Interview with Prof. Dr. Andreas Fischer

Department of Clinical Chemistry, UMG

What is your research focus and what are your major research questions?
The main focus of our research is to understand how blood vessels respond to pathological conditions, in particular solid cancers and metabolic alterations, and how subsequently the vasculature alters organ functions. We are especially interested in how gene expression in the inner lining of blood vessels, the endothelium, is altered within a solid tumor mass and how this contributes to growth of new blood vessels (angiogenesis), the immune response towards cancer cells, and the entry of tumor cells into the circulation. In addition, we address questions about factors released from endothelial cells and how they impact cancer and immune cells.

A fascinating new area of research is to improve our understanding of how the endothelium in distant organs is affected by the presence of a solid tumor mass which has not yet metastasized. Already in early stages of tumor progression, substantial changes in the protein expression of endothelial cells occur in organs far away from the primary tumor. This seems to facilitate the homing of circulating tumors cells and the colonization of distant organs. As such, the endothelium appears to play a major role during metastasis. Our aim is to both understand this and to develop strategies to inhibit several steps of the metastatic cascade.

How did you become a researcher? What were the major influences in your career?
I was always very interested in natural sciences and during my studies at Würzburg Medical School, my MD thesis advisor Professor Manfred Gessler allowed me to work on a challenging project unraveling the function of a new transcription factor which had just been discovered in his laboratory. It turned out that this transcription factor is essential for heart development and angiogenesis and since then I have been fascinated by vascular biology. A predoctoral training at Children’s Hospital Boston and Dana Faber Cancer Institute inspired me to extend my research interest towards understanding basic principles of tumor progression. At Heidelberg University and the German Cancer Research Center I found places to work as a clinician scientist, combining clinical training with research on blood vessels and tumor progression. This was only possible due to excellent support by Professor Hellmut Augustin, a leading expert in vascular biology and metastasis research, and Professor Peter Nawroth, a leading expert in diabetes mellitus and clinical chemistry. Now in Göttingen, I have the chance to further translate our findings into a more clinical setting. In addition we are developing techniques to better monitor cancer progression using patient blood samples.

What are findings you are excited about? And what are your own major recent findings?
The great advances in personalized oncology, the development of anti-cancer vaccines, and of course the new area of artificial intelligence. In my research field I am fascinated by the new findings indicating that endothelial cells control not only organ development but also regeneration and that such mechanisms are re-activated in cancer models.

Recently we were able to show how endothelial cell-derived factors contribute to inhibiting the immune response towards cancer cells. Last month, we published a manuscript showing for the first time that pancreatic cancer changes gene transcription in blood vessels of white adipose tissue. This leads to local inflammation, cell death of adipocytes, fibrosis, and eventually wasting of adipose tissue. As such, we were surprised to see that the endothelial acts as a sensor of cancer at distant sites and that it can mediate cancer-derived signals to induce organ wasting.

What kind of techniques and methods do you use for your research?
We are using a broad range of cellular models, including organoid cultures, but also mouse models to study systemic effects of tumors. Transcriptomic and proteomic analyses, as well as immunofluorescence microscopy are performed on a regular basis. Moreover, we are currently establishing liquid profiling by digital PCR and developing biomarkers for oncology and cardiovascular medicine.

How can translational research activities benefit from the CCC-N research structure?
The CCC-N helps bringing together complementary research and clinical expertise in oncology and allows for easier exchange of data and material. I am convinced that it will be key to fostering even more excellent collaborative research in oncology research in Lower Saxony.

Can you tell us a little about yourself and your working group?
After moving to Göttingen 1,5 years ago, I needed to rebuild my research group, a process that is still ongoing. We are an interdisciplinary group of international scientists, students, and research assistants with expertise in vascular biology, tumor biology, biochemistry, cell biology, and clinical chemistry.

How can patients benefit from your research?
Most projects address basic principles of tumor biology, and it is always difficult to predict whether patients will eventually benefit from our findings. For example, our latest publication suggests that inhibiting retinoic acid signaling, for which drugs are available, could delay organ wasting and weight loss in patients with cancer. Other groups or pharmaceutical companies need to take the next steps in testing this. Also, we proposed that blocking Notch signaling could be highly relevant to interfering with several aspects of tumor progression. Therapeutical antibodies have been developed by pharmaceutical companies and we tested some of these in pre-clinical models. They work very well but we also detected some severe side effects. Our ongoing work on liquid profiling has the potential to improve the monitoring of cancer therapies and the early detection of relapse.

What is the biggest challenge in cancer research?
Cancer cells are very heterogeneous, and this already makes treatment strategies difficult. However, a cancer mass consists not only of cancer cells but also a large variety of immune cells, fibroblasts, endothelial cells, and others. All of these influence each other. This eventually helps the cancer to develop resistance mechanisms against radiochemotherapy and we still do not know how to overcome this.

Selection of publications

Endothelial Notch1 signaling in white adipose tissue promotes cancer cachexia. Taylor J, Uhl L, Moll I, Hasan SS, Wiedmann L, Morgenstern J, Giaimo BD, Friedrich T, Alsina-Sanchis E, De Angelis Rigotti F, Mülfarth R, Kaltenbach S, Schenk D, Nickel F, Fleming T, Sprinzak D, Mogler C, Korff T, Billeter AT, Müller-Stich BP, Berriel Diaz M, Borggrefe T, Herzig S, Rohm M, Rodriguez-Vita J, Fischer A. Nat Cancer. 2023 Sep 25. doi: 10.1038/s43018-023-00622-y. Epub ahead of print. PMID: 37749321.

HAPLN1 potentiates peritoneal metastasis in pancreatic cancer. Wiedmann L, De Angelis Rigotti F, Vaquero-Siguero N, Donato E, Espinet E, Moll I, Alsina-Sanchis E, Bohnenberger H, Fernandez-Florido E, Mülfarth R, Vacca M, Gerwing J, Conradi LC, Ströbel P, Trumpp A, Mogler C, Fischer A, Rodriguez-Vita J. Nat Commun. 2023 Apr 24;14(1):2353. doi: 10.1038/s41467-023-38064-w. PMID: 37095087; PMCID: PMC10126109.

Endothelial RBPJ Is Essential for the Education of Tumor-Associated Macrophages. Alsina-Sanchis E, Mülfarth R, Moll I, Böhn S, Wiedmann L, Jordana-Urriza L, Ziegelbauer T, Zimmer E, Taylor J, De Angelis Rigotti F, Stögbauer A, Giaimo BD, Cerwenka A, Borggrefe T, Fischer A, Rodriguez-Vita J. Cancer Res. 2022 Dec 2;82(23):4414-4428. doi: 10.1158/0008-5472.CAN-22-0076. PMID: 36200806.

Ketone body oxidation increases cardiac endothelial cell proliferation. Weis EM, Puchalska P, Nelson AB, Taylor J, Moll I, Hasan SS, Dewenter M, Hagenmüller M, Fleming T, Poschet G, Hotz-Wagenblatt A, Backs J, Crawford PA, Fischer A. EMBO Mol Med. 2022 Apr 7;14(4):e14753. doi: 10.15252/emmm.202114753. Epub 2022 Feb 18. PMID: 35179309; PMCID: PMC8988203.

Endothelial Notch1 Activity Facilitates Metastasis. Wieland E, Rodriguez-Vita J, Liebler SS, Mogler C, Moll I, Herberich SE, Espinet E, Herpel E, Menuchin A, Chang-Claude J, Hoffmeister M, Gebhardt C, Brenner H, Trumpp A, Siebel CW, Hecker M, Utikal J, Sprinzak D, Fischer A. Cancer Cell. 2017 Mar 13;31(3):355-367. doi: 10.1016/j.ccell.2017.01.007. Epub 2017 Feb 23. PMID: 28238683.

Endothelial Notch signaling controls insulin transport in muscle. Hasan SS, Jabs M, Taylor J, Wiedmann L, Leibing T, Nordström V, Federico G, Roma LP, Carlein C, Wolff G, Ekim-Üstünel B, Brune M, Moll I, Tetzlaff F, Gröne HJ, Fleming T, Géraud C, Herzig S, Nawroth PP, Fischer A. EMBO Mol Med. 2020 Apr 7;12(4):e09271. doi: 10.15252/emmm.201809271. Epub 2020 Mar 18. PMID: 32187826; PMCID: PMC7136962.