PMID- 34805152 OWN - NLM STAT- PubMed-not-MEDLINE VI - 9 TI - Clinical Impact of Molecular Subtyping of Pancreatic Cancer. PG - 743908 CI - Copyright © 2021 Xu, Hu, Bailey, Springfeld, Roth, Kurilov, Brors, Gress, Buchholz, An, Wei, Peccerella, Büchler, Hackert and Neoptolemos. LA - eng PT - Journal Article PT - Review PL - Switzerland TA - Front Cell Dev Biol JT - Frontiers in cell and developmental biology JID - 101630250 IS - 2296-634X (Print) LID - 10.3389/fcell.2021.743908 [doi] FAU - Zhou, Xu AU - Zhou X AD - Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany. AD - Section of Surgical Research, Heidelberg University Hospital, Heidelberg, Germany. FAU - Hu, Kai AU - Hu K AD - Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany. AD - Section of Surgical Research, Heidelberg University Hospital, Heidelberg, Germany. FAU - Bailey, Peter AU - Bailey P AD - Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany. AD - Section of Surgical Research, Heidelberg University Hospital, Heidelberg, Germany. AD - Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom. FAU - Springfeld, Christoph AU - Springfeld C AD - Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany. FAU - Roth, Susanne AU - Roth S AD - Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany. FAU - Kurilov, Roma AU - Kurilov R AD - Division of Applied Bioinformatics, German Cancer Research Center, Heidelberg, Germany. FAU - Brors, Benedikt AU - Brors B AD - Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany. AD - Division of Applied Bioinformatics, German Cancer Research Center, Heidelberg, Germany. FAU - Gress, Thomas AU - Gress T AD - Department of Gastroenterology and Endocrinology, Philipps University of Marburg, Marburg, Germany. FAU - Buchholz, Malte AU - Buchholz M AD - Department of Gastroenterology and Endocrinology, Philipps University of Marburg, Marburg, Germany. FAU - An, Jingyu AU - An J AD - Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany. AD - Section of Surgical Research, Heidelberg University Hospital, Heidelberg, Germany. FAU - Wei, Kongyuan AU - Wei K AD - Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany. AD - Section of Surgical Research, Heidelberg University Hospital, Heidelberg, Germany. FAU - Peccerella, Teresa AU - Peccerella T AD - Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany. AD - Section of Surgical Research, Heidelberg University Hospital, Heidelberg, Germany. FAU - Büchler, Markus W AU - Büchler MW AD - Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany. FAU - Hackert, Thilo AU - Hackert T AD - Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany. FAU - Neoptolemos, John P AU - Neoptolemos JP AD - Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany. AD - Section of Surgical Research, Heidelberg University Hospital, Heidelberg, Germany. IS - 2296-634X (Linking) OTO - NOTNLM OT - ESPAC OT - clinical trials OT - molecular subtypes OT - next generation sequencing OT - precision medicine OT - structural variants OT - transcriptomes PMC - PMC8603393 LR - 20230430 DP - 2021 DEP - 20211105 AB - 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.