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.

Keywords: chemotherapy response; microenvironment; molecular subtypes of pancreatic cancer; myeloid derived suppressor cells; pancreatic stellate cells; regulatory T cells; tumor-associated macrophages.

Figure 1

Squamous molecular profile and microenvironment. (a) Squamous subtype is associated with specific histological characteristics such as squamous and adenosquamous carcinomas. (b) Squamous subtype proposed by Bailey et al., matches perfectly with "quasi-mesenchymal" tumor subtype proposed by Collisson et al., and “basal-like” tumors and “activated” stroma subtypes proposed by Moffitt et al. Green boxes contain upregulated significant factors and activated pathways associated to squamous molecular subtype. Red boxes contain downregulated significant factors (up) and most common mutations found in squamous molecular subtype (down). Percentage of each subcellular population has been obtained from Peng et al., [86]. Abbreviations: TAM: Tumor-associated macrophage; CAF: Cancer-associated fibroblast; PSC: Pancreatic stellate cell.

Figure 2

Immunogenic and progenitor molecular profiles and their microenvironment. (a) Both subtypes proposed by Bailey et al., match perfectly with “classical” tumor subtype proposed by Collisson et al., and “classical” tumor subtype proposed by Moffitt et al. (b) Both subtypes share the same histology derived from premalignant lesions like mucinous non-cystic adenocarcinomas and intraductal papillary mucinous neoplasms (IPMN) characterized by high mucin production. Dotted line separates schematic representation of two subtypes. Green boxes contain upregulated significant factors associated to each subtype. Red box contains the most characteristic gene mutation in progenitor molecular subtype. Pink color represents mucin production. Percentage of each subcellular population has been obtained from Peng et al., [86]. Abbreviations: TAM: tumor-associated macrophage; CAF: cancer-associated fibroblast; PSC: pancreatic stellate cell.4. Microenvironment of ADEX Subtype.

Figure 3

ADEX molecular profile and microenvironment. (a) ADEX subtype proposed by Bailey et al., matches perfectly with “exocrine-like” subtype proposed by Collisson et al., and most of “normal stroma” subtype cases analyzed by Moffitt et al. (b) ADEX molecular subtype is associated with the rare acinar histology. Green boxes contain upregulated transcription factors and other genes involved in ADEX molecular subtype. Red box contains genes commonly mutated in ADEX. Percentage of each subcellular population has been obtained from Peng et al., [86]. Abbreviations: TAM: tumor-associated macrophage; CAF: cancer-associated fibroblast; PSC: pancreatic stellate cell; MODY: maturity onset diabetes of the young.