Comparative Oncogenomics Identifies Novel Regulators and Clinical Relevance of Neural Crest Identities in Melanoma

Cancers often resurrect embryonic molecular programs to promote disease progression. In melanomas, which are tumors of the neural crest (NC) lineage, a molecular signature of the embryonic NC is often reactivated. These NC factors have been implicated in promoting pro-tumorigenic features like proliferation, migration and therapy resistance. However, the molecular mechanisms that establish and maintain NC identities in melanomas are largely unknown. Additionally, whether the presence of a NC identity has any clinical relevance for patient melanomas is also unclear. Here, using comparative genomic approaches, I have a) identified a novel role for GDF6-activated BMP signaling in reawakening a NC identity in melanomas, and b) identified a NC signature as a clinical predictor of melanoma progression. Like the genomes of many solid cancers, melanoma genomes have widespread copy number variations (CNV) harboring thousands of genes. To identify disease-promoting drivers amongst such huge numbers of genes, I used a comparative oncogenomics approach with zebrafish and human melanomas. This approach led to the identification of a recurrently amplified oncogene, GDF6, that acts via BMP signaling to invoke NC identities in melanomas. In maintaining this identity, GDF6 represses the melanocyte differentiation gene MITF and the proapoptotic factor SOX9, allowing melanoma cells to remain undifferentiated and survive. Functional analysis in zebrafish embryos indicated a role of GDF6 in blocking melanocyte differentiation, suggesting that the developmental function of GDF6 is reiterated in melanomas. In clinical assessments, a major fraction of patient melanomas expressed high GDF6, and its expression correlated with poor patient survival. These studies provide novel insights into regulation of NC identities in melanomas and offer GDF6 and components of BMP pathway as targets for therapeutic intervention. In additional studies, I wanted to test whether a broader NC identity in melanomas had any clinical relevance. In these studies, I performed transcriptome analysis of zebrafish melanomas and derived a 15-gene NC signature. This NC gene signature positively correlated with the expression of SOX10, a known NC marker in human melanomas. Patients whose melanomas expressed this signature showed poor overall survival. These findings identify an important predictive signature in human melanomas and also illuminate the clinical importance of NC identity in this disease

Regulation of zebrafish melanocyte development by ligand-dependent BMP signaling

Preventing terminal differentiation is important in the development and progression of many cancers including melanoma. Recent identification of the BMP ligand GDF6 as a novel melanoma oncogene showed GDF6-activated BMP signaling suppresses differentiation of melanoma cells. Previous studies have identified roles for GDF6 orthologs during early embryonic and neural crest development, but have not identified direct regulation of melanocyte development by GDF6. Here, we investigate the BMP ligand gdf6a, a zebrafish ortholog of human GDF6, during the development of melanocytes from the neural crest. We establish that the loss of gdf6a or inhibition of BMP signaling during neural crest development disrupts normal pigment cell development, leading to an increase in the number of melanocytes and a corresponding decrease in iridophores, another neural crest-derived pigment cell type in zebrafish. This shift occurs as pigment cells arise from the neural crest and depends on mitfa, an ortholog of MITF, a key regulator of melanocyte development that is also targeted by oncogenic BMP signaling. Together, these results indicate that the oncogenic role ligand-dependent BMP signaling plays in suppressing differentiation in melanoma is a reiteration of its physiological roles during melanocyte development

A sustained ocean observing system in the Indian Ocean for climate related scientific knowledge and societal needs

© The Author(s), 2019. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Hermes, J. C., Masumoto, Y., Beal, L. M., Roxy, M. K., Vialard, J., Andres, M., Annamalai, H., Behera, S., D'Adamo, N., Doi, T., Peng, M., Han, W., Hardman-Mountford, N., Hendon, H., Hood, R., Kido, S., Lee, C., Lees, T., Lengaigne, M., Li, J., Lumpkin, R., Navaneeth, K. N., Milligan, B., McPhaden, M. J., Ravichandran, M., Shinoda, T., Singh, A., Sloyan, B., Strutton, P. G., Subramanian, A. C., Thurston, S., Tozuka, T., Ummenhofer, C. C., Unnikrishnan, A. S., Venkatesan, R., Wang, D., Wiggert, J., Yu, L., & Yu, W. (2019). A sustained ocean observing system in the Indian Ocean for climate related scientific knowledge and societal needs. Frontiers in Marine Science, 6, (2019): 355, doi: 10.3389/fmars.2019.00355.The Indian Ocean is warming faster than any of the global oceans and its climate is uniquely driven by the presence of a landmass at low latitudes, which causes monsoonal winds and reversing currents. The food, water, and energy security in the Indian Ocean rim countries and islands are intrinsically tied to its climate, with marine environmental goods and services, as well as trade within the basin, underpinning their economies. Hence, there are a range of societal needs for Indian Ocean observation arising from the influence of regional phenomena and climate change on, for instance, marine ecosystems, monsoon rains, and sea-level. The Indian Ocean Observing System (IndOOS), is a sustained observing system that monitors basin-scale ocean-atmosphere conditions, while providing flexibility in terms of emerging technologies and scientificand societal needs, and a framework for more regional and coastal monitoring. This paper reviews the societal and scientific motivations, current status, and future directions of IndOOS, while also discussing the need for enhanced coastal, shelf, and regional observations. The challenges of sustainability and implementation are also addressed, including capacity building, best practices, and integration of resources. The utility of IndOOS ultimately depends on the identification of, and engagement with, end-users and decision-makers and on the practical accessibility and transparency of data for a range of products and for decision-making processes. Therefore we highlight current progress, issues and challenges related to end user engagement with IndOOS, as well as the needs of the data assimilation and modeling communities. Knowledge of the status of the Indian Ocean climate and ecosystems and predictability of its future, depends on a wide range of socio-economic and environmental data, a significant part of which is provided by IndOOS.This work was supported by the PMEL contribution no. 4934

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Not AvailableCordia sinensis, locally known as ‘Goondi’ in India, is an underexploited multipurpose fruit species found in hot arid regions that is well adapted to drought, salt and hot conditions. The present study was undertaken to collect fruit samples from different locations in the Kachchh region of Gujarat, India, and to determine their field establishment for characterization, conservation and utilization. The maximum distribution of the species was observed in Bhuj (45%) and Mandvi (25%). Field boundaries (35%) and scrub forests (30%) had greater frequencies, whereas backyards had rarer fre quencies (10%). The species most commonly occurred on levelled topography (60%) with a soil pH in the range of 8–8.5 (63%). Morphological data of three-year-old plants in the field gene bank showed a maximum coefficient of variation in the number of leaves per plant (66.6), followed by the number of branches per plant (45.62) and collar diameter (27.69). Wide variations were re corded in plant height (121.67–212 cm), spread (118–223 cm2 ) and the number of branches per plant (6–24.33). Specific accessions were identified for fodder (CBCG-12, CBCG-13 and CBCG 16), early flowering and fruiting (CBCG-12, CBCG-13 and CBCG-14), easier propagation by seeds (CBCG-12 and CBCG-13) and salt tolerance (CBCG-15 and CBCG-16). Preliminary findings and in formation provided about this species’ utilization and other aspects might be useful for future re search on its domestication, sole plantation and conservation aspects, improving the exploitation of this species by present and future generationsNot Availabl

Ligand-activated BMP signaling inhibits cell differentiation and death to promote melanoma

Oncogenomic studies indicate that copy number variation (CNV) alters genes involved in tumor progression; however, identification of specific driver genes affected by CNV has been difficult, as these rearrangements are often contained in large chromosomal intervals among several bystander genes. Here, we addressed this problem and identified a CNV-targeted oncogene by performing comparative oncogenomics of human and zebrafish melanomas. We determined that the gene encoding growth differentiation factor 6 (GDF6), which is the ligand for the BMP family, is recurrently amplified and transcriptionally upregulated in melanoma. GDF6-induced BMP signaling maintained a trunk neural crest gene signature in melanomas. Additionally, GDF6 repressed the melanocyte differentiation gene MITF and the proapoptotic factor SOX9, thereby preventing differentiation, inhibiting cell death, and promoting tumor growth. GDF6 was specifically expressed in melanomas but not melanocytes. Moreover, GDF6 expression levels in melanomas were inversely correlated with patient survival. Our study has identified a fundamental role for GDF6 and BMP signaling in governing an embryonic cell gene signature to promote melanoma progression, thus providing potential opportunities for targeted therapy to treat GDF6-positive cancers