GNA15 signaling facilitates the initial phases of pancreas cell transformation and is associated with the basal-like/squamous subtype

Curative intervention of pancreatic ductal adenocarcinoma (PDAC) remains substantially precluded because cancer cells typically spread asymptomatically before diagnosis. We previously described GNA15 ectopic expression in neoplastic and pre-neoplastic PDAC lesions. Here, we show that GNA15 deletion in a mouse model of Kras-dependent PDAC reduced pancreatic neoplastic lesions. Several studies stratified PDAC patients in the “classical/progenitor” and the “basal-like/squamous” molecular subtypes. We find GNA15 expression strongly associated with the “basal-like/squamous” subtype. Bioinformatic data and experimental results from PDAC cell lines and PDX revealed a gene signature implicated in cell-cell or cell-matrix interactions and invasiveness. GNA15 loss-of-function in PDAC cell lines promoted aggregation and reduced the expression of genes supporting cell invasion, such as PLAUR and FN1 . Recently, the observation that cells belonging to both subtypes co-exist in the same patient was interpreted as the clonal evolution of the disease from the “classical/progenitor” to “basal-like/squamous”. The simultaneous association of GNA15 with early PDAC stages and the “basal-like/squamous” phenotype challenges this sequential progression while supporting a role for GNA15 in the early asymptomatic dissemination of the disease. The GNA15 signature could contribute a highly specific combination of bio markers and therapeutic targets to trace and eradicate the cellular component responsible for PDAC lethality.