Maria C. Lecca,
Cynthia Waasdorp,
Tom van den Bosch,
Maarten F. Bijlsma,
Louis Vermeulen
Affiliations
Sophie C. Lodestijn
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
Daniël M. Miedema
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
Kristiaan J. Lenos
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
Lisanne E. Nijman
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
Saskia C. Belt
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
Khalid El Makrini
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
Maria C. Lecca
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
Cynthia Waasdorp
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
Tom van den Bosch
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
Maarten F. Bijlsma
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; Corresponding author
Louis Vermeulen
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; Corresponding author
Summary: 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.
