P2 - Cooperative roles of tumor cell integrins and tumor stroma selectins for primary tumor growth and distant metastasis

presented by

Sandra Genduso, Vera Freytag, Alina Schiecke & Tobias Lange
Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf

Metastasis from solid tumors, such as prostate cancer, constitutes the major cause of death in cancer patients. However, the process of dissemination of tumor cells from the primary tumor site, subsequent survival in the circulation, and final outgrowth in a distant organ remains not fully understood. One crucial step in this metastatic cascade is the extravasation of circulating tumor cells from the blood. Tumor cells attach to the vascular endothelium by imitating the leukocyte adhesion cascade, which is mediated by cell adhesion molecules like selectins and integrins.

In an ongoing DFG project, which is currently funded in its 3rd period until 2025, we revealed that human prostate cancer cells are able to metastasize even in the absence of endothelial selectins. Instead, highly metastatic cells up-regulate the integrin subunit β4 (ITGB4). Interestingly, shRNA-mediated depletion of this subunit significantly delays primary tumor formation in human prostate cancer xenograft models and models of other cancer types. This delay is over-additively increased by additional deficiency of certain selectins in the tumor stroma. Obviously, ITGB4-depleted tumor cells rely on pro-survival signals from tumor-associated leukocytes for tumor initiation. Myeloid-derived suppressor cells (MDSC) are one of the key components of the tumor microenvironment, known for their immunosuppressive activity.

These leukocytes appear to depend on the selectins for infiltration of the tumor stroma particularly in combination with ITGB4 depletion, increasing the recruitment of MDSCs. The aim of this project is to understand the downstream growth-modulating pathways in more detail (collaboration with the Institute of Experimental Immunology and Hepatology, UKE).

This work is carried out in collaboration with UKSH partners Prof. S. Sebens (Institute of Experimental Cancer Research, Kiel University (CAU)) and Prof. S. Perner (Institute of Pathology, University of Luebeck).

Grants: DFG Sachbeihilfen 2013-15, 2016-19, 2022-25

Contact: to.lange@uke.de

  • Tumor Cell Integrin β4 and Tumor Stroma E-/P-Selectin Cooperatively Regulate Tumor Growth in vivo. Genduso S, Freytag V, Schetler D, Kirchner L, Schiecke A, Maar H, Wicklein D, Gebauer F, Bröker K, Stürken C, Milde-Langosch K, Oliveira-Ferrer L, Ricklefs FL, Ewald F, Wolters-Eisfeld G, Riecken K, Unrau L, Krause L, Bohnenberger H, Offermann A, Perner S, Sebens S, Lamszus K, Diehl L, Linder S, Jücker M, Schumacher U, Lange T (2023) J Hematol Oncol, 16(1): 23.

    Systematic analysis of the human tumor cell binding to human vs. murine E- and P-selectin under static vs. dynamic conditions. Starzonek S, Maar H, Labitzky V, Wicklein D, Rossdam C, Buettner FFR, Wolters-Eisfeld G, Guengoer C, Wagener C, Schumacher U, Lange T.Glycobiology. 2020 Aug 20;30(9):695-709. doi: 10.1093/glycob/cwaa019.PMID: 32103235

    Aberrant presentation of HPA-reactive carbohydrates implies Selectin-independent metastasis formation in human prostate cancer. Lange T, Kupfernagel M, Wicklein D, Gebauer F, Maar H, Brügge K, Müller I, Simon R, Schlomm T, Sauter G, Schumacher U.Clin Cancer Res. 2014 Apr 1;20(7):1791-802. doi: 10.1158/1078-0432.CCR-13-2308. Epub 2014 Feb 13.PMID: 24526735