Jager, M. J. | Search bioRxiv

bioRxiv2023

Melanin enhances metastatic melanoma colonization by inhibiting ferroptosis

Melanoma associated death is mainly caused by metastatic disease. Increased melanin levels are associated with decreased melanoma patient survival, yet the contribution of melanin to this process is unknown. Here we show that melanin protects circulating melanoma cells from ferroptosis, enhancing their metastatic potential. We observed that melanin levels in patient-derived uveal melanoma cells as well as cutaneous and conjunctival melanoma cell lines correlate with their metastatic potential in zebrafish xenografts. We find strong associations of the melanin biosynthesis gene TYRP1, ferroptosis related enzyme GPX4 and mitochondrial anion channel (VDAC1) with reduced melanoma-specific survival in TCGA data of cutaneous melanoma. Modulation of melanin levels significantly impacts melanoma metastatic potential, increasing or decreasing in concordance with melanin levels. Furthermore, melanin depletion significantly sensitized melanoma cells to ferroptosis leading to a decreased metastatic capacity and enhanced efficacy of ferroptosis induction based anti-cancer therapeutic strategies. Collectively, our results reveal that combined inhibition of melanin biosynthetic enzymes and induction of ferroptosis has potential as a treatment strategy of metastatic melanoma. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=148 SRC="FIGDIR/small/535376v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1fc21a5org.highwire.dtl.DTLVardef@502b6org.highwire.dtl.DTLVardef@f522beorg.highwire.dtl.DTLVardef@1bbfdfa_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

Patient-derived zebrafish xenograft models reveal ferroptosis as a fatal and druggable weakness in metastatic uveal melanoma

Uveal melanoma (UM) is the most common intraocular melanoma, derived from transformed melanocytes of the uvea. Although treatment of primary UM is usually successful, there is a high risk (up to 50%) of liver metastasis with negligible long-term survival. There are currently no reproducible patient-derived animal models that faithfully recapitulate the latter stages of metastatic dissemination of UM, hindering the discovery of curative treatments. To overcome this problem and to accelerate the development of new metastatic UM treatments, we developed a patient-derived zebrafish xenograft (zf-PDX) model, using spheroid cultures generated from metastatic and primary UM tissues. Engrafted UM cells derived from these spheroid cultures give rise to metastatic lesions and recapitulate the molecular features of UMs and their potential drug sensitivity. Importantly, harnessing this versatile model, we reveal a high sensitivity of circulating UM cells to ferroptosis induction in vivo by Erastin and RSL3. Our findings are further corroborated by supportive analysis of patient data implicating ferroptosis as a new, and druggable, target for the treatment of metastatic UM patients, specifically in those with BAP1 loss in the tumor.

cancer biology↗