Z Gastroenterol 2014; 52 - KG160
DOI: 10.1055/s-0034-1386182

Nicotine triggers initiation and progression of K-Ras driven pancreatic ductal adenocarcinoma via acinar cell de-differentiation

PC Hermann 1, 2, P Sancho 2, P Michl 3, T Gress 3, R De Pascual 4, L Gandia 4, M Canamero 5, C Guerra 6, M Barbacid 6, A Aicher 2, P Martinelli 7, FX Real 7, B Sainz Jr 2, C Heeschen 2
  • 1Ulm University, Department for Internal Medicine I, Ulm, Germany
  • 2Spanish National Cancer Research Centre (CNIO), Stem Cells & Cancer Group, Madrid, Spain
  • 3University of Marburg, Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, Marburg, Germany
  • 4Instituto Teófilo Hernando, Madrid, Spain
  • 5Spanish National Cancer Research Centre (CNIO), Comparative Pathology Unit, Madrid, Spain
  • 6Spanish National Cancer Research Centre (CNIO), Experimental Oncology Group, Madrid, Spain
  • 7Spanish National Cancer Research Centre (CNIO), Epithelial Carcinogenesis Group, Madrid, Spain

Background: Smoking has been identified as a leading risk factor for pancreatic ductal adenocarcinoma. Nicotine is a key active ingredient of tobacco smoke and replacement products, and while nicotine does not have intrinsic carcinogenic properties, we hypothesized that nicotine perpetuates oncogenic transformation of the pancreas by alternative mechanisms.

Methods & Results: Using Elastase-K-RasG12V and PDX1-K-RasG12DTrp53R172 H mouse models of pancreatic cancer, we demonstrate that nicotine promotes PanIN and PDAC development. These effects were independent of groß inflammation as nicotine treatment did not induce pancreatitis. Mechanistically, nicotine treatment strongly induced de-differentiation of acinar cells through downregulation of the Gata6/Mist1 axis, leading to strongly reduced acinar gene expression and cell function, and acinar-to-ductal metaplasia (ADM). In line with the loss of acinar differentiation, nicotine also promoted stem cell activity, identified as enhanced Sox9 and Aldh1a1 expression and increased colony formation.

Pharmacological and genetic targeting experiments demonstrated that the effects of nicotine were mediated through the α7-AChR. Since metformin has been associated with a reduced risk to develop pancreatic cancer, we investigated whether metformin treatment could reverse the effects of nicotine. Intriguingly, co-treatment with metformin prevented the accelerated pancreatic carcinogenesis and progression by preventing acinar cell de-differentiation.

At later stages of pancreatic tumorigenesis, nicotine enhanced epithelial-to-mesenchymal transition, resulting in increased cell migration, and in a significantly higher number of circulating tumor cells and (micro-)metastases in the liver. In primary cancer cells derived from these mouse models, nicotine treatment induced significant upregulation of genes associated with a (cancer) stem cell phenotype such as Oct3/4, Aldh1a1, Sox9, and Hes1 translating into enhanced in vitro and in vivo tumorigenicity.

Conclusions: Our findings reveal for the first time that nicotine promotes de-differentiation of the acinar cell compartment, resulting in increased pancreatic (cancer) stem cell activity, accelerating K-Ras-initiated pancreatic cancer development as well as tumor progression.