Stromal-derived interleukin 6 drives epithelial-to-mesenchymal transition and therapy resistance in esophageal adenocarcinoma

The tissue dynamics that govern maintenance and regeneration of the pancreas remain largely unknown. In particular, the presence and nature of a cellular hierarchy remains a topic of debate. Previous lineage tracing strategies in the pancreas relied on specific marker genes for clonal labeling, which left other populations untested and failed to account for potential widespread phenotypical plasticity. Here we employed a tracing system that depends on replication-induced clonal marks. We found that, in homeostasis, steady acinar replacement events characterize tissue dynamics, to which all acinar cells have an equal ability to contribute. Similarly, regeneration following pancreatitis was best characterized by an acinar self-replication model because no evidence of a cellular hierarchy was detected. In particular, rapid regeneration in the pancreas was found to be driven by an accelerated rate of acinar fission-like events. These results provide a comprehensive and quantitative model of cell dynamics in the exocrine pancreas.

Authors

Eva A. Ebbing, Amber P. van der Zalm, Anne Steins, Aafke Creemers, Simone Hermsen, Rosa Rentenaar, Michelle Klein, Cynthia Waasdorp, Gerrit K. J. Hooijer, Sybren L. Meijer, Kausilia K. Krishnadath, Cornelis J.A. Punt, Mark I. van Berge Henegouwen, Suzanne S. Gisbertz, Otto M. van Delden, Maarten C. C. M. Hulshof, Jan Paul Medema, Hanneke W. M. van Laarhoven and Maarten F. Bijlsma.

Link

https://doi.org/10.1073/pnas.1820459116

Microdissected pancreatic cancer proteomes reveal tumor heterogeneity and therapeutic targets

The tissue dynamics that govern maintenance and regeneration of the pancreas remain largely unknown. In particular, the presence and nature of a cellular hierarchy remains a topic of debate. Previous lineage tracing strategies in the pancreas relied on specific marker genes for clonal labeling, which left other populations untested and failed to account for potential widespread phenotypical plasticity. Here we employed a tracing system that depends on replication-induced clonal marks. We found that, in homeostasis, steady acinar replacement events characterize tissue dynamics, to which all acinar cells have an equal ability to contribute. Similarly, regeneration following pancreatitis was best characterized by an acinar self-replication model because no evidence of a cellular hierarchy was detected. In particular, rapid regeneration in the pancreas was found to be driven by an accelerated rate of acinar fission-like events. These results provide a comprehensive and quantitative model of cell dynamics in the exocrine pancreas.

Authors

Tessa Y.S. Le Large, Giulia Mantini, Laura L. Meijer, Thang V. Pham, Niccola Funel, Nicole C.T. van Grieken, Bart Kok, Jaco Knol, Hanneke W.M. van Laarhoven, Sander R. Piersma, Connie R. Jimenez, G. Kazemier, Elisa Giovannetti, and Maarten F. Bijlsma

Link

https://doi.org/10.1172/jci.insight.138290

Continuous clonal labeling reveals uniform progenitor potential in the adult exocrine pancreas

The tissue dynamics that govern maintenance and regeneration of the pancreas remain largely unknown. In particular, the presence and nature of a cellular hierarchy remains a topic of debate. Previous lineage tracing strategies in the pancreas relied on specific marker genes for clonal labeling, which left other populations untested and failed to account for potential widespread phenotypical plasticity. Here we employed a tracing system that depends on replication-induced clonal marks. We found that, in homeostasis, steady acinar replacement events characterize tissue dynamics, to which all acinar cells have an equal ability to contribute. Similarly, regeneration following pancreatitis was best characterized by an acinar self-replication model because no evidence of a cellular hierarchy was detected. In particular, rapid regeneration in the pancreas was found to be driven by an accelerated rate of acinar fission-like events. These results provide a comprehensive and quantitative model of cell dynamics in the exocrine pancreas.

Authors

Sophie C Lodestijn,¬†Tom van den Bosch,¬†Lisanne E Nijman,¬†Leandro F Moreno,¬†Sophie Schlingemann,¬†Vivek M Sheraton,¬†Sanne M van Neerven,¬†Jasper J Koning,¬†Felipe A Vieira Braga,¬†Nanne J Paauw,¬†Maria C Lecca,¬†Kristiaan J Lenos,¬†Edward Morrissey,¬†Dani√ęl M Miedema,¬†Douglas J Winton,¬†Maarten F Bijlsma,¬†Louis Vermeulen

Link

https://doi.org/10.1016/j.stem.2021.07.004

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

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.

Authors

Sophie C Lodestijn¬†,¬†Dani√ęl 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.

Link

https://doi.org/10.1016/j.celrep.2021.109852

Estrogen-related receptor alpha drives mitochondrial biogenesis and resistance to neoadjuvant chemoradiation in esophageal cancer

Neoadjuvant chemoradiotherapy (nCRT) improves outcomes in resectable esophageal adenocarcinoma (EAC), but acquired resistance precludes long-term efficacy. Here, we delineate these resistance mechanisms. RNA sequencing on matched patient samples obtained pre-and post-neoadjuvant treatment reveal that oxidative phosphorylation was the most upregulated of all biological programs following nCRT. Analysis of patient-derived models confirms that mitochondrial content and oxygen consumption strongly increase in response to nCRT and that ionizing radiation is the causative agent. Bioinformatics identifies estrogen-related receptor alpha (ESRRA) as the transcription factor responsible for reprogramming, and overexpression and silencing of ESRRA functionally confirm that its downstream metabolic rewiring contributes to resistance. Pharmacological inhibition of ESRRA successfully sensitizes EAC organoids and patient-derived xenografts to radiation. In conclusion, we report a profound metabolic rewiring following chemoradiation and demonstrate that its inhibition resensitizes EAC cells to radiation. These findings hold broader relevance for other cancer types treated with radiation as well.

Authors

Mark P.G. Dings, Amber P. van der Zalm, Sanne Bootsma, Tatum F.J. van Maanen, Cynthia Waasrop, Tom van den Ende, Daija Liu, Peter Bailey, Jan Koster, Danny A. Zwijnenburg, C. Arnold Spek, Jan P.G. Klomp, Arthur Oubrie, Gerrit K.J. Hooijer, Sybren L. Meijer, Mark I. van Berge Henegouwen, Maarten C. Hulshof, Jacques Bergman, Cesar Oyarce, Jan Paul Medema, Hanneke W.M. van Laarhoven, Maarten F. Bijlsma.

Link

https://doi.org/10.1016/j.xcrm.2022.100802