Tumor cell metabolism and epigenetic regulation in the development of new therapeutic approaches for colorectal and pancreatic cancer
Conradi Lab
Colorectal Cancer
While great success has been achieved for the treatment of colorectal cancer (CRC) during the last decades, there is still great need for improvement as prognosis is limited by the development of resistance towards established anti-tumor therapies and due to the development of metastasis during the course of disease. In addition to conventional chemo- and radiotherapy, anti-angiogenic therapies such as VEGF signaling inhibition have partly proven to be effective in the treatment of (m)CRC, however these strategies are strongly limited by cellular resistance mechanisms.
Currently in our lab, in vivo patient derived xenograft models and in vitro cultures using patient derived organoids and cell lines are being used to test new therapeutic strategies, combining the concept of tumor vessel normalization by metabolic targeting of tumor endothelial cells together with chemoradiotherapy.
These experimental approaches aid to understand not only the effects of cellular metabolism and epigenetic regulation on cancer cells but also how the tumor microenvironment (and especially the endothelium) influences the development of cancer resistance.
The projects developed in our group are future-oriented translational research projects, with the aim to develop new stategies in the area of gastrointestinal cancer research and treatment options in the field of metabolism-based anti-tumor therapies.
Our research team is especially interested in the underlying mechanisms involved in tumor angiogenesis. The current research projects are designed to: (i) better comprehend the molecular mechanisms by which tumor cells trigger angiogenesis; (ii) investigate the metabolic pathways which can promote tumor vessel formation versus tumor vessel co-option; (iii) to find novel therapeutical targets for the treatment of cancer and (iv) to develop and evaluate new strategies that can undermine tumor resistance towards therapy.
Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) remains a major challenge in cancer medicine with adesperate need to develop better treatment strategies. In fact, despite significant research efforts, PDAC still displays the highest mortality rate among all solid tumors in mankind. Major causes for its devastating disease outcome are the exceptionally aggressive tumor biology and the remarkable resistance to conventional anti-tumor treatments. Both characteristics are mechanistically linked to a very high degree of tumor heterogeneity, which is reflected by recent identification of various molecular and phenotypic PDAC subtypes.
Our research team is interested in the molecular mechanisms involved in specific metabolic PDAC subtypes (glycolytic versus lipolytic) and how they might contribute to tumor progression and therapy resistance. Ultimately our goal is to explore possible PDAC metabolic vulnerabilities which in turn might contribute to better therapies. The current research projects are designed to: (i) characterize different PDAC patient-derived organoids and cancer cell lines’ metabolic subtypes; (ii) to test the effects of novel PFKFB3 glycolytic inhibitors on PDAC cancer organoids and patient-derived xenografts; (iii) to find novel therapeutical targets for the treatment of PDAC that can undermine tumor resistance towards therapy. For further information, please also visit the Clinical Research Unit CRU5002 website.
Lab members
- PD Dr. Dr. Lena-Christin Conradi – group leader
- Dr. Tiago De Oliveira – postdoc
- Mrs. Birgit Jünemann – technical assistant
- Mr. Nikola Dobriniv Kyuchukov, B.A. – MD candidate
- Mr. Johannes Robert Fleischer – MD candidate
- Ms. Shuang Fan – MD candidate
- Mr. Olaf Schulze – MD candidate
- Ms. Teona Midelashvili – PhD student
- Ms. Alexandra M. Schmitt – MD candidate
- Ms. Dorothée Sartorius – MD candidate
- Ms. Chiara Jodszuweit – MD candidate
- Ms. Linde-Allegra Rosen – MD candidate
Lab alumni
- Ms. Gwendolyn Haas – MD candidate
- Ms. Tina Goldhardt – MD candidate
- Mr. Marcus Edelmann – MD candidate
Publications
- Effects of the Novel PFKFB3 Inhibitor KAN0438757 on Colorectal Cancer Cells and Its Systemic Evaluation in vivo.
De Oliveira T, Goldhardt T, Edelmann M, Rogge T, Rauch K, Kyuchukov ND, Menck K, Bleckman A, Kalucka J, Khan S, Gaedcke J, Haubrock M, Beissbarth T, Bohnenberger H, Planque M, Fendt SM, Ackermann L, Ghadimi M, Conradi LC. Cancers (Basel). 2021 Feb 28;13(5):1011. - Prognostic value of the micronucleus assay for clinical endpoints in neoadjuvant radiochemotherapy for rectal cancer.
Dröge LH, Hennies S, Lorenzen S, Conradi LC, Quack H, Liersch T, Helms C, Frank MA, Schirmer MA, Rave-Fränk M, Beißbarth T, Wolff HA.BMC Cancer. 2021 Mar 4;21(1):219. doi: 10.1186/s12885-021-07914-5. - Late-stage stitching enabled by manganese-catalyzed C─H activation: Peptide ligation and access to cyclopeptides.
Kaplaneris N, Kaltenhӓuser F, Sirvinskaite G, Fan S, De Oliveira T, Conradi LC, Ackermann L.
- Hsp90-stabilized MIF supports tumor progression via macrophage recruitment and angiogenesis in colorectal cancer.
Klemke L, De Oliveira T, Witt D, Winkler N, Bohnenberger H, Bucala R, Conradi LC, Schulz-Heddergott R. Cell Death Dis. 2021 Feb 4;12(2):155. doi: 10.1038/s41419-021-03426-z.
- Vascular Heterogeneity With a Special Focus on the Hepatic Microenvironment.
Fleischer JR, Jodszuweit CA, Ghadimi M, De Oliveira T, Conradi LC. Front Physiol. 2020 Nov 11;11:591901. doi: 10.3389/fphys.2020.591901. eCollection 2020.
- An Integrated Gene Expression Landscape Profiling Approach to Identify Lung Tumor Endothelial Cell Heterogeneity and Angiogenic Candidates.
Goveia J, Rohlenova K, Taverna F, Treps L, Conradi LC, Pircher A, Geldhof V, de Rooij LPMH, Kalucka J, Sokol L, García-Caballero M, Zheng Y, Qian J, Teuwen LA, Khan S, Boeckx B, Wauters E, Decaluwé H, De Leyn P, Vansteenkiste J, Weynand B, Sagaert X, Verbeken E, Wolthuis A, Topal B, Everaerts W, Bohnenberger H, Emmert A, Panovska D, De Smet F, Staal FJT, Mclaughlin RJ, Impens F, Lagani V, Vinckier S, Mazzone M, Schoonjans L, Dewerchin M, Eelen G, Karakach TK, Yang H, Wang J, Bolund L, Lin L, Thienpont B, Li X, Lambrechts D, Luo Y, Carmeliet P.Cancer Cell. 2020 Jan 13;37(1):21-36.e13. doi: 10.1016/j.ccell.2019.12.001.
- Enhancer of Zeste Homolog 2 in Colorectal Cancer Development and Progression.
Bremer SCB, Conradi LC, Mechie NC, Amanzada A, Mavropoulou E, Kitz J, Ghadimi M, Ellenrieder V, Ströbel P, Hessmann E, Gaedcke J, Bohnenberger H. Digestion. 2019 Nov 6:1-9. - Combined targeting of HER-2 and HER-3 represents a promising therapeutic strategy in colorectal cancer.
Conradi LC, Spitzner M, Metzger AL, Kisly M, Middel P, Bohnenberger H, Gaedcke J, Ghadimi MB, Liersch T, Rüschoff J, Beißbarth T, König A, Grade M. BMC Cancer. 2019 Sep 5;19(1):880. - Therapeutic Ablation of Gain-of-Function Mutant p53 in Colorectal Cancer Inhibits Stat3-Mediated Tumor Growth and Invasion.
Schulz-Heddergott R, Stark N, Edmunds SJ, Li J, Conradi LC, Bohnenberger H, Ceteci F, Greten FR, Dobbelstein M, Moll UM. Cancer Cell. 2018 Aug 13;34(2):298-314. - RAISEing VEGF-D's importance as predictive biomarker for ramucirumab in metastatic colorectal cancer patients.
Carmeliet P, Li X, Treps L, Conradi LC, Loges S. Ann Oncol. 2018 Mar 1;29(3):527-529. - Tumor vessel disintegration by maximum tolerable PFKFB3 blockade.
Conradi LC, Brajic A, Cantelmo AR, Bouché A, Kalucka J, Pircher A, Brüning U, Teuwen LA, Vinckier S, Ghesquière B, Dewerchin M, Carmeliet P. Angiogenesis. 2017 Nov;20(4):599-613. - The Prognostic Value of Tyrosine Kinase SRC Expression in Locally Advanced Rectal Cancer.
Rühlmann F, Nietert M, Sprenger T, Wolff HA, Homayounfar K, Middel P, Bohnenberger H, Beissbarth T, Ghadimi BM, Liersch T, Conradi LC. J Cancer. 2017 Apr 10;8(7):1229-1237. - Inhibition of the Glycolytic Activator PFKFB3 in Endothelium Induces Tumor Vessel Normalization, Impairs Metastasis, and Improves Chemotherapy.
Cantelmo AR, Conradi LC, Brajic A, Goveia J, Kalucka J, Pircher A, Chaturvedi P, Hol J, Thienpont B, Teuwen LA, Schoors S, Boeckx B, Vriens J, Kuchnio A, Veys K, Cruys B, Finotto L, Treps L, Stav-Noraas TE, Bifari F, Stapor P, Decimo I, Kampen K, De Bock K, Haraldsen G, Schoonjans L, Rabelink T, Eelen G, Ghesquière B, Rehman J, Lambrechts D, Malik AB, Dewerchin M, Carmeliet P. Cancer Cell. 2016 Dec 12;30(6):968-985.