The Match between Molecular Subtypes, Histology and Microenvironment of Pancreatic Cancer and Its Relevance for Chemoresistance

Abstract

In the last decade, several studies based on whole transcriptomic and genomic analyses of pancreatic tumors and their stroma have come to light to supplement histopathological stratification of pancreatic cancers with a molecular point-of-view. Three main molecular studies: Collisson et al. 2011, Moffitt et al. 2015 and Bailey et al. 2016 have found specific gene signatures, which identify different molecular subtypes of pancreatic cancer and provide a comprehensive stratification for both a personalized treatment or to identify potential druggable targets. However, the routine clinical management of pancreatic cancer does not consider a broad molecular analysis of each patient, due probably to the lack of target therapies for this tumor. Therefore, the current treatment decision is taken based on patients´ clinicopathological features and performance status. Histopathological evaluation of tumor samples could reveal many other attributes not only from tumor cells but also from their microenvironment specially about the presence of pancreatic stellate cells, regulatory T cells, tumor-associated macrophages, myeloid derived suppressor cells and extracellular matrix structure. In the present article, we revise the four molecular subtypes proposed by Bailey et al. and associate each subtype with other reported molecular subtypes. Moreover, we provide for each subtype a potential description of the tumor microenvironment that may influence treatment response according to the gene expression profile, the mutational landscape and their associated histology.

Identification of Novel Metabolism-Associated Subtypes for Pancreatic Cancer to Establish an Eighteen-Gene Risk Prediction Model

“…They revealed a complex molecular landscape of pancreatic ductal adenocarcinoma and provided a roadmap for precision medicine (Cancer Genome Atlas Research Network, 2017). Two large researches using PanC samples recently reported gene expression subtypes of PanC, extending the subtypes previously described by Collisson et al (2011), Bailey et al (2016), Martinez-Useros et al (2021). Sinkala et al employed transcriptomic, copy number alteration and mutation profiling datasets from PanC patients together with data on clinical outcomes to show that the three PanC subtypes each display distinctive aberrations in cell signaling and metabolic pathways (Sinkala et al, 2018).…”

Targeting the Stroma in the Management of Pancreatic Cancer

“…Molecular classification could also help to improve patient selection and enable better differentiation of responders and non-responders. For example, as an immunogenic subtype exhibits an upregulation of immune-related genes, this subtype could feasibly be treated with ICIs (148). Meanwhile, a basal-like subtype may benefit more from gemcitabine-based regimens than from FOLFIRINOX (149).…”

Integrating Network Pharmacology and Experimental Verification to Explore the Mechanism of Effect of Zuojin Pills in Pancreatic Cancer Treatment

“…Pancreatic cancer is a common malignancy of the digestive tract. 32,33 In recent years, the antitumor effects of TCMs have received increasing attention because of their clear pharmacological effects and relatively low number of side effects. A large number of patients choose natural therapy with TCM because TCMs are considered to be multicomponent, multitarget and multistage medicines.…”