Ductal obstruction promotes formation of preneoplastic lesions from the pancreatic ductal compartment

Abstract

Pancreatitis is a significant risk factor for pancreatic ductal adenocarcinoma (PDAC). Previous studies in mice have demonstrated that pancreatitis contributes to oncogenic Kras‐driven carcinogenesis, probably initiated in acinar cells; however, oncogenic Kras alone or in combination with caerulein‐induced pancreatitis is not sufficient in initiating PDAC from the ductal compartment. We thus introduced ductal obstruction – which induces a more severe form of pancreatitis – by pancreatic ductal ligation in mice harbouring oncogenic Kras. This induced a particular phenotype with highly proliferative nonmucinous cells with nuclear atypia. Around these lesions, there was a significant proliferation of activated fibroblasts and infiltration of immune cells, corroborating the pathological features of preneoplastic lesions. Lineage‐tracing experiments revealed that these preneoplastic cells derived from two distinctive cellular sources: acinar and ductal cells. Phenotypic characterisation revealed that the duct‐derived preneoplastic lesions show a high proliferative potential with persistent activation of tumour‐promoting inflammatory pathways while the acinar‐derived ones were less proliferative with persistent p53 activation. Furthermore, the duct‐derived preneoplastic cells have a particularly high nuclear‐to‐cytoplasmic ratio. These data demonstrate that ductal obstruction promotes preneoplastic lesion formation from the pancreatic ductal compartment.

Pancreatic duct ligation reduces premalignant pancreatic lesions in a Kras model of pancreatic adenocarcinoma in mice

“…In the present study we triggered the same physiological mechanism but in Kras mice at an early stage (when p53 is still active) in order to wipe out these potentially pro-oncogenic cells with a long period of follow-up (up to 6 months) in comparison to several intergroup controls (control and sham group) and intragroup controls (proximal pancreas). Very recently, two reports 40 , 41 have described the influence of duct obstruction on the remaining distal pancreas in Kras mouse models at the cellular level but without quantitative analysis of preneoplastic lesions. Both of them described similar signs of strong atrophy and a complete loss of the acinar compartment with a ductal replacement but while Shi et al 40 described less preneoplastic lesions in the acinar differentiation models in the distal pancreas, Cheng et al 41 observed a higher number of proliferative non-mucinous cells of both acinar and ductal origins at 2 weeks after PDL, without severe nuclear atypia or tumoral infiltration after 5-month of follow up.…”

“…Very recently, two reports 40 , 41 have described the influence of duct obstruction on the remaining distal pancreas in Kras mouse models at the cellular level but without quantitative analysis of preneoplastic lesions. Both of them described similar signs of strong atrophy and a complete loss of the acinar compartment with a ductal replacement but while Shi et al 40 described less preneoplastic lesions in the acinar differentiation models in the distal pancreas, Cheng et al 41 observed a higher number of proliferative non-mucinous cells of both acinar and ductal origins at 2 weeks after PDL, without severe nuclear atypia or tumoral infiltration after 5-month of follow up.

Figure 7 A resected human PDAC in the body of the pancreas that spontaneously lead to complete occlusion of the main pancreatic duct and complete atrophy of the distal pancreas.

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Key transcriptional effectors of the pancreatic acinar phenotype and oncogenic transformation

“…The disruption of acinar cell differentiation and identity due to stress [ 52 , 53 ], inflammation [ 28 ], injury [ 54 , 55 ], or loss of key regulators of differentiation [ 56 , 57 ] confers susceptibility to oncogenic transformation [ 20 , 58 , 59 ]. For example, serial pharmacologic doses of the acinar secretagogue cholecystokinin or its analog caerulein induce inflammation, degrade differentiation, and weaken cell-identity through a process termed acinar to ductal metaplasia [ 60 ].…”