AG Gudermann/Bach "Cancer Clot and Inflammation"

Gudermann/Bach lab "Cancer Clot and Inflammation"

Head: Dr. Elmina Bach

E-Mail: elmina.bach@med.uni-muenchen.de

Group members:
Medina Mamtimin: (FöFoLe program, MD student, WSI, LMU)
Guoyu Dai (WSI, LMU Klinikum)
Luying Yang (WSI, LMU Klinikum)

Cancer progression is regulated by the dynamic interaction between cancer cells and different components of the surrounding environment. This tumor microenvironment is composed of complex tissues that contain extracellular matrix, growth factors, cytokines, chemokines, and adhesion receptors, also many cell types, such as fibroblasts, immune cells, epithelial cells, adipocytes, lymphatic and endothelial cells and platelets. Compelling evidence indicates that the cellular and molecular components of the tumor microenvironment are critical regulators of immune escape, cancer progression and metastasis and involved in acquired resistance of tumors to therapies. Tumor cell dissemination from primary organs to the metastatic sites involves the transport of cancer cells through the blood or lymphatic circulation. The dissemination of circulating cancer cells is also supported by the close interaction with blood platelets and inflammatory immune cells, enhancing tumor cell survival and establishment of metastatic niches (Figure 1A).

Tumor-related inflammation and thrombosis are hallmarks of many solid cancer types, including, breast, colon, ovarian, pancreatic and renal cell carcinoma. Infiltration of immune cells, such as neutrophils, monocytes and lymphocytes into the tumor is associated with poor outcome, advanced tumor stage and grade, and tumor metastasis (Figure 1B).

Moreover, elevated platelet count and procoagulant tumor microenvironment are indicators for a poor prognosis and imply a higher risk of thromboembolic events and resistance to chemotherapies. However, the underlying molecular signaling of platelet-cancer and immune cell interplay remains poorly understood and the identification of pathomechanisms may help to develop new therapeutic avenues.
We are interested in unraveling the effects of the tumor microenvironment, including inflammatory immune cells and blood platelets on primary tumor growth and understand the molecular mechanisms of tumor invasion and metastasis. We evaluate the regulatory mechanisms using a wide range of biological tools, including genetic and experimental mouse models of carcinogenesis and tumor metastasis, clinically relevant blocking chemical inhibitors and antibodies and cutting-edge 3D cell culture technics. We are also exploring cellular and biochemical markers in tissue and liquid biopsies of cancer patients and integrating bioinformatic analysis and computational modeling. We have a running scientific collaboration with the Division of Nephrology (Department of Medicine IV, University Hospital of the LMU, Munich, Germany), bringing biologists, clinical researchers, and medical doctors together to better understand complex molecular mechanisms of oncogenesis and cancer progression. Our group is also involved in research activities with the University of Strasbourg (France) for testing new pharmacological tools in mouse models of cancer that target tumor microenvironment-relevant cellular and molecular pathways, including platelets and other circulating blood cells.

Publications

Mammadova-Bach E., Braun A. Platelet life without TMEM163: no dense granules. Blood. 2021, accepted manuscript

Balkenhol J, Kaltdorf KV, Mammadova-Bach E, Braun A, Nieswandt B, Dittrich M and Dandekar T. Comparison of the central human and mouse platelet signaling cascade by systems biological analysis. BMC Genomics. 2020 Dec 22;21(1):897

Mammadova-Bach E*, Jaeken J, Gudermann T, Braun A*. Platelets and Defective N-Glycosylation. *corresponding authors, Int J Mol Sci. 2020 Aug 6;21(16):5630

Mammadova-Bach E, Gil-Pulido J, Sarukhanyan E, Burkard P, Shityakov S, Schonhart C, Stegner D, Remer K, Nurden P, Nurden AT, Dandekar T, Nehez L, Dank M, Braun A, Mezzano D, Abrams SI, Nieswandt B. Platelet glycoprotein VI promotes metastasis through interaction with cancer cell-derived galectin-3. Blood. 2020 Apr 2;135(14):1146-1160

Mammadova-Bach E* and Braun A*. Zinc Homeostasis in Platelet-Related Diseases. *corresponding authors, Int J Mol Sci. 2019 Oct 23;20(21):5258

Kiran Gotru S, van Geffen JP, Nagy M, Mammadova-Bach E, Eilenberger J, Volz J, Manukjan G, Schulze H, Wagner L, Eber S, Schambeck C, Deppermann C, Brouns S, Nurden P, Greinacher A, Sachs U, Nieswandt B, Hermanns HM, Heemskerk JWM, Braun A. Defective Zn2+ homeostasis in mouse and human platelets with α- and δ-storage pool diseases. Sci Rep. 2019 Jun 6;9(1):8333

Volz J, Mammadova-Bach E, Gil-Pulido J, Nandigama R, Remer K, Sorokin L, Zernecke A, Abrams SI, Ergün S, Henke E, Nieswandt B. Inhibition of GPVI induces intratumor haemorrhage and increases efficacy of chemotherapy in mice. Blood. 2019 Jun 20;133(25):2696-2706

Mammadova-Bach E., Nagy M., Heemskerk J.W.M., Nieswandt B and Braun A. Store-operated calcium entry in thrombosis and thrombo-inflammation. Cell Calcium. 2019 Jan;77:39-48. doi: 10.1016/j.ceca.2018.11.005.

Mammadova-Bach E, Rupp T, Spenlé C, Jivkov I, Shankaranarayanan P, Klein A, Pisarsky L, Méchine-Neuville A, Cremel G, Kedinger M, De Wever O, Ambartsumian N, Robine S, Pencreach E, Guenot D, Simon-Assmann P, Goetz JG, Orend G, Lefebvre O. Laminin α1 orchestrates VEGFA functions in the ecosystem of colorectal carcinoma. Biol Cell. 2018 Jun 15. doi: 10.1111/boc.201800007

Mammadova-Bach E., Mauler M., Braun A., Duerschmied D. Autocrine and paracrine regulatory functions of platelet serotonin. Platelets. 2018 Sep;29(6):541-548. doi: 10.1080/09537104.2018.1478072

Mammadova-Bach E., Mauler M., Braun A., Duerschmied D. Immuno-Thrombotic Effects of Platelet Serotonin. Chapter 12: “Serotonin – A Chemical Messenger Between All Types of Living Cells”, Book Neuroscience. 2017

Mammadova-Bach E, Zigrino P, Brucker C, Bourdon C, Freund M, De Arcangelis A, Abrams SI, Orend G, Gachet C, Mangin PH. Platelet integrin α6β1 controls lung metastasis through direct binding to cancer cell-derived ADAM9. JCI Insight. 2016 Sep 8;1(14):e88245. doi: 10.1172/jci.insight.88245

Mammadova-Bach E, Ollivier V, Loyau S, Schaff M, Dumont B, Favier R, Freyburger G, Latger-Cannard V, Nieswandt B, Gachet C, Mangin PH, Jandrot-Perrus M. Platelet glycoprotein VI binds to polymerized fibrin and promotes thrombin generation. Blood. 2015 Jul 30;126(5):683-91

Mammadova-Bach E, Mangin P, Lanza F, Gachet C. Platelets in cancer: from basic research to therapeutic implications. Hamostaseologie. 2015;35(4):325-36

Simon-Assmann P., Orend G., Mammadova-Bach E., Spenlé C., and Lefebvre O. Role of laminins in physiological and pathological angiogenesis. Int J Dev Biol. 2011;55(4-5):455-65. doi: 10.1387/ijdb.103223ps

Edwards MM, Mammadova-Bach E, Alpy F, Klein A, Hicks WL, Roux M, Simon-Assmann P, Smith RS, Orend G, Wu J, Peachey NS, Naggert JK, Lefebvre O, Nishina PM. Mutations in Lama1 disrupt retinal vascular development and inner limiting membrane formation. J Biol Chem. 2010 Mar 5;285(10):7697-711