Abstract A43: Activin receptor type IA in pancreatic cancer and its implications in tumor progression
Authors: Mancinelli Georgina E. , Staudacher Jonas , Jung Barbara , Grippo Paul J. 
Published: December 2016

Several studies have shown the importance of the Transforming Growth Factor Beta (TGFβ) pathway in pancreatic tumorigenesis and cancer progression, displaying a seemingly paradoxical role in tumor development. However, Activin, a TGFβ family member and its contributions to tumor development and progression are largely understudied in most cancers, particularly pancreatic cancer. The functions of Activin through its receptors are context and cell-type specific, as they exert different effects in various cancer types, including colon, breast and prostate. In normal pancreas, Activin A isoform levels in serum are low, while in pancreatic cancer Activin A levels positively correlate with shorter survival and metastasis. Activin, like TGFβ, signals through a complex containing Activin A type I and type II receptors. A type II homodimer comprised of Activin receptor type IIA (ACVRIIA) or IIB (ACVRIIB) binds ligand via an extracellular domain and recruits a homodimer of Activin receptor type IA (ACVRIA) or IB (ACVRIB), leading to formation of a tetrameric complex and phosphorylation of type I receptor by the type II serine/threonine kinase activity. ACVRIA and ACVRIB differ in amino acid sequence within the activation region, called the GS region, presumably giving receptor specificity and differences in regulation of canonical (SMAD-dependent) and non-canonical (SMAD-independent) downstream signaling. Human pancreatic ductal adenocarcinomas contain somatic mutations in the ACVR1B gene, and one recent study in vivo showed that pancreatic-specific loss of ACVR1B accelerates development of mutant KRAS-induced intraductal papillary mucinous neoplasms in mice. Our in silico data compiled from human pancreatic cancer patients demonstrates that there is a significant 50% loss of ACVR1B mRNA in cancer patients compared to normal tissue from the same cohort. Moreover, pancreatic cancer patients show a significant 80% upregulation of ACVR1A mRNA compared to normal. Yet, Activin effects through ACVRIA in pancreatic cancer have not yet been established. Our studies aim to characterize the effects of ACVR1A activation in pancreatic tumor development and progression. We hypothesize that the opposing effects of Activin signaling in pancreatic cancer may be due to ACVRIA activation and its subsequent pro-survival and pro-tumorigenic functions.

Pancreatic cancer cell lines were analyzed for levels of ACVR1A expression, MIA PaCa-2 showed the highest level of expression followed by AsPC-1, with PANC-1 showing the lowest expression. MIA PaCa-2 and AsPC-1 cell lines showed increased migration in scratch assays compared to control following treatment with Activin A. We are currently establishing MIA PaCa-2 and AsPC-1 stable cell lines with a knockdown of ACVR1A to assess migratory and proliferative changes upon Activin treatment when ACVR1A is downregulated. Human and murine tissue immunostaining of ACVR1A showed expression of the receptor in the normal pancreas as well as tumor tissue samples. Human pancreas staining for ACVR1A was stronger in the carcinoma sections of tumor tissue samples compared to a lighter staining in normal tissue samples. Murine tissues showed staining in the neoplastic lesions of KC and EL-KRAS transgenic mice, while no strong staining was observed in the wild type mouse.

We conclude that not only TGFβ exerts dual effects in regards to pro and anti-tumor promoting effects in the context of pancreatic cancer, but rather Activin signaling pathway is also important in pancreatic carcinogenesis and a novel target that can be useful for therapeutic interventions in pancreatic cancer. Determining Activin signaling through ACVR1A can be essential in deciphering the role of Activin in pancreatic tumor development and progression.

Citation Format: Georgina E. Mancinelli, Jonas Staudacher, Barbara Jung, Paul J. Grippo.{Authors}. Activin receptor type IA in pancreatic cancer and its implications in tumor progression. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A43.