Identification and functional characterization of cancer cell-derived, stroma-modulating factors in cholangiocarcinoma
Final Report Abstract
Cholangiocarcinoma (CC) is a highly malignant tumor that is characterized by a dense tumor reactive stroma surrounding the cancer cells. This tumor microenvironment (TME) is a site of complex crosstalk between multiple cellular components, such as tumor cells, immune cells and cancerassociated fibroblasts. Whether the stroma supports proliferation of the cancer cells in an oncogenic fashion or actually restrains tumor growth has been a topic of intense debate, and likely the role of the stroma in cancer initiation, progression, metastasis and therapy response is multifaceted. In this project, we have established murine organoid technology and model systems to investigate the molecular mechanisms underlying the tumor promoting effects of the secreted factors GM-CSF and G-CSF. Using an in vivo CRISPR screening approach, we have identified STK11 as a potent tumor suppressor gene in intrahepatic cholangiocarcinoma and now aim to functionally investigate its stroma-modulating capacities. Furthermore, we have compiled a comprehensive clinical and molecular dataset from over 160 patients. To annotate the architectural diversity of the TME in primary human intrahepatic CC, we have performed multiplexed immunohistochemistry and multispectral imaging of the different tumor “regions”, and we have trained programs to perform automated image analysis. These data will now be evaluated both quantitatively and spatially, and correlated to the available clinical outcome data, to determine whether we can define specific “subtypes” of human CC based on the immune infiltrates.
Publications
- Generation of focal mutations and large genomic deletions in the pancreas using inducible in vivo genome editing. Carcinogenesis 2019
Mishra A, Emamgholi F, Erlangga Z, Hartleben B, Unger K, Wolff K, Teichmann U, Kessel M, Woller N, Kuhnel F, Dow LE, Manns MP, Vogel A, Lowe SW, Saborowski A, Saborowski M
(See online at https://doi.org/10.1093/carcin/bgz108) - Genetic Mouse Models as In Vivo Tools for Cholangiocarcinoma Research. Cancers (Basel) 2019;11
Erice O, Vallejo A, Ponz-Sarvise M, Saborowski M, Vogel A, Calvisi DF, Saborowski A, Vicent S
(See online at https://doi.org/10.3390/cancers11121868) - Murine Liver Organoids as a Genetically Flexible System to Study Liver Cancer In Vivo and In Vitro. Hepatol Commun 2019;3:423-436
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
(See online at https://doi.org/10.1002/hep4.1312) - Potent Antitumor Activity of Liposomal Irinotecan in an Organoid- and CRISPR-Cas9-Based Murine Model of Gallbladder Cancer. Cancers (Basel) 2019;11
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
(See online at https://doi.org/10.3390/cancers11121904) - FGFR inhibitors in cholangiocarcinoma: what’s now and what’s next?, Therapeutic Advances in Medical Oncology, Ther Adv Med Oncol 2020
Saborowski A, Vogel A
(See online at https://doi.org/10.1177/1758835920953293) - Immunotherapies in clinical development for biliary tract cancer. Expert Opin Investig Drugs 2021, 30:4, 351-363
Vogel A, Bathon M, Saborowski A
(See online at https://doi.org/10.1080/13543784.2021.1868437) - p53-independent induction of p21 fails to control regeneration and hepatocarcinogenesis in a murine liver injury model. Cell Mol Gastroenterol Hepatol 2021
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
(See online at https://doi.org/10.1016/j.jcmgh.2021.01.006)
