Exoneural biology
The peripheral nervous system (PNS) is the body’s information line, transmitting signals across our bodies. The PNS consists of the nerves that branch out from the brain and spinal cord. It is subdivided into the somatic nervous system and the autonomic nervous system. The somatic nervous system consists of nerves that go to the skin and muscles and is involved in consciousness generation. The autonomic nervous system consists of nerves that connect the central nerve system to the visceral organs such as the stomach and intestines.
The number of neuronal cells in the PNS is suggested to outperform the number of nerves in the CNS. Despite many advances in neuroscience, the intense focus on the biology of the brain has left the PNS compatibly unstudied. Although more evidences occur that nerve cells play roles in the biology of visceral oncology, and despite the advancements in modern molecular biology and electrophysiology, we are lacking a clear understanding of the function of neuronal environment in the biology of cancers from pancreas, colon, rectum, gallbladder or liver. Our aim is to understand what microenvironmental niche signals generated by innervating sensory nerves, if and how healthy cells and malformed cells of the aforementioned organs received those signals, and what consequences these may cause on disease initiation, progression or therapy resistance. Â
MES Organoid Platform (MOP)
Organoids are self-organized three-dimensional tissue cultures, comprising of a heterogeneous cellular architecture, that are derived from stem cells. There are potentially as many types of organoids as there are different tissues and organs in the body. Cancer tissue-derived organoids paving its way as an in vitro technology recapitulating cardinal pathophysiological parameters of the original tumors. The application of those patient avatars in functional assays, such as drug screening or co-clinical trials, proved to be able to generate results that predict the response of the corresponding patient. The generation of patient-specific culture pairs, derived from the tumor material (biopsy prior surgery, or from the tumor resection piece) and the healthy organ, allows to background normalize our findings such as scoring off-target effects of chemo interventions. In our efforts, we are following procedures developed by the Hubrecht Institute, the leading and global pioneer center in organoid and stem cell research, to build MOP.
Human induced pluripotent stem cell platform (MIPS)
Sensory nerves cells are a central component of the peripheral nerve system. Sensory nerve cells and neurons are also the leading pain receptors. With the recent establishment of differentiation protocols for sensory nerve cells from human induced pluripotent stem cells, we utilize this knowledge to develop cancer-nerve co-culture in vitro systems. Our team works to build immunologic matched co culture systems by establishing cancer patient-derived iPSC lines.
Processing of tumor tissue, derived from surgical resection, to establish chronic in vitro models presents the traditional disease-modeling. Historically, this approach has been proven to be successful, as most of our current cancer treatments are based on discoveries made in such patient-derived (PD) model systems. However, the recent advancements in molecular technology revealed that genetic instability of cancer cell lines occur which seems to be a driver of heterogeneity of results. Moreover, the molecular and cellular heterogeneity of the malignant tumors not only reasons why thereof-derived cell models, originating from a spatial isolated piece of the resection specimen, are incapable to sufficiently recapitulate tumor properties, but also makes it virtually impossible to isolate and present a functional model for the cell of origin for the entire tumor. Those fundamental disease modeling aspects have been proposed to be contributing causes to the problems with insufficient reproducibility in cancer research, which is suggested to be a cardinal factor for the ethical and economical debate.
With the technological advancements in cell biology and cell engineering, the recent years documented the emergence of alternative tumor modeling procedures avoiding the dependency on patient material. As such, hiPSCs derived from healthy donors present an unlimited resource of cells to serve as receiver matrixes for genetic elements encoding for cancer relevant transformations. Such healthy donor-derived tumor models manifest themselves as a sustainable alternative disease modeling strategy in the current cancer research community complementing the portfolio of lab tools alongside the use of PD systems. It is speculated, that iPSC models of cancer may be beneficial to homogeneously depict cell of origin of cancers. Moreover, we have recently shown that hiPSC-oncogene models present a functional in vitro platform for substance testing with longitudinal reproducibility.
The project (DisCoVer- Disease modeling and Compound Verification) is funded by the German Federal Ministry of Education and Research (BMBF) under VIP+.