Role of YAP and TAZ in pancreatic ductal adenocarcinoma and in stellate cells associated with cancer and chronic pancreatitis

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibrotic and inflammatory microenvironment that is formed primarily by activated, myofibroblast-like, stellate cells. Although the stellate cells are thought to contribute to tumorigenesis, metastasis and drug resistance of PDAC, the signaling events involved in activation of the stellate cells are not well defined. Functioning as transcription co-factors, Yes-associated protein (YAP) and its homolog transcriptional co-activator with PDZ-binding motif (TAZ) modulate the expression of genes involved in various aspects of cellular functions, such as proliferation and mobility. Using human tissues we show that YAP and TAZ expression is restricted to the centroacinar and ductal cells of normal pancreas, but is elevated in cancer cells. In particular, YAP and TAZ are expressed at high levels in the activated stellate cells of both chronic pancreatitis and PDAC patients as well as in the islets of Langerhans in chronic pancreatitis tissues. Of note, YAP is up regulated in both acinar and ductal cells following induction of acute and chronic pancreatitis in mice. These findings indicate that YAP and TAZ may play a critical role in modulating pancreatic tissue regeneration, neoplastic transformation, and stellate cell functions in both PDAC and pancreatitis.

Molecular Pathogenesis of Pancreatic Cancer

“…Deregulation of Hippo signaling in PDAC is evidenced by increased YAP/TAZ protein levels and nuclear localization 100-102 . However, the underlying mechanisms accounting for increased YAP/TAZ activation remain an area of active investigation.…”

YAP Inhibition by Resveratrol via Activation of AMPK Enhances the Sensitivity of Pancreatic Cancer Cells to Gemcitabine

“…The YES-associated protein (YAP), a main component of the Hippo pathway, has been proved to be overexpressed and to participate in the tumorigenesis of a variety of cancers, including breast cancer [9], lung cancer [10], ovarian cancer [11], liver cancer [12], and pancreatic cancer [13,14]. YAP functions as an oncogene and promotes the survival of cancer cells by regulating cancer cell proliferation and apoptosis.…”

Verteporfin suppresses cell survival, angiogenesis and vasculogenic mimicry of pancreatic ductal adenocarcinoma via disrupting the YAP‐TEAD complex

“…YAP serves as a transcriptional co‐activator and regulates the activity of various transcription factors, such as TEADs and CTGF, which are implicated in cell proliferation, apoptosis, chemoresistance and angiogenesis . YAP is highly expressed in several types of malignant tumors including pancreatic cancer, and is shown to participate in the development, progression and recurrence of PDAC . Hyperactivated YAP could enhance the secretion of microfibrillar associated protein 5 (MFAP5) to promote neoangiogenesis in vitro and in vivo .…”

“…(6) YAP is highly expressed in several types of malignant tumors including pancreatic cancer, (7)(8)(9) and is shown to participate in the development, progression and recurrence of PDAC. (10,11) Hyperactivated YAP could enhance the secretion of microfibrillar associated protein 5 (MFAP5) to promote neoangiogenesis in vitro and in vivo. (12) Therefore, YAP may be a potential target for cancer therapies.As one of the hallmarks of cancer, angiogenesis is characterized by the formation of new and irregular blood vessels to supply nutrients and oxygen in tumors.…”