Univ.-Prof. Dr. Maria Sibilia
My group employs genetically engineered mouse models (GEMMs), tumor patient material, and primary cell cultures including tumor-derived organoids as model systems to unravel the molecular mechanisms leading to inflammatory diseases and cancer. One longstanding interest addresses the function of the EGFR during normal physiology and tumorigenesis focusing on its role in tumor cells as well as in cells of the tumor microenvironment like myeloid cells/macrophages, which we have identified to promote liver and colorectal tumors when expressing EGFR. Recent studies have focused on characterizing these EGFR positive myeloid cells in promoting primary tumor development and liver metastasis. For this purpose, we have established a syngeneic mouse organoid-based CRC model (with oncogenic mutations in p53, APC, RAS) that allows to model primary CRC and CRC liver metastasis. These organoids have been characterized extensively in vitro employing multiOMICs approaches (metabolomics, proteomics, RNAseq and scRNA seq) and used in vivo to study the interactions between tumor cells and the microenvironment within primary tumors and the metastatic niche. Another key focus of the lab is exploring the role of the innate immune system in skin inflammation and anti-tumor immune responses in melanoma, with a particular emphasis on different subsets of macrophages and dendritic cells (DCs). In summary, our group exploits novel concepts to modulate tumors to become more sensitive to current immunomodulatory therapies with the goal to translate this to patients for more effective personalized treatments.
Focal points of interest
Nerve fibers represent an important component of the tumor microenvironment, and recent studies have reported on the role of the nervous system in promoting cancer development and metastasis. However, the molecular mechanism how neural regulatory signaling networks can affect tumorigenesis and the response to therapies are still poorly understood. Within the CoE we would like to understand how cancer-nerve and neuro-immune signaling interactions affect the development of primary liver cancer and liver metastasis focusing in particular on GABAergic signaling. While the liver is not traditionally recognized as a site rich in classical GABAergic neurons, various liver cells including certain immune cells express components of the GABAergic system like GABA-A and GABA-B receptors as well as GABA transporters and enzymes. However, the role of GABAergic signaling in liver physiology and pathology remains poorly understood. Thus, we will investigate if and how local GABA signaling affects liver inflammation, tumorigenesis and metastasis. Interactions with other key signaling networks (e.g. EGFR, VEGFR, AP1) and their contribution to malignant progression in conjunction with inflammatory conditions (e.g. high fat diet) will also be investigated. In future, targeting GABAergic signaling may offer new therapeutic strategies against liver cancer and liver metastasis.
Technical proficiency and instrumentation
Our experimental approaches include the generation (transgenic and knock-out) and use of various GEMMs of cancer and inflammation (more than 100 different GEMMs including Cre lines), various phenotyping approaches ranging from histology and immunohistochemistry to sophisticated multiplex imaging methods, complex immunological phenotyping (multicolor FACS etc.), various cell culture (primary/stem cell cultures, organoids, 3D cultures) and molecular biology (RNAseq, scRNAseq, RT-PCR etc.) approaches, genetic engineering by CRISPR/Cas9 technology. Besides standard lab equipment, instrumentation includes several FACS devices like spectral flowcytometry (Cytek), LSR, Fortessa, Melody cell sorter and Laser Scan, live-cell and spinning-disc confocal microscopy including multiplexed imaging (e.g. Vectra Polaris). Moreover, large scale OMICS approaches including scRNAseq, spatial transcriptomics and their bioinformatic exploration are available.
Aspirations for the next 5 years
Within the next 5 years we would like to understand the cellular and molecular mechanisms how GABAergic signaling regulate the tumor microenvironment (TME), thus influencing tumor growth, metastasis, metabolism and immune responses. Therapeutic approaches employing GABA-modulating drugs will be tested preclinically. The key findings obtained in our organoid-based metastatic CRC mouse model will be validated in patients (collaboration Trauner). An additional goal would be to understand if pathological changes in the liver can also affect the GABAergic system in the CNS and identify the underlying molecular mechanism.
References
- Tagore et, al. GABA Regulates Electrical Activity and Tumor Initiation in Melanoma, Cancer Discovery 2023 Oct 5;13(10):2270-2291. doi: 10.1158/2159-8290.CD-23-0389.
- Li et. al. Insights into the leveraging of GABAergic signaling in cancer therapy, Cancer Med 2023 Jul;12(13):14498-14510. doi: 10.1002/cam4.6102.
- Mancusi, R., Monje, M. The neuroscience of cancer. Nature 618, 467–479 (2023). https://doi.org/10.1038/s41586-023-05968-y
