Cell Lineage Infidelity in PDAC Progression and Therapy Resistance

Abstract

Infidelity to cell fate occurs when differentiated cells lose their original identity and either revert to a more multipotent state or transdifferentiate into a different cell type, either within the same embryonic lineage or in an entirely different one. Whilst in certain circumstances, such as in wound repair, this process is beneficial, it can be hijacked by cancer cells to drive disease initiation and progression. Cell phenotype switching has been shown to also serve as a mechanism of drug resistance in some epithelial cancers. In pancreatic ductal adenocarcinoma (PDAC), the role of lineage infidelity and phenotype switching is still unclear. Two consensus molecular subtypes of PDAC have been proposed that mainly reflect the existence of cell lineages with different degrees of fidelity to pancreatic endodermal precursors. Indeed, the classical subtype of PDAC is characterised by the expression of endodermal lineage specifying transcription factors, while the more aggressive basal-like/squamous subtype is defined by epigenetic downregulation of endodermal genes and alterations in chromatin modifiers. Here, we summarise the current knowledge of mechanisms (genetic and epigenetic) of cell fate switching in PDAC and discuss how pancreatic organoids might help increase our understanding of both cell-intrinsic and cell-extrinsic factors governing lineage infidelity during the distinct phases of PDAC evolution.

Blockage of retinoic acid signaling via RARγ suppressed the proliferation of pancreatic cancer cells by arresting the cell cycle progression of the G1-S phase

“…Several studies have reported that, in some types of cancer, including PDAC, the expression of squamous lineage markers, including esophagus tissuespeci c genes, correlated with a poor patient prognosis [8, 41,42]. Recent studies have also suggested that a "basal-like/squamous type," which expresses squamous lineage phenotypes, leads to PDAC progression and a poor prognosis [7]. However, the mechanism by which the acquisition of squamous lineage phenotypes led to a poor patient prognosis is unclear.…”

“…Two consensus molecular subtypes of PDAC have recently been proposed based on transcriptomic data: "classical/progenitor type," with a relatively favorable prognosis; and "basal-like/squamous type," with a poor prognosis [7]. Whereas the "classical/progenitor type" preserves the high expression of pancreatic endodermal cell-fate determinants, the "basal-like/squamous type" loses pancreatic identity and expresses many squamous lineage markers related to the upregulation of the ΔNp63 transcription network [7]. Mutation patterns of well-known PDAC driver genes alone cannot explain the difference between these molecular subtypes of PDAC, and the determining mechanism remains incompletely understood.…”

Sesquiterpene Lactones as Promising Candidates for Cancer Therapy: Focus on Pancreatic Cancer

“…The rest of the pancreatic tissue, about 90%, is composed by acini where the pancreas acinar cells synthesize and secrete digestive enzymes that are transported to the duodenum through the interconnected ducts [ 8 ]. From these last structures, acini and ducts, the pre-tumoral lesions termed PanINs (pancreas intraepithelial neoplasms) are developed [ 9 ]. There are several types of pancreatic cancer, such as neuroendocrine tumors, squamous cell carcinoma and adenosquamous carcinoma, though more than 90% of cases correspond to the pancreatic adenocarcinoma (PDAC) [ 9 ].…”

“…From these last structures, acini and ducts, the pre-tumoral lesions termed PanINs (pancreas intraepithelial neoplasms) are developed [ 9 ]. There are several types of pancreatic cancer, such as neuroendocrine tumors, squamous cell carcinoma and adenosquamous carcinoma, though more than 90% of cases correspond to the pancreatic adenocarcinoma (PDAC) [ 9 ]. The initial low-grade PanINs potentially progress with morphological and molecular alterations towards high-grade dysplastic lesions and data support that those tissue lesions can eventually evolve to PDAC [ 10 , 11 , 12 ].…”

Emerging Role of Epigenetic Alterations as Biomarkers and Novel Targets for Treatments in Pancreatic Ductal Adenocarcinoma

“…PDAC is currently classified into several subgroups, ranging from 3 to 5 subtypes depending on the system used [24][25][26]. Two major molecular subtypes of PDAC have been found through transcriptome profiling, namely the classical and basal type [27]. The classical type has a better prognosis, demonstrating a clinical relevance.…”