Project 4 Ocular Melanoma

The role of midkine in tumor-associated lymphangiogenesis and metastasis of ocular malignant melanoma


Malignant melanoma is the most frequent cancer of the eye in adults. Ocular melanoma predominantly originates in the uveal tract and conjunctiva. Despite availability of effective treatment options for primary uveal and conjunctival melanoma, none of these therapies prevent development of metastases and to date there is no therapy that increases survival in metastatic uveal and conjunctival melanoma. Previously, we identified that outgrowth of new lymphatic vessels from preexisting ones (lymphangiogenesis) is a decisive risk factor for metastatic spread and an indicator of poor prognosis in ocular melanoma. In the first funding period, we investigated the underlying cellular and molecular mechanisms both in vitro and in vivo in a novel mouse model of conjunctival melanoma. This led us to identify midkine as a key cytokine in tumor-associated lymphangiogenesis, immune cell infiltration and metastasis in uveal and conjunctival melanoma.
In the second funding period, we plan to study in depth the molecular signaling mechanisms and cellular function of midkine in ocular melanoma. Specifically, we will focus on the role of midkine in ocular melanoma-associated lympangiogenesis and metastasis both in vitro and in vivo. In addition, the role of midkine in the tumor microenvironment, specifically tumor cell- stroma interaction via lymphatic endothelial cells and infiltration of tumor-associated macrophages will be addressed. Based on these findings we will explore whether targeting midkine could be a novel anti-(lymph)angiogenic therapy for attenuation of tumor metastasis and recurrence in our novel mouse model of metastatic conjunctival melanoma.

(until 2015 funded by DFG HE 6743/2-1, BO 4000/2-1, CU 47/6-1)

Malignant melanomas represent the most frequent and the most fatal malignancies of the eye. An effective curative treatment for metastatic conjunctival and uveal melanoma is currently not available. The outgrowth of new lymphatic vessels from preexisting ones (lymphangiogenesis) has been identified as a decisive risk factor for metastatic spread in non-ocular melanomas. In previous clinicopathological studies we were able to demonstrate the presence of tumor-associated lymphangiogenesis in (peri-)ocular melanomas. The density of these novel tumor-associated lymphatics correlates significantly with the risk for local recurrence, lymphatic spread, distant metastasis, and tumor-related death. The knowledge about underlying molecular mechanisms, however, is so far very limited. With the present project, we therefore want to investigate in vitro and in vivo the lymphangiogenic potency of ocular melanoma cells and their interaction with lymphatic endothelial cells and tumor-associated macrophages. Furthermore, we want to investigate, by which means tumor-associated lymphangiogenesis and melanoma-associated immune cell infiltrate are influencing each other. Based on these experiments, the second goal is to study in a murine model of conjunctival melanoma, whether the new concept of an anti(lymph)angiogenic therapy to minimize the risk of local recurrence and metastatic spread is generally feasible. In the medium term, our findings should preferably be translated into clinically used adjuvant therapeutic strategies in order to improve the recurrence-free and metastasis-free survival rates of ocular melanoma patients.

Selected Key Publications of Project 4

Bosch JJ, Heindl LM (2017) [Novel Adjuvant Therapy for Ocular Melanoma]. Klinische Monatsblatter fur Augenheilkunde 234: 670-673

Heindl LM, Koch KR, Hermann MM, Merkelbach-Bruse S, Schultheis AM, Wagener S, Buttner R, Mauch C, Schuler-Thurner B, Schuler G, Cursiefen C (2017) Block Excision of Iridociliary Tumors Enables Molecular Profiling and Immune Vaccination. Ophthalmology 124: 268-270

Resheq YJ, Menzner A-K, Bosch J, Tickle J, Li K-K, Wilhelm A, Hepburn E, Murihead G, Ward ST, Curbishley SM, Zimmermann HW, Bruns T, Gilbert DF, Tripal P, Mackensen A, Adams DH, Weston CJ (2017) Impaired Transmigration of Myeloid-Derived Suppressor Cells across Human Sinusoidal Endothelium Is Associated with Decreased Expression of CD13. The Journal of Immunology 199: 1672-1681

Grajewski RS, Bosch JJ, Bruns H, Cursiefen C, Heindl LM (2016) The Trojan Horse Tale Revisited: An Eye on Metastatic Spread of Carcinoma Cells. Cancer immunology research 4: 92-4

Schlereth SL, Kremers S, Schrodl F, Cursiefen C, Heindl LM (2016) Characterization of Antigen-Presenting Macrophages and Dendritic Cells in the Healthy Human Sclera. Investigative ophthalmology & visual science 57: 4878-4885

Kaser-Eichberger A, Schrodl F, Trost A, Strohmaier C, Bogner B, Runge C, Motloch K, Bruckner D, Laimer M, Schlereth SL, Heindl LM, Reitsamer HA (2015) Topography of Lymphatic Markers in Human Iris and Ciliary Body. Investigative ophthalmology & visual science 56: 4943-53

Refaian N, Schlereth SL, Koch KR, Notara M, Hos D, Mescher M, Iden S, Bosch JJ, Jager MJ, Cursiefen C, Heindl LM (2015) Comparing the Hem- and Lymphangiogenic Profile of Conjunctival and Uveal Melanoma Cell Lines. Investigative ophthalmology & visual science 56: 5691-7

Schlereth SL, Iden S, Mescher M, Ksander BR, Bosch JJ, Cursiefen C, Heindl LM (2015) A Novel Model of Metastatic Conjunctival Melanoma in Immune-Competent Mice. Investigative ophthalmology & visual science 56: 5965-73

Schrodl F, Kaser-Eichberger A, Trost A, Strohmaier C, Bogner B, Runge C, Motloch K, Bruckner D, Laimer M, Heindl LM, Reitsamer HA (2015) Lymphatic Markers in the Adult Human Choroid. Investigative ophthalmology & visual science 56: 7406-16

Schuler-Thurner B, Bartz-Schmidt KU, Bornfeld N, Cursiefen C, Fuisting B, Grisanti S, Heindl LM, Holbach L, Keseru M, Knorr H, Koch K, Kruse F, Meiller R, Metz C, Meyer-ter-Vehn T, Much M, Reinsberg M, Schliep S, Seitz B, Schuler G et al. (2015) [Immunotherapy of uveal melanoma: vaccination against cancer. Multicenter adjuvant phase 3 vaccination study using dendritic cells laden with tumor RNA for large newly diagnosed uveal melanoma]. Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft 112: 1017-21

More Publications of Project 4

Cursiefen C, Bock F, Clahsen T, Regenfuss B, Reis A, Steven P, Heindl LM, Bosch JJ, Hos D, Eming S, Grajewski R, Heiligenhaus A, Fauser S, Austin J, Langmann T. [New Therapeutic Approaches in Inflammatory Diseases of the Eye – Targeting Lymphangiogenesis and Cellular Immunity: Research Unit FOR 2240 Presents Itself]. Klin Monbl Augenheilkd. 2017 May;234(5):679-685.

Bucher F, Schneider C, Blau T, Cursiefen C, Fink GR, Lehmann HC, Heindl LM (2015) Small-Fiber Neuropathy Is Associated With Corneal Nerve and Dendritic Cell Alterations: An In Vivo Confocal Microscopy Study. Cornea. 34(9):1114-9.

Matthaei M, Gillessen J, Muether PS, Hoerster R, Bachmann BO, Hueber A, Cursiefen C, Heindl LM (2015) Epithelial-Mesenchymal Transition (EMT)-Related Cytokines in the Aqueous Humor of Phakic and Pseudophakic Fuchs’ Dystrophy Eyes. Invest Ophthalmol Vis Sci. 56(4):2749-54.

Bucher F, Fricke J, Cursiefen C, Heindl LM (2015) Trigeminal involvement in parry-romberg syndrome: an in vivo confocal microscopy study of the cornea. Cornea. 34(4):e10-1.

Koch KR, Refaian N, Hos D, Schlereth SL, Bosch JJ, Cursiefen C, Heindl LM (2014) Autocrine impact of VEGF-A on uveal melanoma cells. Invest Ophthalmol Vis Sci 55:2697-2704.

Hos D, Koch KR, Bucher F, Cursiefen C, Heindl LM (2013) Serum eyedrops antagonize the anti(lymph)angiogenic effects of bevacizumab in vitro and in vivo. Invest Ophthalmol Vis Sci 54:6133-6142.

Gary R, Voelkl S, Palmisano R, Ullrich E, Bosch JJ, Mackensen A (2012) Antigen-specific transfer of functional programmed death ligand 1 from human APCs onto CD8+ T cells via trogocytosis. J Immunol. 188(2):744-52.

Bosch JJ (2012) Immunotherapy of uveal melanoma. Dev Ophthalmol. 49:137-49.

Heindl LM, Hofmann-Rummelt C, Adler W, Bosch JJ, Holbach LM, Naumann GO, Kruse FE, Cursiefen C (2011) Prognostic significance of tumor-associated lymphangiogenesis in malignant melanomas of the conjunctiva. Ophthalmology 118:2351-2360.

Haile ST*, Bosch JJ*, Agu NI, Zeender AM, Somasundaram P, Srivastava MK, Britting S, Wolf JB, Ksander BR, Ostrand-Rosenberg S (2011) Tumor cell programmed death ligand 1-mediated T cell suppression is overcome by coexpression of CD80. J Immunol. 186:6822-9. *these authors contributed equally

Heindl LM, Hofmann TN, Adler W, Knorr HL, Holbach LM, Naumann GO, Kruse FE, Cursiefen C (2010) Intraocular tumor-associated lymphangiogenesis: a novel prognostic factor for ciliary body melanomas with extraocular extension? Ophthalmology 117:334-342.

Heindl LM, Hofmann-Rummelt C, Adler W, Holbach LM, Naumann GO, Kruse FE, Cursiefen C (2010) Tumor-associated lymphangiogenesis in the development of conjunctival squamous cell carcinoma. Ophthalmology 117:649-658.

Bosch JJ, Iheagwara UK, Reid S, Srivastava MK, Wolf J, Lotem M, Ksander BR, Ostrand-Rosenberg S (2010) Uveal melanoma cell-based vaccines express MHC II molecules that traffic via the endocytic and secretory pathways and activate CD8(+) cytotoxic, tumor-specific T cells. Cancer Immunol Immunother. 59:103-12.

Bosch JJ, Thompson JA, Srivastava MK, Iheagwara UK, Murray TG, Lotem M, Ksander BR, Ostrand-Rosenberg S (2007) MHC class II-transduced tumor cells originating in the immune-privileged eye prime and boost CD4(+) T lymphocytes that cross-react with primary and metastatic uveal melanoma cells. Cancer Res. 67:4499-506.