Project

3D lung cancer model

Goal: Applying tissue engineering technologies to generate a human lung cancer model for applied research.

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Thorsten Walles
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PRELIMINARY WORK Krebs-assoziierte Fibroblasten (CAFs) sind ein wichtiger zellulärer Bestandteil der Mikroumgebung des NSCLC sowie anderer solider Tumoren. Die CAF Entstehung durch Aktivierung und Umprogrammierungvon gesunden Fibroblasten durch Tumorzellen ist bisher wenig untersucht. Wir haben für die Untersuchung 3D Lungentumormodelle bestehend aus der Tumorzelllinie HCC827 und gesunden Fibroblasten entwickeltund die Fibroblasten im Zeitverlauf charakterisiert.
Thorsten Walles
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The potential of preclinical tumor models to predict the outcome of substances in the clinic is limited. More advanced models that include features of living tissues and parts of the microenvironment are urgently needed. At the chair of “Tissue Engineering and Regenerative Medicine” (TERM) and the Translational Center “Regenerative therapies in oncology and musculoskelettal disease” in Wuerzburg tumor models for lung-, breast- and colorectal cancer are currently developed on a decellularized porcine jejunal scaffold. This 3D tumor model exhibits unique features such as a preserved basement membrane structure and (shows in most cell lines) a lower proliferation-rate than in 2D. This better mimics the situation in the patient and should reduce false-positive predictions (failure-rates) of cytostatic compound screening. In parallel, tailored in silico tumor models are established at the chair of “Bioinformatics” at the University of Wuerzburg that integrate data from the 3D models as well as from the clinic and enable the prediction of tumor responses upon targeted treatment.
Thorsten Walles
added a research item
Treatment of malignant pleural mesothelioma (MPM) remains challenging as the tumor is diagnosed at a late stage and only inadequately responds to chemotherapy and radiation [3]. Furthermore the incidence of MPM will increase worldwide over the next years [3]. Preclinical testing proves to be difficult due to a lack of appropriate in vitro tumor models. Consequently, we aimed to establish a 3D model reflecting the physiological environment of the MPM. • For the development of a complex 3D tumor model acellular porcine small intestinal submucosa (SIS) based on the BioVaSc® was used [1]. • Two MPM cell lines, JL-1 and MSTO-211H, were cultured for 14 days on the SIS matrix fixed in cell crowns under static culture conditions (Fig. 1) and in an advanced bioreactor system under perfusion (Fig 2). • To enhance complexity, cancer-associated fibroblasts (CAFs) from surgical specimen of MPM were isolated and used to create co-culture models. Different cell seeding concentrations between tumor cells and CAFS were tested. • Histological and immunohistological stainings were used to examine the effects of the 3D environment on proliferation and expression of mesothelial markers
Thorsten Walles
added a research item
3D respiratory tissue models have been generated using, for example, human primary airway epithelial cells (hAEC) or respective cell lines. To investigate ciliopathies, such as primary ciliary dyskinesia, the presence of functional kinocilia in vitro is an essential prerequisite. Since access to hAEC of healthy donors is limited, we aimed to identify a respiratory epithelial cell line that is capable to display functional kinocilia on at least 60 % of the apical surface. Thus, we cultured four different human respiratory cell lines with human primary airway fibroblasts under airlift conditions, characterized the morphology and analyzed ciliary function. Only one of the tested cell lines showed beating kinocilia, however, less than 10 % of the whole surface was covered and ciliary beating was undirected. Positive control tissue models using hAEC and fibroblasts displayed expected directed ciliary beating pattern around 11 Hz. Our data show that the available cell lines are not suitable for basic and applied research questions whenever functional kinocilia are required and that, rather, hAEC- or human induced pluripotent stem cells-derived tissue models need to be generated.
Thorsten Walles
added 2 research items
MicroRNAs are well-known strong RNA regulators modulating whole functional units in complex signaling networks. Regarding clinical application, they have potential as biomarkers for prognosis, diagnosis, and therapy. In this review, we focus on two microRNAs centrally involved in lung cancer progression. MicroRNA-21 promotes and microRNA-34 inhibits cancer progression. We elucidate here involved pathways and imbed these antagonistic microRNAs in a network of interactions, stressing their cancer microRNA biology, followed by experimental and bioinformatics analysis of such microRNAs and their targets. This background is then illuminated from a clinical perspective on microRNA-21 and microRNA-34 as general examples for the complex microRNA biology in lung cancer and its diagnostic value. Moreover, we discuss the immense potential that microRNAs such as microRNA-21 and microRNA-34 imply by their broad regulatory effects. These should be explored for novel therapeutic strategies in the clinic.
This review article addresses the relevance and potential of bioartificial tissues in oncologic research and therapy and reconstructive oncologic surgery. In order to translate the findings from basic cellular research into clinical applications, cell-based models need to recapitulate both the 3D organization and multicellular complexity of an organ but at the same time accommodate systematic experimental intervention. Here, tissue engineering, the generation of human tissues and organs in vitro, provides new perspectives for basic and applied research by offering 3D tissue cultures resolving fundamental obstacles encountered in currently applied 2D and 3D cell culture systems. Tissue engineering has already been applied to create replacement structures for reconstructive surgery. Applied in vitro, these complex multicellular 3D tissue cultures mimic the microenvironment of human tissues. In contrast to the currently available cell culture systems providing only limited insight into the complex interactions in tissue differentiation, carcinogenesis, angiogenesis and the stromal reaction, the more realistic (micro)environment afforded by the bioartificial tissuespecific 3D test systems may accelerate the progress in design and development of cancer therapies.
Thorsten Walles
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The objective of our research is to study the oncological pathways of lung cancer and to develop a clinically relevant model to develop and test cancer therapies. To be able to mimic the effects of a 3D environment, the tumor stroma and perfusion gradients in the tumor we developed vascularized biological scaffolds that are seeded with cancer cell lines or primary cancer and stroma cells. The first models have been established at our lab. Each tissue-model has a life-span of >8 weeks. These models allow us to treat the (human) tumor tissues in vitro and to study the escape mechanisms of the tumor.
 
Thorsten Walles
added a project goal
Applying tissue engineering technologies to generate a human lung cancer model for applied research.