From early pancreatic carcinogenesis to molecular subtyping

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease. Despite enormous advances in the understanding of molecular tumor biology, the overall survival rate of PDAC patients has remained almost unchanged for the past 20 years. This is mainly attributed to the facts:

1. lack of biomarkers for early detection and therapy response;

2. extreme heterogeneity on clinical, histological, and genetic levels. A variety of molecular subtypes with distinctive tumor biology seem to exist, but current therapies are applied without taking these putative differences into account.

In our lab we are focusing on three major topics:

As human PDAC is diagnosed at a very late stage, understanding the processes leading to its initiation enables the discovery of biomarkers for early detection. We have established a number of in vivo models for early pancreatic carcinogenesis. Here, we provide genetic evidence that defines ductal obstruction as an important mechanism to induce formation of pre-neoplastic lesions from the pancreatic ductal compartment. However, it is the acinar cells that were susceptible to oncogenic Kras and caerulein-induced pancreatitis. Under physiological circumstances, acinar-to-ductal (ADM) is a default and reversible metaplastic process in which acinar cells transiently adopt a ductal phenotype with an acquisition of progenitor-like features and the capability of re-differentiating into acinar cells. In response to oncogenic Kras signaling and caerulein-induced pancreatitis, however, this metaplastic phenotype of acinar cells is irreversible, and ADM lesions progress into PanIN lesions and eventually PDAC, forming a distinctive acinar-ADM/PanIN-PDAC transformation pathway. Certainly, this cellular type-dependent diversity in transformation pathways adds another layer of complexity to the current endeavor of biomarker development and intervention studies in patients with pancreatitis. The ductal obstruction- and caerulein-induced pancreatitis model will serve as a platform to be able to better differentiate between these putative subtypes of PDAC.

Previously, we used a reverse-translational approach to define PDAC subtypes and generated a number of novel GEMMs of PDAC entities with different levels of aggressiveness. We could identify different subtypes of pancreatic cancer. Detailed analyses revealed that metastasis is driven by the KrasG12D/Mek-mTOR signaling axis, for which Aldh1a3 (aldehyde dehydrogenase family 1, subfamily A3) constitutes a specific marker. In humans, ALDH1A3 defines a micro-metastatic PDAC subtype with very short postoperative survival, suggesting that the current standard of care is not the ideal therapeutic pathway for these patients. It is, therefore, crucial to develop subtype-specific targeted therapies.

IHC staining of human PDAC tissue samples for ALDH1A3 and survival analysis

One of the major characteristics of PDAC is the dense desmoplastic stroma consisting of extracellular matrix, cancer-associated fibroblasts (CAFs), immune cells, endothelial cells and others. During tumor progression CAFs get activated by tumor-derived factors already at early stages. Several different subtypes of CAFs have been identified in PDAC with distinctive markers, functions, and unique spatial positions. In a previous study was shown that PDAC cell harboring oncogenic Kras activate CAFs via sonic hedgehog signaling in a paracrine manner. Those activated CAFs can then reciprocally stimulate tumor cell proliferation and survival. The specific signaling and interaction between cancer cells and CAFs still needs to be investigated because the clinical relevance remains so far elusive.

 

 

 

Head of the working group

  • Profilbild von Priv.-Doz. Dr. med. Bo Kong

    Priv.-Doz. Dr. med. Bo Kong

    Oberarzt

Team

  • Profilbild von Dr. biol. hum. Hend Abdelrasoul

    Dr. biol. hum. Hend Abdelrasoul

    Postdoc, Senior Scientist (Tumor Immunology)

Students

  • Xiufen Yang

  • Lingling Zhang

  • Jingxiong Hu

  • Yiqi Niu

  • Yifeng Sun

  • Chao Fang

Zhang Z, Li H, Deng Y, Schuck K, Raulefs S, Maeritz N, Yu Y, Hechler T, Pahl A, Fernández-Sáiz V, Wan Y, Wang G, Engleitner T, Öllinger R, Rad R, Reichert M, Diakopoulos KN, Weber V, Li J, Shen S, Zou X, Kleeff J, Mihaljevic A, Michalski CW, Algül H, Friess H, Kong B. AGR2-Dependent Nuclear Import of RNA Polymerase II Constitutes a Specific Target of Pancreatic Ductal Adenocarcinoma in the Context of Wild-Type p53. Gastroenterology. 2021 Jul 23:S0016-5085(21)03281-9. doi: 10.1053/j.gastro.2021.07.030. Epub ahead of print. PMID: 34303658. epub

Zhao Y, Schoeps B, Yao D, Zhang Z, Schuck K, Tissen V, Jäger C, Schlitter AM, van der Kammen R, Ludwig C, D'Haese JG, Raulefs S, Maeritz N, Shen S, Zou X, Krüger A, Kleeff J, Michalski CW, Friess H, Innocenti M, Kong B. mTORC1 and mTORC2 Converge on the Arp2/3 Complex to Promote Kras(G12D)-Induced Acinar-to-Ductal Metaplasia and Early Pancreatic Carcinogenesis. Gastroenterology. 2021 Apr;160(5):1755-1770.e17. doi: 10.1053/j.gastro.2020.12.061. Epub 2021 Jan 1. [PMID: 33388318] epub

Cheng T, Zhang Z, Jian Z, Raulefs S, Schlitter AM, Steiger K, Maeritz N, Zhao Y, Shen S, Zou X, Ceyhan GO, Friess H, Kleeff J, Michalski CW, Kong B. Ductal obstruction promotes formation of preneoplastic lesions from the pancreatic ductal compartment. Int J Cancer. 2019 May 15;144(10):2529-2538. [Pubmed ID: 30412288] epub

Kong B, Bruns P, Behler NA, Chang L, Schlitter AM, Cao J, Gewies A, Ruland J, Fritzsche S, Valkovskaya N, Jian Z, Regel I, Raulefs S, Irmler M, Beckers J, Friess H, Erkan M, Mueller NS, Roth S, Hackert T, Esposito I, Theis FJ, Kleeff J, Michalski CW. Dynamic landscape of pancreatic carcinogenesis reveals early molecular networks of malignancy. Gut. 2018 Jan;67(1):146-156. [Pubmed ID: 27646934] epub

Kong B, Wu W, Cheng T, Schlitter AM, Qian C, Bruns P, Jian Z, Jäger C, Regel I, Raulefs S, Behler N, Irmler M, Beckers J, Friess H, Erkan M, Siveke JT, Tannapfel A, Hahn SA, Theis FJ, Esposito I, Kleeff J, Michalski CW. A subset of metastatic pancreatic ductal adenocarcinomas depends quantitatively on oncogenic Kras/Mek/Erk-induced hyperactive mTOR signalling. Gut. 2016; 65:647-57 [Pubmed ID: 25601637] epub

Kong B, Cheng T, Wu W, Regel I, Raulefs S, Friess H, Erkan M, Esposito I, Kleeff J, Michalski CW. Hypoxia-induced endoplasmic reticulum stress characterizes a necrotic phenotype of pancreatic cancer. Oncotarget. 2015; 6:32154-60 [Pubmed ID: 26452217] epub

Kong B, Cheng T, Qian C, Wu W, Steiger K, Cao J, Schlitter AM, Regel I, Raulefs S, Friess H, Erkan M, Esposito I, Kleeff J, Michalski CW.Pancreas-specific activation of mTOR and loss of p53 induce tumors reminiscent of acinar cell carcinoma. Mol Cancer. 2015 Dec 18; 14:212 [Pubmed ID: 26683340] epub

 

Our research is funded by Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe and Zentrale Innovationsprogramm Mittelstand (ZIM) des Bundesministeriums für Wirtschaft und Energie.