Lukas Kenner, MD

Department of Experimental Pathology
& Laboratory Animal Pathology (Head)
MedUni Viann and VetMedUni Vienna
Währingergürtel 18-20
1090 Vienna, Austria

Phone: +43 1 40400-51760
Mobile: +43 664 602572421

E-Mail: lukas.kenner@meduniwien.ac.at
» Website

Research interests

Research in my laboratory is focused to understand the pathogenesis of cancer, specifically prostate cancer (PC) and Non-Hodgkin Lymphoma (NHL). One important focus of my work relates to the role AP-1 transcription factor complexes as well as the Jak/Stat regulatory axis. This research has already led to successful clinical applications in cancer medicine, namely the blockage of the AP-1 target PDGFRß with imatinib in therapy resistant ALCL. To investigate the role of prostate cancer (PC) in more detail, we have established a mouse model by activating the oncogenic PI3K-AKT signaling pathway through ablation of PTEN in the prostate. Using this transgenic tumor model, we explored how prostate cancer develops and progresses in the presence or absence of IL-6-STAT3 signaling. We have shown a previously unknown interaction between the loss of IL-6-activated Stat3 transcription factor and the tumor suppressor p53. Tumors developing in this model are very similar to the expression profile of human PC tumors. Moreover, these models are also metastatic, which is the life-threatening complication in the clinic. PC patients with advanced, metastatic disease cannot be cured and we strongly believe that our translational models will serve as excellent tools for pre-clinical drug testing.

Advertised project

Role of IL-6/STAT3 signaling in cellular plasticity and progression to therapy resistant prostate cancer (CRPC). We have shown that genetic inactivation of the IL6-STAT3/p14ARF axis in mice accelerates prostate cancer progression, leading to metastasis and early lethality due to loss of senescence¹. We hypothesize that loss of IL-6/STAT3 signaling promotes a malignant cancer metabolic phenotype, which is driven by aberrant LKB1/AMPK/mTOR signaling after loss of PTEN (Kenner L., unpublished).  In mutant Kras-driven lung cancer LKB1 inactivation promotes transdifferentiation from adenocarcinoma to squamous cells carcinoma and thus promotes resistance to therapy². Recently, we established organoids from prostate tumors of Pb-Cre4 Pten^fl/fl mice, and prostates of wild type controls (with GE). To understand the role of IL-6/STAT3 signaling in metastatic remodeling during CRPC, we will use CRISPR/Cas9 for ex vivo engineering of organoids and human prostate cancer xenografts. Genetically modified organoids will be subjected to in vitro high throughput metabolic drug screens (collaboration with S. Kubicek, CEMM and PH) and will be orthotopically implanted in syngeneic C57BL/6 mice to study the dependency of IL-6/STAT3/mTOR pathway for cellular plasticity and susceptibility to treatment. To prove the clinical relevance of the most important genetic aberrations during CRPC we will establish patient-derived organoid (PDO) models through orthotopic implantation of organoids derived from prostate cancer patients according to recently published protocols from our lab³. Genetically modified PDO will be xenografted into humanized MISTRG-IL6-IL15-HLA-A2 mice together with CD³⁴⁺ hematopoietic progenitor cells (with DHB).

Reference

1. Pencik, J.; Schlederer, M.; Gruber, W.; Unger, C.; Walker, S. M.; Chalaris, A.; Marié, I. J.; Hassler, M. R.; Javaheri, T.; Aksoy, O.; et al. STAT3 Regulated ARF Expression Suppresses Prostate Cancer Metastasis. Nat. Commun. 2015, 6, 7736. doi.org/10.1038/ncomms8736.
2. Li, F.; Han, X.; Li, F.; Wang, R.; Wang, H.; Gao, Y.; Wang, X.; Fang, Z.; Zhang, W.; Yao, S.; et al. LKB1 Inactivation Elicits a Redox Imbalance to Modulate Non-Small Cell Lung Cancer Plasticity and Therapeutic Response. Cancer Cell 2015, 27 (5), 698–711. doi.org/10.1016/j.ccell.2015.04.001.
3. Riedl, A.; Schlederer, M.; Pudelko, K.; Stadler, M.; Walter, S.; Unterleuthner, D.; Unger, C.; Kramer, N.; Hengstschläger, M.; Kenner, L.; et al. Comparison of Cancer Cells in 2D vs 3D Culture Reveals Differences in AKT–MTOR–S6K Signaling and Drug Responses. J Cell Sci 2017, 130 (1), 203–218. doi.org/10.1242/jcs.188102.