Project 4 Ocular Melanoma

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

Summary

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

Heindl LM, Platzl C, Wolfmeier H, Herwig-Carl MC, Kaser-Eichberger A, Strohmaier C, Schroedl F. Choroidal melanocytes: subpopulations of different origin? Ann Anat 2021; 238: 151775.

Grajewski RS, Rokohl AC, Becker M, Paulsen F, Heindl LM. Malignancy going viral: ACE2 and TMPRSS2 expression in conjunctival neoplastic diseases. Ann Anat 2021; 234: 151661.

Mor JM, Rokohl AC, Dahm S, Kraywinkel K, Heindl LM. Epidemiology of uveal melanomas in Germany. Acta Ophthalmol 2021.

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.

Rokohl AC, Koch KR, Trester M, Trester W, Pine KR, Heindl LM. Concerns of anophthalmic patients wearing cryolite glass prosthetic eyes. Ophthalmic Plast Reconstr Surg 2018; 34: 369-374.

Matthaei M, Elsner E, Caramoy A, Adler W, Siebelmann S, Schaub F, Skevas C, Liakopoulos S, Bachmann B, Cursiefen C, Heindl LM. Fuchs endothelial corneal dystrophy and macular drusen: evidence for coincidence? Eye 2018; 32: 840-841.

Enders P, Schaub F, Adler W, Hermann MM, Dietlein TS, Cursiefen C, Heindl LM. Bruch’s membrane opening-based optical coherence tomography of the optic nerve head: a useful diagnostic tool to detect glaucoma in macrodiscs. Eye 2018; 32: 314-323.

Glossmann JP, Skoetz N, Starbatty B, Bischoff M, Leyvraz S, Westekemper H; AG SOP; Unter-AG Konjunktivales Melanom, Heindl LM. Conjunctival melanoma: standard operating procedures in diagnosis, treatment and follow-up care [in German]. Ophthalmologe 2018; 115: 489-498

Rokohl AC, Koch KR, Adler W, Trester M, Trester W, Pine NS, Pine KR, Heindl LM. Concerns of anophthalmic patients – a comparison between cryolite glass and polymethyl methacrylate prosthetic eye wearers. Graefes Arch Clin Exp Ophthalmol 2018; 256: 1203-1208.

Schaub F, Adler W, Enders P, Koenig MC, Koch KR, Cursiefen C, Kirchhof B, Heindl LM. Preexisting epiretinal membrane is associated with pseudophakic cystoid macular edema. Graefes Arch Clin Exp Ophthalmol 2018; 256: 909-917.

Heindl LM, Adler W, El-Malahi O, Schaub F, Hermann MM, Dietlein TS, Cursiefen C, Enders P. The optimal diameter for circumpapillary retinal nerve fiber layer thickness measurement by SD-OCT in glaucoma. J Glaucoma 2018; 27: 1086-1093.

Gietzelt C, Lemke J, Schaub F, Hermann MM, Dietlein TS, Cursiefen C, Enders P, Heindl LM. Structural reversal of disc cupping after trabeculectomy alters Bruch membrane opening-based parameters to assess neuroretinal rim. Am J Ophthalmol 2018; 194: 143-152.

Hoerster R, Cursiefen C, Streichert T, Heindl LM. Impact of systemic inhibition on ocular levels of angiotensin-converting enzyme (ACE). Graefes Arch Clin Exp Ophthalmol 2018; 256: 2487-2488.

Mor JM, Matthaei M, Schrumpf H, Koch KR, Bölke E, Heindl LM. Transcanalicular laser dacryocystorhinostomy for acquired nasolacrimal duct obstruction: an audit of 104 patients. Eur J Med Res 2018; 23: 58.

Enders P, Adler W, Kiessling D, Weber V, Schaub F, Hermann MM, Dietlein T, Cursiefen C, Heindl LM. Evaluation of two-dimensional Bruch’s membrane opening minimum rim area for glaucoma diagnostics in a large patient cohort. Acta Ophthalmol 2019; 97: 60-67.

Grajewski RS, Boelke AC, Adler W, Pape A, Schroedl F, Hueber A, Albus C, Vitinius F, Heindl LM. Perceived stress levels in adult patients with uveitis. Front Psychiatry 2019; 10: 916.

Guo Y, Koch KR, Heindl LM. Transcaruncular laser-assisted StopLoss Lester Jones tube surgery for lacrimal canalicular obstructions. Graefes Arch Clin Exp Ophthalmol 2019; 257: 1569-1570.

Guo Y, Rokohl AC, Schaub F, Hou X, Liu J, Ruan Y, Jia R, Koch KR, Heindl LM. Reliability of periocular anthropometry using three-dimensional digital stereophotogrammetry. Graefes Arch Clin Exp Ophthalmol 2019; 257: 2517-2531.

Heindl LM, Augustin AJ, Messmer EM. ADenoVirus initiative study in epidemiology (ADVISE) – results of a multicenter epidemiology study in Germany. Graefes Arch Clin Exp Ophthalmol 2019; 257: 249-251.

Kiessling D, Christ H, Gietzelt C, Schaub F, Dietlein TS, Cursiefen C, Heindl LM(*), Enders P(*). Impact of ab-interno trabeculectomy on Bruch’s membrane opening-based morphometry of the optic nerve head for glaucoma progression analysis. Graefes Arch Clin Exp Ophthalmol 2019; 257: 339-347.

Loeser J, Schwemmer J, Gostian AO, Gostian M, Bachmann B, Cursiefen C, Heindl LM. Postoperative pain following Descemet membrane endothelial keratoplasty (DMEK): a prospective study. Graefes Arch Clin Exp Ophthalmol 2019; 257: 2203-2211.

Matthaei M, Leitl C, Cursiefen C, Heindl LM. Correlation of extracellular matrix-related gene expression with objective Fuchs endothelial corneal dystrophy severity. Clin Exp Ophthalmol 2019; 47: 671-673.

Rokohl AC, Adler W, Koch KR, Mor JM, Jia R, Trester M, Pine NS, Pine KR, Heindl LM. Cryolite glass prosthetic eyes – the response of the anophthalmic socket. Graefes Arch Clin Exp Ophthalmol 2019; 257: 2015- 2023.

Rokohl AC, Trester M, Pine KR, Heindl LM. Risk of breakage of cryolite glass prosthetic eyes. Graefes Arch Clin Exp Ophthalmol 2019; 257: 437-438.

Schlereth SL, Karlstetter M, Hos D, Matthaei M, Cursiefen C, Heindl LM. Detection of pro- and antiangiogenic factors in the human sclera. Curr Eye Res 2019; 44: 172-184.

Siggel R, Christofi E, Giasoumi F, Adler W, Siebelmann S, Bachmann B, Cursiefen C, Heindl LM. Changes in corneal biomechanical properties after Descemet membrane endothelial keratoplasty. Cornea 2019; 38: 964-969.

Enders P, Longo V, Adler W, Horstmann J, Schaub F, Dietlein T, Cursiefen C, Heindl LM. Analysis of peripapillary vessel density and Bruch’s membrane opening-based neuroretinal rim parameters in glaucoma using OCT and OCT-angiography. Eye (Lond) 2020; 34: 1086-1093.

Guo Y, Hou X, Rokohl AC, Jia R, Heindl LM. Reliability of periocular anthropometry: a comparison of direct, 2-dimensional, and 3-dimensional techniques. Dermatol Surg 2020; 46: e23-e31.

Guo Y, Rokohl AC, Kroth K, Li S, Lin M, Jia R, Heindl LM. Endoscopy-guided diode laser-assisted transcaruncular StopLoss Jones tube implantation for canalicular obstructions in primary surgery. Graefes Arch Clin Exp Ophthalmol 2020; 258: 2809-2817.

Guo Y, Schaub F, Mor JM, Jia R, Koch KR, Heindl LM. A simple standardized three-dimensional anthropometry for the periocular region in a European population. Plast Reconstr Surg 2020; 145: 514e-523e.

Luers JC, Rokohl AC, Loreck N, Wawer Matos PA, Augustin M, Dewald F, Klein F, Lehmann C, Heindl LM. Olfactory and gustatory dysfunction in coronavirus disease 2019 (COVID-19). Clin Infect Dis 2020; 71: 2262-2264.

Rokohl AC, Loreck N, Wawer Matos PA, Zwingelberg S, Augustin M, Dewald F, Grajewski RS, Klein F, Lehmann C, Heindl LM. More than loss of taste and smell: burning watering eyes in coronavirus disease 2019. Clin Microbiol Infect 2020; 26: 1560.

Rokohl AC, Trester M, Guo Y, Adler W, Jaeger VK, Loreck N, Mor JM, Pine KR, Heindl LM. Dry anophthalmic socket syndrome – standardized clinical evaluation of symptoms and signs. Ocul Surf 2020; 18: 453-459.

Siggel R, Schroedl F, Dietlein T, Koch KR, Platzl C, Kaser-Eichberger A, Cursiefen C, Heindl LM. Absence of lymphatic vessels in non-functioning bleb capsules of glaucoma drainage devices. Histol Histopathol 2020; 35: 1521-1531.

Chichan H, Maus M, Heindl LM. Subthreshold nanosecond laser, from trials to real-life clinical practice: a cohort study. Clin Ophthalmol 2021; 15: 1887- 1895.

Grajewski RS, Rokohl AC, Becker M, Dewald F, Lehmann C, Fätkenheuer G, Cursiefen C, Klein F, Heindl LM. A missing link between SARS-CoV-2 and the eye? ACE2 expression on the ocular surface. J Med Virol 2021; 93: 78-79.

Guo Y, Liu J, Ruan Y, Rokohl AC, Hou X, Li S, Jia R, Koch KR, Heindl LM. A novel approach quantifying the periorbital morphology: A comparison of direct, 2-dimensional, and 3-dimensional technologies. J Plast Reconstr Aesthet Surg 2021; 74: 1888-1899.

Heindl LM, Trester M, Guo Y, Zwiener F, Sadat N, Pine NS, Pine KR, Traweger A, Rokohl AC. Anxiety and depression in patients wearing prosthetic eyes. Graefes Arch Clin Exp Ophthalmol 2021; 259: 495-503.

Hou X, Rokohl AC, Meinke MM, Li S, Liu J, Fan W, Lin M, Jia R, Guo Y, Heindl LM. A novel standardized distraction test to evaluate lower eyelid tension using three-dimensional stereophotogrammetry. Quant Imaging Med Surg 2021; 11: 3735-3748.

Hou X, Rokohl AC, Meinke MM, Liu J, Li S, Fan W, Lin M, Jia R, Guo Y, Heindl LM. Standardized three-dimensional lateral distraction test: its reliability to assess medial canthal tendon laxity. Aesthetic Plast Surg 2021; 45 (6):2798-2807.

Kopecký A, Rokohl AC, Wawer Matos PA, Němčanský J, Heindl LM. Cheek- midface lifting with lateral canthoplasy for the repair of complex iatrogenic lower eyelid ectropion. Eur J Ophthalmol 2021: 11206721211039334.

Li S, Guo Y, Hou X, Liu J, Fan W, Ju S, Matos PAW, Rokohl AC, Heindl LM. Mapping research trends of uveal melanoma: a bibliometric analysis. Int Ophthalmol 2021.
Li S, Siggel R, Guo Y, Loreck N, Rokohl AC, Kurschat C, Heindl LM. Corneal densitometry: a potential indicator for early diagnosis of Fabry disease. Graefes Arch Clin Exp Ophthalmol 2021; 259: 941-948.

Liu J, Guo Y, Arakelyan M, Rokohl AC, Heindl LM. Accuracy of areal measurement in the periocular region using stereophotogrammetry. J Oral Maxillofac Surg 2021; 79: 1106.
Liu J, Rokohl AC, Guo Y, Li S, Hou X, Fan W, Formuzal M, Lin M, Heindl LM. Reliability of stereophotogrammetry for area measurement in the periocular region. Aesthetic Plast Surg 2021; 45: 1601-1610.

Mor JM, Rokohl AC, Mauch C, Heindl LM. Interdisciplinary surveillance of ocular melanomas: experiences in a German tertiary centre. Klin Monbl Augenheilkd 2021; 238: 85-91.
Rokohl AC, Grajewski RS, Wawer Matos PA, Koch HL, Dewald F, Klein F, Fätkenheuer G, Lehmann C, Cursiefen C, Heindl LM. No secret hiding place? Absence of SARS-CoV-2 on the ocular surface of 1145 hospitalized patients in a pandemic area. Graefes Arch Clin Exp Ophthalmol 2021; 259: 1605-1608.

Rokohl AC, Trester M, Naderi P, Loreck N, Zwingelberg S, Bucher F, Pine KR, Heindl LM. Dry anophthalmic socket syndrome – morphological alterations in meibomian glands. Eye (Lond) 2021; 35: 3358-3366.

Hou X, Rokohl AC, Meinke MM, Zhang M, Guo Y, Heindl LM. Digital photogrammetry for assessing medial canthal tendon laxity: novel standardized three-dimensional versus traditional two-dimensional lateral distraction test. J Oral Maxillofac Surg 2022.