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Proc Natl Acad Sci U S A. 2019 Jun 25;116(26):13026-13035. doi: 10.1073/pnas.1900703116. Epub 2019 Jun 10.

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

Crottès D1,2,3, Lin YT4, Peters CJ1,2,3, Gilchrist JM1,2,3, Wiita AP4, Jan YN1,2,3, Jan LY5,2,3.

Author information

1
Department of Physiology, University of California, San Francisco, CA 94143.
2
Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143.
3
Howard Hughes Medical Institute, University of California, San Francisco, CA 94143.
4
Department of Laboratory Medicine, University of California, San Francisco, CA 94143.
5
Department of Physiology, University of California, San Francisco, CA 94143; Lily.Jan@ucsf.edu.

Abstract

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.

KEYWORDS:

EGFR; TMEM16A; calcium-activated chloride channel; pancreatic cancer; store-operated calcium entry

PMID:
31182586
PMCID:
PMC6600921
[Available on 2019-12-10]
DOI:
10.1073/pnas.1900703116

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