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.

Publications

Gurlevik E, Fleischmann-Mundt B, Brooks J, Demir IE, Steiger K, Ribback S, Yevsa T, Woller N, Kloos A, Ostroumov D, Armbrecht N, Manns MP, Dombrowski F, Saborowski M, Kleine M, Wirth TC, Oettle H, Ceyhan GO, Esposito I, Calvisi DF, Kubicka S, Kühnel F (2016) Administration of Gemcitabine After Pancreatic Tumor Resection in Mice Induces an Antitumor Immune Response Mediated by Natural Killer Cells. Gastroenterology 151:338-350 e337.
Knocke S, Fleischmann-Mundt B, Saborowski M, Manns MP, Kuhnel F, Wirth TC, Woller N (2016) Tailored Tumor Immunogenicity Reveals Regulation of CD4 and CD8 T Cell Responses against Cancer. Cell Rep 17: 2234-2246.
Endig J, Buitrago-Molina LE, Marhenke S, Reisinger F, Saborowski A, Schütt J, Limbourg F, Könecke C, Schreder A, Michael A, Misslitz AC, Healy ME, Geffers R, Clavel T, Haller D, Unger K, Finegold M, Weber A, Manns MP, Longerich T, Heikenwälder M, Vogel A (2016) Dual Role of the Adaptive Immune System in Liver Injury and Hepatocellular Carcinoma Development. Cancer Cell 30:308-22.
Harmsen S, Huang R, Wall MA, Karabeber H, Samii JM, Spaliviero M, White JR, Monette S, O'Connor R, Pitter KL, Sastra SA, Saborowski M, Holland EC, Singer S, Olive KP, Lowe SW, Blasberg RG, Kircher MF (2015) Surface-enhanced resonance Raman scattering nanostars for high-precision cancer imaging. Sci Transl Med 7:271ra277.
Saborowski M, Saborowski A, Morris JP 4th, Bosbach B, Dow LE, Pelletier J, Klimstra DS, Lowe SW (2014) A modular and flexible ESC-based mouse model of pancreatic cancer. Genes Dev 28:85- 97.
Weissmueller S, Manchado E, Saborowski M, Morris JP 4th, Wagenblast E, Davis CA, Moon SH, Pfister NT, Tschaharganeh DF, Kitzing T, Aust D, Markert EK, Wu J, Grimmond SM, Pilarsky C, Prives C, Biankin AV, Lowe SW (2014) Mutant p53 Drives Pancreatic Cancer Metastasis through Cell- Autonomous PDGF Receptor beta Signaling. Cell 157:382-394.
Dow LE, Nasr Z, Saborowski M, Ebbesen SH, Manchado E, Tasdemir N, Lee T, Pelletier J, Lowe SW (2014) Conditional Reverse Tet-Transactivator Mouse Strains for the Efficient Induction of TRERegulated Transgenes in Mice. PLoS One 9:e95236.
Lito P*, Saborowski A*, Yue J, Solomon M, Joseph E, Gadal S, Saborowski M, Kastenhuber E, Fellmann C, Ohara K, Morikami K, Miura T, Lukacs C, Ishii N, Lowe S, Rosen N (2014) Disruption of CRAF-Mediated MEK Activation Is Required for Effective MEK Inhibition in KRAS Mutant Tumors. Cancer Cell 25(5):697-710.*authors contributed equally
Saborowski A*, Saborowski M*, Davare MA, Druker BJ, Klimstra DS, Lowe SW (2013) Mouse model of intrahepatic cholangiocarcinoma validates FIG-ROS as a potent fusion oncogene and therapeutic target. Proc Natl Acad Sci USA 110:19513-18. *authors contributed equally
Davare MA*, Saborowski A*, Eide CA, Tognon C, Smith RL, Elferich J, Agarwal A, Tyner JW, Shinde UP, Lowe SW, Druker BJ (2013) Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins. Proc Natl Acad Sci USA 110:19519-24. *authors contributed equally