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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2021
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oai:doaj.org-article:6ac554b584fe45208d4983a549229ada2021-11-05T15:18:47ZClinical Impact of Molecular Subtyping of Pancreatic Cancer2296-634X10.3389/fcell.2021.743908https://doaj.org/article/6ac554b584fe45208d4983a549229ada2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcell.2021.743908/fullhttps://doaj.org/toc/2296-634XPancreatic 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.Zhou XuZhou XuKai HuKai HuPeter BaileyPeter BaileyPeter BaileyChristoph SpringfeldSusanne RothRoma KurilovBenedikt BrorsBenedikt BrorsThomas GressMalte BuchholzJingyu AnJingyu AnKongyuan WeiKongyuan WeiTeresa PeccerellaTeresa PeccerellaMarkus W. BüchlerThilo HackertJohn P. NeoptolemosJohn P. NeoptolemosFrontiers Media S.A.articlemolecular subtypestranscriptomesstructural variantsprecision medicinenext generation sequencingclinical trialsBiology (General)QH301-705.5ENFrontiers in Cell and Developmental Biology, Vol 9 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
molecular subtypes transcriptomes structural variants precision medicine next generation sequencing clinical trials Biology (General) QH301-705.5 |
| spellingShingle |
molecular subtypes transcriptomes structural variants precision medicine next generation sequencing clinical trials Biology (General) QH301-705.5 Zhou Xu Zhou Xu Kai Hu Kai Hu Peter Bailey Peter Bailey Peter Bailey Christoph Springfeld Susanne Roth Roma Kurilov Benedikt Brors Benedikt Brors Thomas Gress Malte Buchholz Jingyu An Jingyu An Kongyuan Wei Kongyuan Wei Teresa Peccerella Teresa Peccerella Markus W. Büchler Thilo Hackert John P. Neoptolemos John P. Neoptolemos Clinical Impact of Molecular Subtyping of Pancreatic Cancer |
| 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. |
| format |
article |
| author |
Zhou Xu Zhou Xu Kai Hu Kai Hu Peter Bailey Peter Bailey Peter Bailey Christoph Springfeld Susanne Roth Roma Kurilov Benedikt Brors Benedikt Brors Thomas Gress Malte Buchholz Jingyu An Jingyu An Kongyuan Wei Kongyuan Wei Teresa Peccerella Teresa Peccerella Markus W. Büchler Thilo Hackert John P. Neoptolemos John P. Neoptolemos |
| author_facet |
Zhou Xu Zhou Xu Kai Hu Kai Hu Peter Bailey Peter Bailey Peter Bailey Christoph Springfeld Susanne Roth Roma Kurilov Benedikt Brors Benedikt Brors Thomas Gress Malte Buchholz Jingyu An Jingyu An Kongyuan Wei Kongyuan Wei Teresa Peccerella Teresa Peccerella Markus W. Büchler Thilo Hackert John P. Neoptolemos John P. Neoptolemos |
| author_sort |
Zhou Xu |
| title |
Clinical Impact of Molecular Subtyping of Pancreatic Cancer |
| title_short |
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_sort |
clinical impact of molecular subtyping of pancreatic cancer |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/6ac554b584fe45208d4983a549229ada |
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