TMEM16A controls EGF-induced calcium signaling implicated in pancreatic cancer prognosis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 26; pp. 13026 - 13035
• Main Authors: Crottès, David, Lin, Yu-Hsiu T., Peters, Christian J., Gilchrist, John M., Wiita, Arun P., Jan, Yuh Nung, Jan, Lily Yeh
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25.06.2019
• Series: PNAS Plus
• Subjects: Anoctamin-1 - genetics; Anoctamin-1 - metabolism; Biological Sciences; Biomarkers; Biomarkers, Tumor - metabolism; Calcium; Calcium chloride; Calcium Signaling; Calcium signalling; Cancer; Carcinoma, Pancreatic Ductal - diagnosis; Carcinoma, Pancreatic Ductal - mortality; Carcinoma, Pancreatic Ductal - pathology; Cell adhesion & migration; Cell Line, Tumor; Cell migration; Cell Movement; Chloride channels (calcium-gated); Chloride ions; Datasets as Topic; Diagnosis, Differential; Epidermal Growth Factor - metabolism; Epidermal growth factor receptors; ErbB Receptors - metabolism; HEK293 Cells; Humans; Ion channels; Medical prognosis; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Pancreas - pathology; Pancreatic cancer; Pancreatic Neoplasms - diagnosis; Pancreatic Neoplasms - mortality; Pancreatic Neoplasms - pathology; PNAS Plus; Prognosis; RNA, Small Interfering - metabolism; RNA-Seq; Signal transduction; Survival; Survival Rate; Tumors; Up-Regulation; pancreatic cancer; TMEM16A; calcium-activated chloride channel; EGFR; store-operated calcium entry
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1900703116

Pancreatic cancer typically spreads rapidly and has poor survival rates. Here, we report that the calcium-activated chloride channel TMEM16A is a biomarker for pancreatic cancer with a poor prognosis. TMEM16A is up-regulated in 75% of cases of pancreatic cancer and high levels of TMEM16A expression are correlated with low patient survival probability. TMEM16A up-regulation is associated with the ligand-dependent EGFR signaling pathway. In vitro, TMEM16A is required for EGF-induced store-operated calcium entry essential for pancreatic cancer cell migration. TMEM16A also has a profound impact on phosphoproteome remodeling upon EGF stimulation. Moreover, molecular actors identified in this TMEM16A-dependent EGFR-induced calcium signaling pathway form a gene set that makes it possible not only to distinguish neuro-endocrine tumors from other forms of pancreatic cancer, but also to subdivide the latter into three clusters with distinct genetic profiles that could reflect their molecular underpinning.