ACVR1C/SMAD2 signaling promotes invasion and growth in retinoblastoma

Retinoblastoma is the most common intraocular cancer in children. While the primary tumor can often be treated by local or systemic chemotherapy, metastatic dissemination is generally resistant to therapy and remains a leading cause of pediatric cancer death in much of the world. In order to identif...

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Published in:	Oncogene Vol. 38; no. 12; pp. 2056 - 2075
Main Authors:	Asnaghi, Laura, White, David T., Key, Nolan, Choi, Joshua, Mahale, Alka, Alkatan, Hind, Edward, Deepak P., Elkhamary, Sahar M., Al-Mesfer, Saleh, Maktabi, Azza, Hurtado, Christopher G., Lee, Grace Y., Carcaboso, Angel M., Mumm, Jeff S., Safieh, Leen Abu, Eberhart, Charles G.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-03-2019 Nature Publishing Group
Subjects:	13/2 13/89 13/95 14/35 38/77 38/91 45/29 631/67/395 631/80/2373 64/116 82/80 96/2 Activin Activin Receptors, Type I - genetics Activin Receptors, Type I - metabolism Apoptosis Bone morphogenetic proteins Cancer Cancer invasiveness Cancer metastasis Cancer treatment Care and treatment Cell Biology Cell Line, Tumor Cell Proliferation Cell receptors Cellular signal transduction Chemotherapy Childhood cancer Danio rerio Death Development and progression Down-Regulation Gene Expression Regulation, Neoplastic Genetic aspects Health aspects Human Genetics Humans Internal Medicine Medical schools Medicine Medicine & Public Health Mesenchyme Messenger RNA Metastases Neoplasm Invasiveness Neoplasm Metastasis Oncology Optic nerve Pediatrics Phenotype Retina Retinoblastoma Retinoblastoma - pathology RNA Signal Transduction Smad2 protein Smad2 Protein - genetics Smad2 Protein - metabolism Smad3 protein Stem cells Therapeutic applications Transforming growth factors Tumor cells Tumors
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Summary:	Retinoblastoma is the most common intraocular cancer in children. While the primary tumor can often be treated by local or systemic chemotherapy, metastatic dissemination is generally resistant to therapy and remains a leading cause of pediatric cancer death in much of the world. In order to identify new therapeutic targets in aggressive tumors, we sequenced RNA transcripts in five snap frozen retinoblastomas which invaded the optic nerve and five which did not. A three-fold increase was noted in mRNA levels of ACVR1C/ALK7, a type I receptor of the TGF-β family, in invasive retinoblastomas, while downregulation of DACT2 and LEFTY2, negative modulators of the ACVR1C signaling, was observed in most invasive tumors. A two- to three-fold increase in ACVR1C mRNA was also found in invasive WERI Rb1 and Y79 cells as compared to non-invasive cells in vitro. Transcripts of ACVR1C receptor and its ligands (Nodal, Activin A/B, and GDF3) were expressed in six retinoblastoma lines, and evidence of downstream SMAD2 signaling was present in all these lines. Pharmacological inhibition of ACVR1C signaling using SB505124, or genetic downregulation of the receptor using shRNA potently suppressed invasion, growth, survival, and reduced the protein levels of the mesenchymal markers ZEB1 and Snail. The inhibitory effects on invasion, growth, and proliferation were recapitulated by knocking down SMAD2, but not SMAD3. Finally, in an orthotopic zebrafish model of retinoblastoma, a 55% decrease in tumor spread was noted ( p = 0.0026) when larvae were treated with 3 µM of SB505124, as compared to DMSO. Similarly, knockdown of ACVR1C in injected tumor cells using shRNA also resulted in a 54% reduction in tumor dissemination in the zebrafish eye as compared to scrambled shRNA control ( p = 0.0005). Our data support a role for the ACVR1C/SMAD2 pathway in promoting invasion and growth of retinoblastoma.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0950-9232 1476-5594
DOI:	10.1038/s41388-018-0543-2