B07: Identification and functional characterization of cancer cell-derived, stroma-modulating factors in cholangiocarcinoma

Cholangiocarcinoma (CC) is a highly malignant tumor that is characterized by a dense desmoplastic stroma surrounding the cancer cells. This tumor microenvironment is a site of complex crosstalk between multiple cellular components, such as tumor cells, immune cells and cancer-associated fibroblasts.
Whether the stroma supports proliferation of the cancer cells in an oncogenic fashion or actually restrains tumor growth has been a topic of extensive debate, and likely the role of the stroma in cancer initiation, progression, metastasis and therapy response is multifaceted. In CC, the stromal compartment has so far been insufficiently investigated. Thus, the overall objective of this project is to characterize the stromal pathobiology in CC and to assess the potential therapeutic benefits, but also risks, associated with targeting the tumor stroma. Specifically, we aim to functionally test designated stroma-modifying mediators such as platelet derived growth factor D (PDGFD) and sonic hedgehog (SHH), as well as to identify and characterize additional cancer cell-derived, secreted factors that promote the extensive structural remodeling of the tumor reactive microenvironment. To do so, we will integrate innovative mouse models that allow for the reversible regulation of candidate factors in established CC with data derived from microdissected human CC specimens and organoid-culture based secretome analysis.


a) Peer-reviewed publications and books
• Kendre G, Marhenke S, Lorz G, Kühnel F, Woller N, Reineke-Plaaß T, Poth T, Becker D, Marquardt JU, Wirtz RM, Bonin M, Saborowski M, Vogel A*, Saborowski A* (2021). The co-mutational spectrum determines the therapeutic response in murine FGFR2 fusion - driven cholangiocarcinoma. Hepatology. doi: 10.1002/hep.31799. *equal contribution.
• Buitrago-Molina LE, Marhenke S, Becker D, Geffers R, Itzel T, Teufel A, Jaeschke H, Lechel A, Unger K, Markovic J, Sharma AD, Marquardt JU, Saborowski M, Saborowski A*, Vogel A* (2021). p53-independent induction of p21 fails to control regeneration and hepatocarcinogenesis in a murine liver injury model. Cell Mol Gastroenterol Hepatol 11:1387-1404. *equal contribution.
• Dai Z, Song G, Balakrishnan A, Yang T, Yuan Q, Mobus S, Weiss AC, Bentler M, Zhu J, Jiang X, Shen X, Bantel H, Jaeckel E, Kispert A, Vogel A, Saborowski A, Buning H, Manns M, Cantz T, Ott M, Sharma AD (2020) Growth differentiation factor 11 attenuates liver fibrosis via expansion of liver progenitor cells. Gut 69:1104-1115.
• Saborowski A, Wolff K, Spielberg S, Beer B, Hartleben B, Erlangga Z, Becker D, Dow LE, Marhenke S, Woller N, Unger K, Schirmacher P, Manns MP, Marquardt JU, Vogel A, Saborowski M (2019) Murine liver organoids as a genetically flexible system to study liver cancer in vivo and in vitro. Hepatol Commun 3:423-436.
• Erice O, Vallejo A, Ponz-Sarvise M, Saborowski M, Vogel A, Calvisi DF, Saborowski A*, Vicent S* (2019) Genetic mouse models as in vivo tools for cholangiocarcinoma research. Cancers (Basel) 11:1868. *equal contribution.
• Erlangga Z, Wolff K, Poth T, Peltzer A, Nahnsen S, Spielberg S, Timrott K, Woller N, Kuhnel F, Manns MP, Saborowski A, Vogel A, Saborowski M (2019) Potent antitumor activity of liposomal irinotecan in an organoid- and CRISPR-Cas9-based murine model of gallbladder cancer. Cancers (Basel) 11:1904.
• Vicent S, Lieshout R, Saborowski A, Verstegen MMA, Raggi C, Recalcati S, Invernizzi P, van der Laan LJW, Alvaro D, Calvisi DF, Cardinale V (2019) Experimental models to unravel the molecular pathogenesis, cell of origin and stem cell properties of cholangiocarcinoma. Liver Int 39Suppl1:79-97.
• Ostroumov D, Fekete-Drimusz N, Saborowski M, Kühnel F, Woller N (2018) CD4 and CD8 T lymphocyte interplay in controlling tumor growth. Cell Mol Life Sci 75:689-713.
b) Other publications, both peer-reviewed and non-peer-reviewed
• Saborowski A, Lehmann U, Vogel A (2020) FGFR inhibitors in cholangiocarcinoma: what's now and what's next? Ther Adv Med Oncol 12:1758835920953293.
• Vogel A, Saborowski A (2017) Cholangiocellular carcinoma. Digestion 95:181-185.