Laboratory of Thoracic Surgery, University Hospital Bern, Murtenstrasse 50

The general aim of the laboratory of thoracic surgery is to develop new treatment options for the malignant lung. In this context we are focussing on stem cells in the context of lung regeneration and cancer. The research is headed by the leading investigators Dr. Hall, Dr. Marti and Dr. Peng and is an extension of the work on stem cells previously performed by our group (1).

Introduction
Stem cells have the potential for self-renewal and give rise to differentiated progeny. In doing so, stem cells have been proposed to be involved in normal lung tissue maintenance and repair [reviewed in (2)]. Lung desease is one of the leading causes of death in the world. The World Health Organization estimates that by 2020, 11.9 million of a total of 68.3 million deaths worldwide will be due to lung diseases. However, the role of stem cells in lung injury, repair and remodeling is still unclear [reviewed in (2)]. Emphysema is associated with smoking and it was recently shown that the repair of smoke-induced emphysema in the animal model is enhanced by mesenchymal stem cells (MSCs). Lung cancer is the most common cause of cancer-related mortality worldwide (3). This is mainly due to the difficulty of early detection and lack of effective treatment methods, thus more effective treatement options are desperately needed. It has been postulated that tumor initiation and propagation are mediated by cancer stem cells (CSCs) or tumor-initiating cells (TICs). CSCs or TICs might also confer therapeutic resistance (4), which was recently also shown in lung cancer (5).

 

Hall Group
There is emerging evidence to suggest that tumor (mesenchymal) microenvironment acts in concert with the cancer cell-centric changes driving tumor phenotype. In line with this, we have recently identified rare mesenchymal stromal cells in primary human lung adenocarcinomas and are interested in how these cells promote tumor growth. Initially, mesenchymal stromal cells, first identified in the bone marrow, have been shown to posses broad immunomodulatory properties. Based on our initial observations, we postulate that these rare cells may act as key effectors in regulating the composition and function of infiltrating leukocytes within the tumor microenvironment tipping the balance towards immunosuppression. Therefore, our aim is to translate our findings using a combined pharmacological and genetic approach using patient-derived samples and inducible mouse models of human lung adenocarcinoma to determine the potential of this tumor-derived mesenchymal subset to serve as a novel therapeutic target in lung cancer. In a second project, we are interested in identifying stem and progenitor cells that are critically involved in alveolar regeneration. To achieve this, we aim to utilize primary human samples and genetic fate mapping tools to identify cellular hierarchies in alveolar development and cell fate during injury and alveolar regeneration.

 

Marti and Peng Groups
More than 80% of lung tumors are non-small-cell lung cancers (NSCLC). In NSCLC, TICs were identified and subsequent analysis indicated that the DNA damage response and the nucleotide synthesis pathway are deregulated in TICs (6). DNA damage response (DDR) is a complex and multifaceted signaling network, wich evolved to maintain genome integrity that is essencial for the proper function and survival of all organisms. Our aim is to identify TICs in primary NSCLC and to characterize differentially regulated DDR factors of TICs, which will allow us to identify novel targets for pharmacological or genetic intervention to treat lung cancer.

 

Chemotherapy is one of the standard treatment options for lung cancer in particular NSCLC that is often diagnosed at a late stage. However, resistance to chemotherapy and ensuring tumor relapse are common and the major cause of therapeutic failure and mortality in the clinic. Our previous findings indicate that resistance of tumors to chemotherapy is linked to tumor subsets with stem cell-like features, i.e. TICs (1). We intend to isolate chemotherapy resistant cells from primary patient samples after exposure to chemotherapeutics used in the clinical setting. Characterization of the selected subpopulation will provide insights into the mechanism by which chemoresistance occurs in vivo, thereby uncovering new therapeutic targets in human lung cancer.

 

  1. Cortes-Dericks L, Galetta D, Spaggiari L, Schmid RA, Karoubi G (2012) High expression of octamer-binding transcription factor 4A, prominin-1 and aldehyde dehydrogenase strongly indicates involvement in the initiation of lung adenocarcinoma resulting in shorter disease-free intervals. European journal of cardio-thoracic-surgery : official journal of the European Association for cardio-thoracic surgery 41(6):e173-181
  2. Hogan BL, et al. (2014) Repair and Regeneration of the Respiratory System: Complexity, Plasticity, and Mechanisms of Lung Stem Cell Function. Cell stem cell 15(2):123-138
  3. Jemal A, et al. (2011) Global cancer statistics. CA Cancer J Clin 61(2):69-90
  4. Bao S, et al. (2006) Gilioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444(7120):756-760
  5. Liu YP, et al. (2013) Cisplatin selects for multidrug-resistant CD133+ cells in lung adenocarcinoma by activating Notch signaling. Cancer research 73(1):406-416
  6. Zhang WC, et al. (2012) Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorgenesis. Cell 148(1-2):259-272