Review ArticleReviewsR

The Hippo Signaling Pathway in Pancreatic Cancer

DANIEL ANSARI, HENRIK OHLSSON, CARL ALTHINI, MONIKA BAUDEN, QIMIN ZHOU, DINGYUAN HU and ROLAND ANDERSSON
Anticancer Research July 2019, 39 (7) 3317-3321; DOI: https://doi.org/10.21873/anticanres.13474

Abstract

Hippo signaling is a key regulator of organ size, tissue hemostasis and regeneration. Dysregulation of the Hippo pathway has been recognized in a variety of human cancers, including pancreatic cancer. YES-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the two major downstream effectors of the Hippo pathway. YAP and TAZ have been found to promote pancreatic tumor development and progression, even in the absence of mutant Kirsten RAS (KRAS). Pancreatic cancer is associated with an abundant stromal reaction leading to tumor growth and immune escape. It has been found that YAP and TAZ modulate behavior of pancreatic stellate cells and recruitment of tumor-associated macrophages and myeloid-derived suppressor cells. Moreover, YAP and TAZ are associated with chemoresistance and poor prognosis in pancreatic cancer. This review dissects the role of Hippo signaling in pancreatic cancer, focusing on molecular mechanisms and prospects for future intervention.

Pancreatic cancer is the third most common cause of cancer-related death (1). Despite advances in surgery and chemotherapy, the overall prognosis has remained virtually unchanged for many decades (2). The median survival of patients with pancreatic cancer, overall, is about 6 months and the 5-year survival rate is below 5% (3). Most patients are diagnosed with disease at late stages due to lack of early symptoms and accurate diagnostic markers. Fewer than 20% of patients have up-front resectable disease. However, even after radical resection, most patients develop recurrence and die of their disease. Pancreatic cancer is a heterogenous disease harboring multiple genomic, proteomic and epigenetic alterations related to alterations in several core signaling pathways (4). The complex interplay between cancer cells and the surrounding stroma also represents a challenge to development of treatment (5). These statistics highlight the need for new approaches to pancreatic cancer diagnosis and therapy.

The Hippo signaling pathway was first discovered from studies in Drosophila melanogaster (6). Under physiological conditions, Hippo signaling governs normal organ development and tissue regeneration (7). Deregulation of Hippo signaling has been recognized in a variety of human malignancies, including pancreatic cancer (8, 9). Deregulation of the Hippo pathway has been related to tumor cell behavior, as well as prognosis in patients with cancer (9). The Hippo pathway has become extensively studied in pancreatic cancer and results of these studies have corroborated the biological importance of this pathway.

In this review, we summarize the mechanisms by which Hippo signaling affects pancreatic cell growth, invasion and metastatic behavior. We further discuss how Hippo signaling interacts with the stroma and host immune response. Finally, we review the role of Hippo signaling in treatment resistance and clinical outcome.

The Hippo Signaling Pathway

Hippo signaling is an evolutionarily conserved network that plays a key role in regulating cell proliferation, organ growth and regeneration (Figure 1). Its core consists of the serine/threonine kinases mammalian sterile 20-like kinase 1 and 2 (MST1 and MST2, HPO in Drosophila) and large tumor suppressor 1 and 2 (LATS1 and LATS2). MST1 and -2 work with Salvador homolog 1 (SAV1) to phosphorylate and activate LATS1 and -2 kinases. Subsequently, LATS1 and -2 kinases combine with the adaptor, MOB kinase activator 1 (MOB1), and result in the phosphorylation of the Hippo transducers YES-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). By phosphorylation, YAP and TAZ are prevented from nuclear accumulation and interaction with transcription factors such as TEA transcriptional factor (TEAD)-1, TEAD2, TEAD3 and TEAD4. If the regulatory module is inactivated, or in the presence of stimuli that activate YAP/TAZ independently from the Hippo kinases, the Hippo transducers YAP/TAZ accumulate in the nucleus and interact with transcriptional factors, thereby mediating transcription of target genes such as connective tissue growth factor (CTGF), cysteine-rich angiogenic inducer 61 (CYR61), ankyrin repeat domain 1 (ANKRD1), baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) and AXL receptor tyrosine kinase (AXL) (7). Multiple inputs control Hippo signaling, spanning from mechanical cues instructed by the cellular microenvironment (mechano-transduction) to soluble factors and metabolic pathways (10, 11). The Hippo pathway is involved in extensive crosstalk with other signaling pathways such as transforming growth factor-beta, Wnt, Sonic hedgehog and Notch (12).

YAP Expression in Pancreatic Cancer

Several studies have indicated that YAP is overexpressed in tumor samples from patients with pancreatic cancer (13-17). Activating mutations in KRAS are among the most frequent events in pancreatic cancer. YAP has been identified as a critical partner to mutant KRAS in driving pancreatic carcinogenesis in experimental models. YAP reportedly acts as a transcriptional switch downstream of KRAS, promoting expression of genes that promote neoplastic proliferation, stromal response and the progression to invasive carcinoma (18). Furthermore, it has been found that deletion of the tumor suppressor F-box and WD repeat domain containing 7 (FBXW7) accelerates KRAS-driven pancreatic tumorigenesis via YAP accumulation (19). At the same time, it has been demonstrated that tumor cells can survive without KRAS signaling, with bypass mechanisms involving YAP (13).

Tumor Growth

There is accumulating evidence that YAP and TAZ promote proliferation and growth of pancreatic cancer cells. Treatment of pancreatic cancer cells with YAP-targeting small interfering RNA oligonucleotides significantly reduced tumor growth (16). It has been reported that eukaryotic translation initiation factor 5A (eIF5A)-pseudopodium enriched atypical kinase 1 (PEAK1) signaling regulates YAP and TAZ expression and pancreatic cancer cell growth. Disrupting eIF5A-PEAK1 signaling in pancreatic cancer cells inhibited protein expression to YAP and TAZ, reducing expression of stem cell-associated transcription factors and tumor sphere growth (20).

Epithelial–Mesenchymal Transition (EMT), Invasion and Metastasis

EMT is a developmental regulatory program defined by the phenotypical transition from an epithelial to a mesenchymal cell state. EMT is an essential step for metastasis and confers resistance to therapy. Active YAP promotes pancreatic cancer cell motility, invasion and tumorigenesis in a mitotic phosphorylation-dependent manner and contributes to EMT in pancreatic cancer cells by several mechanisms, including hyperactivation of AKT signaling (14, 15, 21, 22).

Stroma

Pancreatic cancer is characterized by a dense stroma that can promote tumor growth. The stroma contains cancer-associated fibroblasts (CAFs), immune cells, endothelial cells and extracellular matrix. Pancreatic stellate cells are resident mesenchymal cells of the pancreas that represent the major source of CAFs. It has been found that YAP and TAZ are expressed at high levels in activated pancreatic stellate cells in pancreatic cancer, as well as in chronic pancreatitis (23). Transglutaminase 2 secreted by pancreatic cancer cells modulates the stroma by cross-linking collagen, which, in turn, activates CAFs and pancreatic stellate cells and stimulates their proliferation. The stiff fibrotic stromal reaction confers mechanical signals to cancer cells, leading to activation of the YAP and TAZ transcription factors and tumor progression (24).

Immunomodulation

Pancreatic cancer is characterized by a profound inflammatory reaction and immunosuppressive state (25). Pancreatic tumors are associated with immune dysfunction, partly mediated by the recruitment of immunosuppressive cells, such as tumor-associated macrophages and myeloid-derived suppressor cells (26-28). These cells are recruited to the tumor microenvironment and can inhibit T-cell activity. YAP has been identified as a critical regulator of the immunosuppressive microenvironment in pancreatic cancer. YAP inactivation prevented recruitment of myeloid-derived suppressor cells while in turn supporting infiltration of antigen presenting macrophages and T-cell activation, thereby promoting apoptosis of tumor cells (29).

Chemoresistance

Gemcitabine has been the standard chemotherapeutic agent in pancreatic cancer since 1997 (30). However, pancreatic cancer is characterized by a high degree of chemoresistance. Several mechanisms of YAP-induced chemoresistance have been proposed. One mechanism suggests that YAP overexpression induces EMT in pancreatic cancer cells by activating the AKT cascade, which can cause resistance to gemcitabine (21). Another mechanism involves microRNAs. It has been suggested that microRNA 181c is overexpressed in pancreatic cancer samples and correlated with poor prognosis. MicroRNA 181c directly repressed MST1, LATS2, MOB1 and SAV1, leading to YAP and TAZ activation, and gemcitabine resistance in vitro and in vivo (31).

Figure 1.
Figure 1.

The Hippo signaling pathway. Mammalian sterile 20-like kinase 1 and 2 (MST1/2) work with scaffolding proteins Salvador homolog (SAV) to phosphorylate and activate large tumor suppressor 1 and 2 (LATS1/2) kinases. Subsequently, LATS1/2 kinases combine with the adaptor, MOB kinase activator 1A and 1B (MOB1A/B), and result in the phosphorylation of the Hippo transducers YES-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). By phosphorylation, YAP and TAZ are retained in the cytoplasm or degraded and thereby prevented from nuclear accumulation and interaction with transcription factors such as TEA transcriptional factor (TEAD)-1, TEAD2, TEAD3 and TEAD4. Aberrant Hippo signaling in pancreatic cancer is related to tumorigenesis, tumor growth, epithelial–mesenchymal transition (EMT), stroma, immunomodulation and chemoresistance. ANKRD1: Ankyrin repeat domain 1; AXL: AXL receptor tyrosine kinase; BIRC5: baculoviral inhibitor of apoptosis repeat-containing 5; CTGF: connective tissue growth factor; CYR61: cysteine-rich angiogenic inducer 61.

Patient Survival

Despite extensive research, no single prognostic molecular marker is used in the clinical management of pancreatic cancer. The clinical significance of YAP as a prognostic marker has been investigated in several studies. It has been found that nuclear overexpression of YAP is an independent prognostic marker for poor survival and is associated with liver metastasis (17). Furthermore, using public messenger RNA expression data, YAP was confirmed to be correlated with poor survival (32). The 5-year survival rate was 0% in patients with high YAP mRNA expression compared to 32% in those with low expression. Furthermore, multiple YAP/TEAD-regulated genes were associated with poor prognosis, such as transforming growth factor alpha (TGFα), heparin binding EGF like growth factor (HBEGF), integrin subunit alpha 2 (ITGA2), P2Y2 receptor (P2Y2R), G protein-coupled receptor 87 (GPR87) and mucin 1 (MUC1). On the other hand, YAP-inhibitory pathways were associated favorable prognosis, such as STE20-related kinase adaptor/liver kinase B1 (STRAD/LKB-1), protein kinase A/large tumor suppressor (PKA/LATS), and tuberous sclerosis complex/mammalian target of rapamycin complex 1 (TSC/mTORC1).

Therapeutic Targeting of Hippo Signaling

Considering the role of YAP and TAZ in pancreatic tumor biology and clinical outcome, it is reasonable to develop drugs that target YAP and TAZ activity. Of the evaluated treatments in pancreatic cancer to date, only verteporfin (33, 34) has a direct effect upon Hippo signaling. Erlotinib (35), BIS 1 (35) and LY3009120 (33) indirectly affect YAP and TAZ signaling. The mechanism of action is not fully clarified for several natural substances, such as curcumin (36), resveratrol (37), Stiehopus japonieus acidic mucopolysaccharide (38) and pseudolaric acid B (39).

Conclusion

The Hippo pathway is an evolutionary conserved signaling pathway, involved in organ size control and tissue homeostasis. YAP and TAZ are key downstream regulators in the Hippo pathway that are found to be up-regulated in pancreatic cancer. Aberrant transcriptional activity of YAP and TAZ has a crucial role in pancreatic tumor cell biology, including growth, EMT, microenvironmental signaling and drug resistance. YAP and TAZ are prognostic factors in pancreatic cancer. In the future, direct or indirect pharmacological modulation of the Hippo pathway or YAP and TAZ targeting genes may become promising approaches to treat pancreatic cancer.

Footnotes

  • This article is freely accessible online.

  • Received December 10, 2018.
  • Revision received December 13, 2018.
  • Accepted December 14, 2018.

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The Hippo Signaling Pathway in Pancreatic Cancer
DANIEL ANSARI, HENRIK OHLSSON, CARL ALTHINI, MONIKA BAUDEN, QIMIN ZHOU, DINGYUAN HU, ROLAND ANDERSSON
Anticancer Research Jul 2019, 39 (7) 3317-3321; DOI: 10.21873/anticanres.13474
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