Identification of Sox9-Dependent Acinar-to-Ductal Reprogramming as the Principal Mechanism for Initiation of Pancreatic Ductal Adenocarcinoma

Abstract

Summary Tumors are largely classified by histological appearance, yet morphological features do not necessarily predict cellular origin. To determine the origin of pancreatic ductal adenocarcinoma (PDA), we labeled and traced pancreatic cell populations after induction of a PDA-initiating Kras mutation. Our studies reveal that ductal and stem-like centroacinar cells are surprisingly refractory to oncogenic transformation, whereas acinar cells readily form PDA precursor lesions with ductal features. We show that formation of acinar-derived premalignant lesions depends on ectopic induction of the ductal gene Sox9. Moreover, when concomitantly expressed with oncogenic Kras, Sox9 accelerates formation of premalignant lesions. These results provide insight into the cellular origin of PDA and suggest that its precursors arise via induction of a duct-like state in acinar cells.

Endocrine Pancreas Development and Regeneration: Noncanonical Ideas From Neural Stem Cell Biology

“…These data are supported by reports that the expression of Ngn3 and Hes1 is mutually exclusive in the developing pancreas (27,35), as is the expression of Sox9 and Ngn3 at the endocrine progenitor stage (46,(103)(104)(105). Furthermore, Sox9 occupancy regions on the Ngn3 gene promoter have been identified (104,106).…”

GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras -driven pancreatic tumorigenesis in mice

“…Although the relationship between ER stress and ADM is not well understood, a recent report suggests that ER stress resulting from perturbation of basal autophagy via loss of ATG7 is associated with spontaneous activation of ADM in a mouse model (42). ADM is critical for the initiation of pancreatic tumorigenesis (5,32). In the PKC acinar cells, GRP78 was highly elevated, suggesting that it could play a role in ADM under oncogenic stress.…”

“…Mutationally activated oncogenic KRAS signals through the PI3K-PDK1-AKT pathway and the canonical mitogen-activated protein kinase pathway via RAF-MEK1/2-ERK1/2, as well as via positive feedback activation of receptor tyrosine kinases engaged by autocrine and paracrine stimuli (3). Although the histological appearance of PDAC suggests a ductal cell of origin, accumulating evidence reveals that PDAC originates primarily through transdifferentiation of acinar cells into ductal cells in a process referred to as acinar-to-ductal metaplasia (ADM), although centroacinar cells and pancreas precursor cells could also give rise to PDAC (2,4,5). To study PDAC, a pancreatic cancer mouse model mimicking human PDAC has been established using the pancreatic and duodenal homeobox 1 promoter-driven Cre-recombinase (Pdx1-Cre) to conditionally activate the Kras lox-stop-lox G12D allele and delete one allele of p53.…”

Long-term evolution of acinar-to-ductal metaplasia and β-cell mass after radiofrequency-assisted transection of the pancreas in a controlled large animal model

“…However, the validity of PDL as a model of endocrine regeneration has now been called into question [5][6][7]11,13,14]. Recent results from PDL in mouse models have shown that some acinar cells can escape death [7] and that acinar compartment can regenerate in a long-term evolution after PDL (over 6 months), probably by restoration of pancreatic drainage [6].…”

“…Since ADM is characterized by a switch from acinar to ductal phenotype with active proliferation, and since metaplasic ductal lesions are frequently seen in chronic pancreatitis as well as in specimens of pancreatic ductal adenocarcinoma (PDAC), ADM is thought to represent a preneoplastic condition [1,3,4]. Even though some areas of ADM could revert to normal acinar morphology [5,6] in the absence of oncogenic Kras mutations or in the presence of acute pancreatitis, the transition of acinar cells into a duct-like state (as in ADM) has been recognized as an important early event in tumor initiation.…”