Abstract 5088: ACVRIB-dependent regulation of extracellular matrix protein in squamous cell carcinoma progression

Abstract

Abstract Squamous cell carcinomas (SCC) of the head and neck and esophagus pose a substantial public health risk globally. As SCC is often diagnosed in late stage, therapeutic options are limited. A more thorough understanding of the mechanisms involved their progression is needed. One potential mode by which SCCs progress is via Activin A signaling. The downstream effects of Activin A signaling have been primarily characterized as growth inhibiting and anti-angiogenic. However, Activin A is commonly overexpressed in SCC. Therefore, we hypothesized that SCC become insensitive to Activin A stimulation through the dysregulation of the signaling pathway. To model this dysregulation we utilized CRISPR-mediated regulation of ACVRIB (ACVRIB-kd), the necessary type IB receptor to transduce Activin A signaling in three SCC cell lines. Downregulation of ACVRIB enhanced invasiveness in the OSC19 SCC three-dimensional organotypic cultures. Additionally, ACVRIB-kd cells showed significant changes in protein expression, when compared to control. In particular, the correlative markers of SCC aggressiveness and putative downstream Activin A targets, podoplanin and fibronectin, were substantially altered in ACVRIB-kd cells. Integrin expression, particularly integrins β3, α5, and αv, was markedly changed in ACVRIB-kd cells, indicating additional ACVRIB-mediated effects to ECM proteins. We are currently analyzing ACVRIB-kd SCC tumor growth and metastasis in vivo using tongue orthotopic xenografts and subcutaneous flank injections. In conclusion, SCC-specific disruption of Activin A signaling promotes an aggressive phenotype. Re-activation of the canonical Activin A pathway may provide a novel therapeutic strategy to combat SCC. Citation Format: Holli A. Loomans, Laura L. Quast, Claudia A. Andl. ACVRIB-dependent regulation of extracellular matrix protein in squamous cell carcinoma progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5088.