Which cells inside the tumor can be targeted by different cGMP-increasing molecules like NO, peptide hormones, and drugs? Especially, can pharmacological stimulators of NO‑GC increase cGMP in the pericytes of tumor blood vessels? We will address these questions with real-time in situ cGMP imaging in intact tumor tissues of “cGMP sensor mice” ex vivo, and will expand our findings with in vivo experiments by using two-photon microscopy.
What is the functional relevance of cGMP in pericytes of the tumor vasculature? We will perform state-of-the-art in vitro vessel-on-a-chip experiments (collaboration with Dr. Natalia Pashkovskaia and Prof. Dr. Stefan Liebau) to answer this question. Combined with the in situ cGMP imaging data, this will improve our understanding of the cellular mechanisms underlying the effect of cGMP on the tumor vasculature.
How does genetic and pharmacological modulation of the NO‑GC/cGMP pathway affect the tumor vascularization in vivo? To follow this question, we will monitor the tumor growth in treated and control mice, and finally examine structural and functional parameters of the tumor vasculature by combining classical immunostaining of tumor cryosections with light-sheet microscopy of whole tumors. (collaboration with Prof. Dr. Bettina Weigelin)
Our hypothesis is that stimulation of NO‑GC/cGMP signaling in tumor pericytes - for example, with the FDA-approved drug riociguat - normalizes the tumor vasculature, thereby improving tumor perfusion and delivery of anti-cancer co-therapies to the tumor cells!
Daniel studied biochemistry in Tübingen with a focus on immune response, oncology and cell biology. Among other things, he analyzed the mechanism of neutrophil-mediated pathogen clearance and the molecular mechanism of apoptosis induction. Daniel then moved on to do his PhD in the lab of Robert Feil. Here, his achievements included the establishment of several protocols for the real-time in situ cGMP imaging of various tissues, like the kidney and tumors. In collaboration with other labs, he used his newly-established protocols to analyze how the NO/cGMP pathway can be modulated to improve the renal blood flow, and identified new cell types with functional cGMP signaling in the melanoma tumor microenvironment. Daniel’s postdoc work now aims to resolve the functional relevance of cGMP in these cells of the tumor microenvironment and to identify potential target points for pharmacological intervention. After Daniel's start-up funding ended in summer 2023, he accepted a postdoc position in the lab of Jin Zhang at the University of California San Diego (UCSD).
