Cell of Origin Influences Pancreatic Cancer Subtype

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a 5-year survival rate of approximately 9%. An improved understanding of PDAC initiation and progression is paramount for discovering strategies to better detect and combat this disease. Although transcriptomic analyses have uncovered distinct molecular subtypes of human PDAC, the factors that influence subtype development remain unclear. Here, we interrogate the impact of cell of origin and different Trp53 alleles on tumor evolution, using a panel of tractable genetically engineered mouse models. Oncogenic KRAS expression, coupled with Trp53 deletion or point mutation, drives PDAC from both acinar and ductal cells. Gene-expression analysis reveals further that ductal cell–derived and acinar cell–derived tumor signatures are enriched in basal-like and classical subtypes of human PDAC, respectively. These findings highlight cell of origin as one factor that influences PDAC molecular subtypes and provide insight into the fundamental impact that the very earliest events in carcinogenesis can have on cancer evolution. Significance: Although human PDAC has been classified into different molecular subtypes, the etiology of these distinct subtypes remains unclear. Using mouse genetics, we reveal that cell of origin is an important determinant of PDAC molecular subtype. Deciphering the biology underlying pancreatic cancer subtypes may reveal meaningful distinctions that could improve clinical intervention. This article is highlighted in the In This Issue feature, p. 521

Crosstalk between KRAS, SRC and YAP Signaling in Pancreatic Cancer: Interactions Leading to Aggressive Disease and Drug Resistance

“…The resulting lesions could be divided into two main subtypes: a slow-progressing subtype with a glandular phenotype (similar to the classical subtype) and a fast-growing more invasive and less glandular subtype with abundant stromal deposition (similar to the basal-like/squamous subtype). Thus, the results of these studies support the notion that the cell of origin and/or the surrounding microenvironment (rather than genetics) play significant roles in determining PDAC subtype [29,84].…”

“…This mouse model displays similar histopathologic features to the human PDAC, including the development and progression of PanINs [24]. However, there is increasing recognition that oncogenic Kras promotes different lesions depending on whether is expressed in acinar or ductal cells [26][27][28][29]. Specifically, acinar cell-derived tumors proceed through low-grade PanINs whereas ductal cell-derived tumors give rise to high-grade PanIN and invasive PDAC bypassing low-grade PanINs [28].…”

“…Transcriptomic analyses indicated that the ductal cell-derived tumor signature is enriched in the basal-like/squamous subtype, whereas the acinar cell-derived tumor signature is enriched in the classical subtype. These results imply that cell of origin may be one of the factors that determines subtypes of PDAC [29]. In another study, single-cell suspensions of patient-derived organoids were injected directly into the ducts of the murine pancreas [84].…”

“…Interestingly, a recent preclinical study using a set of genetically engineered mouse models induced expression of oncogenic Kras and deletion of Tp53 in either acinar or ductal cell compartments of the pancreas in adult mice [29]. Transcriptomic analyses indicated that the ductal cell-derived tumor signature is enriched in the basal-like/squamous subtype, whereas the acinar cell-derived tumor signature is enriched in the classical subtype.…”

Molecular Analysis of Prognosis and Immune Pathways of Pancreatic Cancer Based on TNF Family Members

“…Pancreatic adenocarcinoma (PAAD) has a 5-year survival rate of less than 10%, which is one of the most aggressive malignant tumors with the worst prognosis [ 1 , 2 ]. About 90% of PAADs are ductal adenocarcinomas originating from the glandular epithelium.…”