Uveal melanoma is the most common intraocular tumor in adults, representing approximately 5% of all melanoma cases. Up to 50% of uveal melanoma patients develop metastases that are resistant to... Show moreUveal melanoma is the most common intraocular tumor in adults, representing approximately 5% of all melanoma cases. Up to 50% of uveal melanoma patients develop metastases that are resistant to most of the commonly used antineoplastic treatments. Virtually all uveal melanoma tumors harbor activating mutations in GNAQ or GNA11, encoding Gαq and Gα11, respectively. Constant activity of these proteins causes deregulation of multiple downstream signaling pathways including PKC, MAPK and YAP1/TAZ. While the importance of YAP1 signaling for the proliferation of uveal melanoma has recently been demonstrated, much less is known about the paralog of YAP1 transcriptional coactivator, named TAZ; however, similar to YAP1, TAZ is expected to be a therapeutic target in uveal melanoma. We performed a small-scale drug screen to discover a compound synergistically inhibiting uveal melanoma proliferation/survival in combination with YAP1/TAZ inhibition. We found that the combination of genetic depletion of YAP1/TAZ together with Mcl-1 inhibition demonstrates a synergistic inhibitory effect on the viability of uveal melanoma cell lines. Similarly, indirect attenuation of the YAP1/TAZ signaling pathway with an inhibitor of the mevalonate pathway, that is, the geranyl-geranyl transferase inhibitor GGTI-298, synergizes with Mcl-1 inhibition. This combination could be potentially used as a treatment for metastatic uveal melanoma. Show less
Uveal melanoma (UM) is a rare malignant cancer of the eye, with up to 50% of patients dying from metastasis, for which no effective treatment is available. Due to the rarity of the disease, there... Show moreUveal melanoma (UM) is a rare malignant cancer of the eye, with up to 50% of patients dying from metastasis, for which no effective treatment is available. Due to the rarity of the disease, there is a great need to harness the limited material available from primary tumors and metastases for advanced research and preclinical drug screening. We established a platform to isolate, preserve, and transiently recover viable tissues, followed by the generation of spheroid cultures derived from primary UM. All assessed tumor-derived samples formed spheroids in culture within 24 h and stained positive for melanocyte-specific markers, indicating the retention of their melanocytic origin. These short-lived spheroids were only maintained for the duration of the experiment (7 days) or re-established from frozen tumor tissue acquired from the same patient. Intravenous injection of fluorescently labeled UM cells derived from these spheroids into zebrafish yielded a reproducible metastatic phenotype and recapitulated molecular features of the disseminating UM. This approach allowed for the experimental replications required for reliable drug screening (at least 2 individual biological experiments, with n > 20). Drug treatments with navitoclax and everolimus validated the zebrafish patient-derived model as a versatile preclinical tool for screening anti-UM drugs and as a preclinical platform to predict personalized drug responses. Show less
Microphthalmia-associated transcription factor (MITF) is an important regulator of melanogenesis and melanocyte development. Although it has been studied extensively in cutaneous melanoma, the role... Show moreMicrophthalmia-associated transcription factor (MITF) is an important regulator of melanogenesis and melanocyte development. Although it has been studied extensively in cutaneous melanoma, the role of MITF in uveal melanoma (UM) has not been explored in much detail. We review the literature about the role of MITF in normal melanocytes, in cutaneous melanoma, and in UM. In normal melanocytes, MITF regulates melanocyte development, melanin synthesis, and melanocyte survival. The expression profile and the behaviour of MITF-expressing cells suggest that MITF promotes local proliferation and inhibits invasion, inflammation, and epithelial-to-mesenchymal (EMT) transition. Loss of MITF expression leads to increased invasion and inflammation and is more prevalent in malignant cells. Cutaneous melanoma cells switch between MITF-high and MITF-low states in different phases of tumour development. In UM, MITF loss is associated with loss of BAP1 protein expression, which is a marker of poor prognosis. These data indicate a dual role for MITF in benign and malignant melanocytic cells. Show less
Magnetic resonance imaging of the eye and orbit (MReye) is a cross-domain research field, combining (bio)physics, (bio)engineering, physiology, data sciences and ophthalmology. A growing number of... Show moreMagnetic resonance imaging of the eye and orbit (MReye) is a cross-domain research field, combining (bio)physics, (bio)engineering, physiology, data sciences and ophthalmology. A growing number of reports document technical innovations of MReye and promote their application in preclinical research and clinical science. Realizing the progress and promises, this review outlines current trends in MReye. Examples of MReye strategies and their clinical relevance are demonstrated. Frontier applications in ocular oncology, refractive surgery, ocular muscle disorders and orbital inflammation are presented and their implications for explorations into ophthalmic diseases are provided. Substantial progress in anatomically detailed, high-spatial resolution MReye of the eye, orbit and optic nerve is demonstrated. Recent developments in MReye of ocular tumors are explored, and its value for personalized eye models derived from machine learning in the treatment planning of uveal melanoma and evaluation of retinoblastoma is highlighted. The potential of MReye for monitoring drug distribution and for improving treatment management and the assessment of individual responses is discussed. To open a window into the eye and into (patho)physiological processes that in the past have been largely inaccessible, advances in MReye at ultrahigh magnetic field strengths are discussed. A concluding section ventures a glance beyond the horizon and explores future directions of MReye across multiple scales, including in vivo electrolyte mapping of sodium and other nuclei. This review underscores the need for the (bio)medical imaging and ophthalmic communities to expand efforts to find solutions to the remaining unsolved problems and technical obstacles of MReye, with the objective to transfer methodological advancements driven by MR physics into genuine clinical value. Show less
Olvido Perea-García, J.; Kret, M.E.; Monteiro, A.; Hobaiter, C. 2019
Gaze following has been argued to be uniquely human, facilitated by our depigmented, white sclera [M. Tomasello, B. Hare, H. Lehmann, J. Call, J. Hum. Evol. 52, 314–320 (2007)]—the pale area around... Show moreGaze following has been argued to be uniquely human, facilitated by our depigmented, white sclera [M. Tomasello, B. Hare, H. Lehmann, J. Call, J. Hum. Evol. 52, 314–320 (2007)]—the pale area around the colored iris—and to underpin human-specific behaviors such as language. Today, we know that great apes show diverse patterns of scleral coloration [J. A. Mayhew, J. C. Gómez, Am. J. Primatol. 77, 869–877 (2015); J. O. Perea García, T. Grenzner, G. Hešková, P. Mitkidis, Commun. Integr. Biol. 10, e1264545 (2016)]. We compare scleral coloration and its relative contrast with the iris in bonobos, chimpanzees, and humans. Like humans, bonobos’ sclerae are lighter relative to the color of their irises; chimpanzee sclerae are darker than their irises. The relative contrast between the sclera and iris in all 3 species is comparable, suggesting a perceptual mechanism to explain recent evidence that nonhuman great apes also rely on gaze as a social cue. Show less