Synergistic inhibition of tumor initiation of solid human cancers by combined depletion of beta4-integrin on the tumor cells and E-/P-selectin in the tumor stroma

• Applicant: Professor Dr. Tobias Lange, Ph.D.
• Subject Area: Hematology, Oncology
• Term: since 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 246505577

Human tumor cells of different entities are significantly dependent on the expression of integrin beta 4 (ITGB4) for growth as a primary tumor in vivo. In the absence of the E- and P-selectins in the endothelial cells of the micro-vessels of the surrounding tumor stroma (E-/P-selectin-KO), tumor establishment is synergistically reduced. However, E-/P-selectin-KO alone has no effect on tumor establishment. In preliminary work for this project, we found that ITGB4-depleted (ITGB4-KD) tumor cell clusters show an increased infiltration of myeloid-derived suppressor cells (MDSC), which is not the case with simultaneous E-/P-selectin-KO. ITGB4-KD tumor cells attract more leukocytes in 3D culture models by increased release of different chemokines. MDSC are known for their growth-promoting effects on tumor cells. Our hypothesis is that MDSC need to interact with E-/P-selectin on the luminal side of tumor microvasculature to migrate into developing tumors. ITGB4-KD tumor cells appear to be specifically dependent on growth stimuli from MDSC. If they lack this stimulus, they are obviously more prone to anoikis. The aim of the proposed continuation project is to prove the pathophysiological and molecular relationships assumed on the basis of the preliminary data by extensive further analyses, to transfer them to alternative mouse models and clinical material and to make the new knowledge available for a possible therapeutic application in humans, at least to some extent. The continuation project therefore addresses the following key questions: Do MDSCs have a direct growth-promoting effect on ITGB4-KD tumour cells or on control cells with normal ITGB4 status as well? Does co-injection with MDSC help ITGB4-KD tumor cells to grow in the E-/P-selectin-KO environment? Do endothelial cells of tumor microvasculature express E-/P-selectins and can MDSC interact with these molecules? Do ITGB4-KD and E-/P-selectin-KO also act synergistically on tumor growth in an immunocompetent host? Is there an inverse correlation between ITGB4 expression and tumor-associated leukocytes/ MDSC in clinical patient material? Is a potentially functionally important aberrant glycosylation of ITGB4 on tumor cells suitable as a potential therapeutic target?

• DFG Programme: Research Grants
• International Connection: Australia, Switzerland
• Cooperation Partners: Dr. Arun Everest-Dass; Dr. Francis Jacob