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Clinical Impact of Molecular Subtyping of Pancreatic Cancer

Pancreatic ductal adenocarcinoma is a highly lethal malignancy, which has now become the seventh most common cause of cancer death in the world, with the highest mortality rates in Europe and North America. In the past 30 years, there has been some progress in 5-year survival (rates increasing from...

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Autores principales: Zhou, Xu, Hu, Kai, Bailey, Peter, Springfeld, Christoph, Roth, Susanne, Kurilov, Roma, Brors, Benedikt, Gress, Thomas, Buchholz, Malte, An, Jingyu, Wei, Kongyuan, Peccerella, Teresa, Büchler, Markus W., Hackert, Thilo, Neoptolemos, John P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8603393/
https://www.ncbi.nlm.nih.gov/pubmed/34805152
http://dx.doi.org/10.3389/fcell.2021.743908
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author Zhou, Xu
Hu, Kai
Bailey, Peter
Springfeld, Christoph
Roth, Susanne
Kurilov, Roma
Brors, Benedikt
Gress, Thomas
Buchholz, Malte
An, Jingyu
Wei, Kongyuan
Peccerella, Teresa
Büchler, Markus W.
Hackert, Thilo
Neoptolemos, John P.
author_facet Zhou, Xu
Hu, Kai
Bailey, Peter
Springfeld, Christoph
Roth, Susanne
Kurilov, Roma
Brors, Benedikt
Gress, Thomas
Buchholz, Malte
An, Jingyu
Wei, Kongyuan
Peccerella, Teresa
Büchler, Markus W.
Hackert, Thilo
Neoptolemos, John P.
author_sort Zhou, Xu
collection PubMed
description Pancreatic ductal adenocarcinoma is a highly lethal malignancy, which has now become the seventh most common cause of cancer death in the world, with the highest mortality rates in Europe and North America. In the past 30 years, there has been some progress in 5-year survival (rates increasing from 2.5 to 10%), but this is still extremely poor compared to all other common cancer types. Targeted therapies for advanced pancreatic cancer based on actionable mutations have been disappointing, with only 3–5% showing even a short clinical benefit. There is, however, a molecular diversity beyond mutations in genes responsible for producing classical canonical signaling pathways. Pancreatic cancer is almost unique in promoting an excess production of other components of the stroma, resulting in a complex tumor microenvironment that contributes to tumor development, progression, and response to treatment. Various transcriptional subtypes have also been described. Most notably, there is a strong alignment between the Classical/Pancreatic progenitor and Quasi-mesenchymal/Basal-like/Squamous subtype signatures of Moffit, Collinson, Bailey, Puleo, and Chan-Seng-Yue, which have potential clinical impact. Sequencing of epithelial cell populations enriched by laser capture microscopy combined with single-cell RNA sequencing has revealed the potential genomic evolution of pancreatic cancer as being a consequence of a gene expression continuum from mixed Basal-like and Classical cell populations within the same tumor, linked to allelic imbalances in mutant KRAS, with metastatic tumors being more copy number-unstable compared to primary tumors. The Basal-like subtype appears more chemoresistant with reduced survival compared to the Classical subtype. Chemotherapy and/or chemoradiation will also enrich the Basal-like subtype. Squamous/Basal-like programs facilitate immune infiltration compared with the Classical-like programs. The immune infiltrates associated with Basal and Classical type cells are distinct, potentially opening the door to differential strategies. Single-cell and spatial transcriptomics will now allow single cell profiling of tumor and resident immune cell populations that may further advance subtyping. Multiple clinical trials have been launched based on transcriptomic response signatures and molecular subtyping including COMPASS, Precision Promise, ESPAC6/7, PREDICT-PACA, and PASS1. We review several approaches to explore the clinical relevance of molecular profiling to provide optimal bench-to-beside translation with clinical impact.
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spelling pubmed-86033932021-11-20 Clinical Impact of Molecular Subtyping of Pancreatic Cancer Zhou, Xu Hu, Kai Bailey, Peter Springfeld, Christoph Roth, Susanne Kurilov, Roma Brors, Benedikt Gress, Thomas Buchholz, Malte An, Jingyu Wei, Kongyuan Peccerella, Teresa Büchler, Markus W. Hackert, Thilo Neoptolemos, John P. Front Cell Dev Biol Cell and Developmental Biology Pancreatic ductal adenocarcinoma is a highly lethal malignancy, which has now become the seventh most common cause of cancer death in the world, with the highest mortality rates in Europe and North America. In the past 30 years, there has been some progress in 5-year survival (rates increasing from 2.5 to 10%), but this is still extremely poor compared to all other common cancer types. Targeted therapies for advanced pancreatic cancer based on actionable mutations have been disappointing, with only 3–5% showing even a short clinical benefit. There is, however, a molecular diversity beyond mutations in genes responsible for producing classical canonical signaling pathways. Pancreatic cancer is almost unique in promoting an excess production of other components of the stroma, resulting in a complex tumor microenvironment that contributes to tumor development, progression, and response to treatment. Various transcriptional subtypes have also been described. Most notably, there is a strong alignment between the Classical/Pancreatic progenitor and Quasi-mesenchymal/Basal-like/Squamous subtype signatures of Moffit, Collinson, Bailey, Puleo, and Chan-Seng-Yue, which have potential clinical impact. Sequencing of epithelial cell populations enriched by laser capture microscopy combined with single-cell RNA sequencing has revealed the potential genomic evolution of pancreatic cancer as being a consequence of a gene expression continuum from mixed Basal-like and Classical cell populations within the same tumor, linked to allelic imbalances in mutant KRAS, with metastatic tumors being more copy number-unstable compared to primary tumors. The Basal-like subtype appears more chemoresistant with reduced survival compared to the Classical subtype. Chemotherapy and/or chemoradiation will also enrich the Basal-like subtype. Squamous/Basal-like programs facilitate immune infiltration compared with the Classical-like programs. The immune infiltrates associated with Basal and Classical type cells are distinct, potentially opening the door to differential strategies. Single-cell and spatial transcriptomics will now allow single cell profiling of tumor and resident immune cell populations that may further advance subtyping. Multiple clinical trials have been launched based on transcriptomic response signatures and molecular subtyping including COMPASS, Precision Promise, ESPAC6/7, PREDICT-PACA, and PASS1. We review several approaches to explore the clinical relevance of molecular profiling to provide optimal bench-to-beside translation with clinical impact. Frontiers Media S.A. 2021-11-05 /pmc/articles/PMC8603393/ /pubmed/34805152 http://dx.doi.org/10.3389/fcell.2021.743908 Text en Copyright © 2021 Zhou, Hu, Bailey, Springfeld, Roth, Kurilov, Brors, Gress, Buchholz, An, Wei, Peccerella, Büchler, Hackert and Neoptolemos. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Zhou, Xu
Hu, Kai
Bailey, Peter
Springfeld, Christoph
Roth, Susanne
Kurilov, Roma
Brors, Benedikt
Gress, Thomas
Buchholz, Malte
An, Jingyu
Wei, Kongyuan
Peccerella, Teresa
Büchler, Markus W.
Hackert, Thilo
Neoptolemos, John P.
Clinical Impact of Molecular Subtyping of Pancreatic Cancer
title Clinical Impact of Molecular Subtyping of Pancreatic Cancer
title_full Clinical Impact of Molecular Subtyping of Pancreatic Cancer
title_fullStr Clinical Impact of Molecular Subtyping of Pancreatic Cancer
title_full_unstemmed Clinical Impact of Molecular Subtyping of Pancreatic Cancer
title_short Clinical Impact of Molecular Subtyping of Pancreatic Cancer
title_sort clinical impact of molecular subtyping of pancreatic cancer
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8603393/
https://www.ncbi.nlm.nih.gov/pubmed/34805152
http://dx.doi.org/10.3389/fcell.2021.743908
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