Research Group Prof. Dr. Henner Farin
Experimental models of the colon cancer microenvironment
Our research group is investigating the cellular and molecular processes in the development of colorectal cancer. In particular, we are interested in the communication of different cell types in the immediate surrounding of the tumor, the so-called “tumor microenvironment”. For this purpose, we use “organoids”, a novel three-dimensional tissue culture system.
Colorectal cancer (CRC) is a leading cause of cancer-related deaths and is characterized by multiple genetic and epigenetic alterations. The individual tumor phenotype is strongly influenced by the tumor microenvironment that includes surrounding fibroblasts, vasculature, and immune cells. To study this complex disease and develop personalized therapeutic strategies a comprehensive approach is required.
Patient-derived tumor organoids and co-culture models
Patient derived organoids (PDOs) have emerged as a research tool that mimics the 3D organization of the gastrointestinal epithelium. Furthermore, co-cultures with stromal cells can be performed to recreate a tissue-like context. PDOs can be expanded and cryopreserved as “living biobanks” that represent the tumor heterogeneity among patients. In collaboration with the University Tumor Center Frankfurt and supported by Frankfurt Cancer Institute (FCI), we are operating the FCI Organoid Biobank to provide support for culture and analysis of PDOs.
Genetic regulators of the CRC microenvironment
Tissue homeostasis depends on the interaction of stem cells with signals from the microenvironment. In tumors, this interaction is perturbed causing uncontrolled growth. To study tissue crosstalk we employ organoid co-cultures and transplantation models. Recently, we have identified that tumor mutations that activate Wnt signaling also influence cancer-associated fibroblasts (CAFs). Wnt inhibition induces a CAF subtype that renders tumor cells more invasive (Mosa et al., Cancer Research 2020), highlighting how stromal cell plasticity can regulate tumor malignancy.
To study influences of the tumor microenvironment on a global level we have performed genetic screens in human colon organoids using the CRISPR/Cas9 technology. This allows unbiased identification of tumor suppressor genes that promote growth in vitro and after organoid xenotransplantation (Michels et al., Cell Stem Cell 2020). In future, this platform could help to discover individualized therapeutic targets for colon cancer.
Personalized models for CRC therapy and pharmacogenomic screening
PDOs can serve as a preclinical model to identify therapeutic strategies. In collaboration with Prof. Wels (Georg-Speyer-Haus), we have used chimeric antigen receptors (CAR)-modified NK cells to induce cytotoxicity of CRC cells. We have developed enzymatic and live imaging assays to evaluate efficacy CAR cells (Schnalzger et al., EMBO Journal 2019).
As participant of the EU-consortium “EUbOPEN” (Enabling and unlocking biology in the OPEN, 2020-2024), we have developed a PDO drug screening platform. The EUbOPEN consortium is funded by the Innovative Medicines Initiative (IMI2) and aims to generate an open access chemogenomic library of compounds covering the “druggable human genome”. Together with our partners from academia and pharmacologic industry, we develop “Human
Tissue Assays” for CRC. We conduct high-throughput pharmacologic screens using the organoid biobank to identify resistance mechanisms and therapeutic strategies.
The EUbOPEN project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 875510. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme, EFPIA companies and Associated Partners: KTH, OICR, Diamond and McGill. This communication reflects the views of the authors and neither IMI nor the European Union, EFPIA or any Associated Partners are liable for any use that may be made of the information contained herein.
The EUbOPEN project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 875510. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme, EFPIA companies and Associated Partners: KTH, OICR, Diamond and McGill. This communication reflects the views of the authors and neither IMI nor the European Union, EFPIA or any Associated Partners are liable for any use that may be made of the information contained herein.
Team
Schnalzger TE, de Groot MHP, Zhang C, Mosa MH, Michels BE, Röder J, Darvishi T, Wels WS, Farin HF. (2019)
3D model for CAR-mediated cytotoxicity using patient-derived colorectal cancer organoids.
The EMBO Journal. 38(12):e100928.
Michels BE, Mosa MH, Streibl BI, Zhan T, Menche C, Abou-El-Ardat K, Darvishi T, Członka E, Wagner S, Winter J, Medyouf H. Boutros M, Farin HF. (2020)
Pooled In Vitro and In Vivo CRISPR-Cas9 Screening Identifies Tumor Suppressors in Human Colon Organoids.
Cell Stem Cell. 26: 782-792.e7.
Farin HF*, Mosa MH, Ndreshkjana B, Grebbin BM, Ritter B, Menche C, Kennel KB, Ziegler PK, Szabo L, Bollrath J, Rieder D, Michels BE, Kress A, Bozlar M, Darvishi T, Stier S, Kur I-M, Bankov K, Kesselring R, Fichtner-Feigl S, Brune B, Goetze TO, Al-Batran S-E, Brandts CH, Bechstein WO, Wild PJ, Weigert A, Muller S, Knapp S, Trajanoski Z, Greten FR*. (2023)
Colorectal cancer organoid-stroma biobank allows subtype-specific assessment of individualized therapy responses.
Cancer Discovery. 13(10):2192–2211. * corresponding authors
Menche C*, Schuhwerk H*, Armstark I, Gupta P, Fuchs K, van Roey R, Mosa MH, Hartebrodt A, Hajjaj Y, Clavel Ezquerra A, Selvaraju MK, Geppert CI, Bärthel S, Saur D, Greten FR, Brabletz S, Blumenthal DB, Weigert A, Brabletz T**, Farin HF**, Stemmler MP**. (2024)
ZEB1-mediated fibroblast polarization controls inflammation and sensitivity to immunotherapy in colorectal cancer.
EMBO reports. 25(8):3406–3431. * first authors ** corresponding authors
More Publications
Author Correction: Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways
Nat Commun. 2024 Dec 19;15(1):10698. doi: 10.1038/s41467-024-55044-w.
NO ABSTRACT
PMID:39702301 | PMC:PMC11659427 | DOI:10.1038/s41467-024-55044-w
Toward target 2035: EUbOPEN - a public-private partnership to enable & unlock biology in the open
RSC Med Chem. 2024 Nov 29. doi: 10.1039/d4md00735b. Online ahead of print.
ABSTRACT
Target 2035 is a global initiative that seeks to identify a pharmacological modulator…
Establishment of Patient-Derived Organoids from Colorectal Cancer Resection Samples
Methods Mol Biol. 2024 Nov 10. doi: 10.1007/7651_2024_575. Online ahead of print.
ABSTRACT
Colorectal cancer (CRC) organoids can serve as powerful preclinical cell…
ZEB1-mediated fibroblast polarization controls inflammation and sensitivity to immunotherapy in colorectal cancer
EMBO Rep. 2024 Aug;25(8):3406-3431. doi: 10.1038/s44319-024-00186-7. Epub 2024 Jun 27.
ABSTRACT
The EMT-transcription factor ZEB1 is heterogeneously expressed in tumor…
Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways
Nat Commun. 2024 May 15;15(1):4096. doi: 10.1038/s41467-024-48422-x.
ABSTRACT
The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to…
Downregulation of V-ATPase V0 Sector Induces Microvillus Atrophy Independently of Apical Trafficking in the Mammalian Intestine
Cell Mol Gastroenterol Hepatol. 2024;17(6):1072-1075. doi: 10.1016/j.jcmgh.2024.02.011. Epub 2024 Feb 16.
NO ABSTRACT
PMID:38369130 | PMC:PMC11127621 | DOI:10.1016/j.jcmgh.2024.02.011
Functional and spatial proteomics profiling reveals intra- and intercellular signaling crosstalk in colorectal cancer
iScience. 2023 Nov 4;26(12):108399. doi: 10.1016/j.isci.2023.108399. eCollection 2023 Dec 15.
ABSTRACT
Precision oncology approaches for patients with colorectal cancer…
Colorectal Cancer Organoid-Stroma Biobank Allows Subtype-Specific Assessment of Individualized Therapy Responses
Cancer Discov. 2023 Oct 5;13(10):2192-2211. doi: 10.1158/2159-8290.CD-23-0050.
ABSTRACT
In colorectal cancers, the tumor microenvironment plays a key role in prognosis…
Actin dynamics regulation by TTC7A/PI4KIIIα limits DNA damage and cell death under confinement
J Allergy Clin Immunol. 2023 Oct;152(4):949-960. doi: 10.1016/j.jaci.2023.06.016. Epub 2023 Jun 29.
ABSTRACT
BACKGROUND: The actin cytoskeleton has a crucial role in the…
Deep Annotation of Donated Chemical Probes (DCP) in Organotypic Human Liver Cultures and Patient-Derived Organoids from Tumor and Normal Colorectum
ACS Chem Biol. 2023 Apr 21;18(4):822-836. doi: 10.1021/acschembio.2c00877. Epub 2023 Mar 21.
ABSTRACT
Well-characterized small molecules are essential tools for studying…
Synthetic enforcement of STING signaling in cancer cells appropriates the immune microenvironment for checkpoint inhibitor therapy
Sci Adv. 2023 Mar 17;9(11):eadd8564. doi: 10.1126/sciadv.add8564. Epub 2023 Mar 15.
ABSTRACT
Immune checkpoint inhibitors (ICIs) enhance anticancer immunity by releasing…
Immune escape of colorectal tumours via local LRH-1/Cyp11b1-mediated synthesis of immunosuppressive glucocorticoids
Mol Oncol. 2023 Aug;17(8):1545-1566. doi: 10.1002/1878-0261.13414. Epub 2023 Mar 9.
ABSTRACT
Control of tumour development and growth by the immune system critically…
Loss of SUV420H2-Dependent Chromatin Compaction Drives Right-Sided Colon Cancer Progression
Gastroenterology. 2023 Feb;164(2):214-227. doi: 10.1053/j.gastro.2022.10.036. Epub 2022 Nov 17.
ABSTRACT
BACKGROUND & AIMS: Epigenetic processes regulating gene…
Expansion of T memory stem cells with superior anti-tumor immunity by Urolithin A-induced mitophagy
Immunity. 2022 Nov 8;55(11):2059-2073.e8. doi: 10.1016/j.immuni.2022.09.014. Epub 2022 Oct 19.
ABSTRACT
T memory stem cells (TSCM) display increased self-renewal and…
Strategies for genetic manipulation of adult stem cell-derived organoids
Exp Mol Med. 2021 Oct;53(10):1483-1494. doi: 10.1038/s12276-021-00609-8. Epub 2021 Oct 18.
ABSTRACT
Organoid technology allows the expansion of primary epithelial cells…