bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B42: YAP1/Hippo pathway and SWI/SNF as critical players in squamous cancers and normal development
Authors: Ellisen Leif , Tata Purushothama Rao , Zhao Rui , Rajagopal Jayaraj , Saladi Srinivas Vinod 
Published: September 2020

Abstract
Cancer development is a multistep process involving deregulation of transcription/epigenetic factors and signaling pathways. Accordingly, gene expression lies at the nexus of oncogenic cellular processes. The recent advent of The Cancer Genome Atlas (TCGA) has shed light on multiple genes involved in signaling, transcription, and other cellular processes that are subjected to genomic alterations in multiple cancers. These oncogenic drivers are involved in regenerative proliferation, metastasis, and other cellular processes that contribute to tumorigenesis. Epithelial-stromal interactions and the infiltrating immune response contribute significantly to tumor progression. Our recent studies revealed Hippo pathway activation as a critical component in ACTL6A (subunit of SWI/SNF chromatin remodeling complex) amplified squamous cancers. Our published genetic studies indicate that YAP is a key mediator of the oncogenic function of ACTL6A/p63 in head and neck squamous cancers. P63 is a master transcription factor in epithelial development. We have shown that YAP and p63 biochemically interact to maintain airway architecture and regeneration. YAP and p63 deletion are phenocopies and are required to maintain normal respiratory epithelial stem cells. P63/ACTL6A act as upstream regulators of YAP in squamous cancers. ACTL6A and p63 physically interact and cooperatively control a transcriptional program that promotes proliferation and suppresses differentiation, through activation of the Hippo-YAP pathway via regulators including WWC1 and GPRC5A. Consequently, loss of ACTL6A or p63 in tumor cells induces YAP phosphorylation and inactivation, associated with growth arrest and terminal differentiation, all phenocopied by WWC1 overexpression. YAP activation predicts poor patient survival in squamous cancers. These findings are also in keeping with the emerging role of the YAP pathway as a tumor driver in multiple contexts. Given interest in YAP as a therapeutic target, our studies reveal contribution of p63 and TEAD to YAP function as evident from global transcription profiling. Our most recent studies also indicate contribution of YAP in tumor progression by evading host immune response. All these indicate an important intrinsic role of YAP in development and disease, making it one of the ideal therapeutic targets to control cancer.
Citation Format: Leif Ellisen, Purushothama Rao Tata, Rui Zhao, Jayaraj Rajagopal, Srinivas Vinod Saladi. YAP1/Hippo pathway and SWI/SNF as critical players in squamous cancers and normal development [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B42.
Abstract B43: Division of labor between YAP and TAZ in lung cancer
Authors: Shreberk-Shaked Michal , Dassa Bareket , Di Agostino Silvia , Nuriel Yarden , Wigoda Noa , Rotkopf Ron , Blandino Giovanni , Aylon Yael , Oren Moshe 
Published: September 2020

Abstract
Paralogs originating from a gene duplication event can diverge and accumulate changes that contribute to a division of labor. Therefore, we wished to explore differential activities of YAP and TAZ. Traditionally, research has tended to consider YAP and TAZ as functionally redundant transcriptional cofactors, with similar biologic impact. However, there is growing evidence that each of them possesses distinct attributes. Hence, it is of great interest to find out whether YAP and TAZ have nonredundant involvement in cancer. Lung cancer is the leading cause of cancer-related deaths worldwide. Despite significant progress, the 5-year survival is still lower than 15%. Therefore, there is an urgent need for novel lung cancer biomarkers. Recent evidence suggests that YAP/TAZ play important roles in lung tumorigenesis. We explored differences in the transcriptional programs regulated by YAP and TAZ in lung adenocarcinoma cells, and the physiologic implications of such differences. Towards this aim, we performed RNA-sequencing in lung cancer cells following knockdown of either YAP or TAZ. Our analysis revealed a broad spectrum of expression patterns, including genes that are regulated preferentially by either YAP, TAZ, or both. Interestingly, a group of genes related to extracellular matrix remodeling was substantially regulated by TAZ but not YAP, while cell cycle- and proliferation-related genes were affected mainly by YAP but not TAZ. These differences in gene regulation correlated with functional differences between YAP and TAZ. Knockdown of TAZ strongly affected cell migration, whereas depletion of YAP had only mild effects on migration. Conversely, YAP silencing resulted in reduced proliferation compared to TAZ silencing. Importantly, YAP- and TAZ-dependent transcriptomes were correlated to lung cancer patient survival. In summary, our findings suggest that YAP and TAZ have distinct but complementary roles, which are associated with different cancer features. Hopefully, the identification of different activities and downstream effects of YAP and TAZ may enable more refined stratification of lung cancers and provide clues for the development of more effective targeted therapies.
Citation Format: Michal Shreberk-Shaked, Bareket Dassa, Silvia Di Agostino, Yarden Nuriel, Noa Wigoda, Ron Rotkopf, Giovanni Blandino, Yael Aylon, Moshe Oren. Division of labor between YAP and TAZ in lung cancer [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B43.
Abstract IA01: Targeting developmental pathways in cancer
Authors: de Sauvage Frederic 
Published: September 2020

Abstract
Signaling pathways such as Notch, Wnt, Hedgehog, and Hippo play critical roles during embryonic development through modulation of proliferation, cell migration, and differentiation. In adults, these pathways remain important in regulating stem cell function during normal tissue homeostasis. However, inappropriate activation either through mutation or misexpression can result in tumorigenesis, making potential targets for the development of novel targeted therapeutics. The Hedgehog pathway provides a textbook example of this scenario where aberrant activation of the pathway through Patched (PTCH) loss of function mutations or Smoothened (SMO) activating mutation leads to the development of various types of cancers such as basal cell carcinoma or medulloblastoma. These observations drove the development of Hedgehog pathway inhibitors (HPI) for the treatment of various cancers, resulting in the approval of two SMO inhibitors, vismodegib and sonidegib, for the treatment of advanced BCC. Lessons learned from targeting the Hedgehog pathway may inform the development of future therapies.
Citation Format: Frederic de Sauvage. Targeting developmental pathways in cancer [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr IA01.
Abstract IA08: Regulation of YAP by tyrosine phosphorylation of core Hippo pathway components: Lessons learned from the GNAQ oncogene and FAK
Authors: Gutkind J. Silvio 
Published: September 2020

Abstract
Dysregulation of the Hippo signaling pathway and the consequent YAP1 activation is a frequent event in human malignancies, yet the underlying molecular mechanisms are still poorly understood. In prior studies we have focused on uveal melanoma, the most frequent eye malignancy in adults that is caused by constitutively active mutations in the GNAQ oncogenes, which encode Gαq and Gα11 heterotrimeric G protein α subunits. We found that GNAQ promotes the activation of YAP1 by a mechanism involving the activation of RhoA by the direct association of Gαq to TRIO, a Rho-GEF, and the consequent stimulation of acting polymerization and the release of YAP from its complex with AMOT. We also showed that YAP1 is essential for uveal melanoma cell growth, thus representing a potential therapeutic target for this malignancy. However, no effective and safe YAP1 inhibitors are currently available. Using a novel integrated bioinformatics pipeline, we recently found that PTK2, encoding Focal Adhesion Kinase (FAK), represents a candidate synthetic lethal gene with GNAQ activation (Feng et al., Cancer Cell 2019). We found that Gαq activates FAK through the TRIO-RhoA noncanonical Gαq-signaling, and that genetic ablation or pharmacologic inhibition of FAK inhibits uveal melanoma growth. Surprisingly, analysis of the FAK-regulated transcriptome indicated that GNAQ stimulates YAP1 through FAK. Dissection of the underlying mechanism revealed that FAK regulates YAP1 by tyrosine phosphorylation of MOB1, thereby disrupting MOB1/LATS association and core Hippo pathway signaling. By coupling the power of an unbiased computational pipeline to the unique genetic landscape of uveal melanoma, we uncovered a molecular framework regulating YAP1 and identified FAK as a druggable signaling hub downstream from GNAQ in uveal melanoma. Our findings established FAK as a potential therapeutic target for uveal melanoma and other diseases that may involve FAK activation and unrestrained YAP1 function. Further studies on how multiple growth promoting and oncogenic tyrosine kinase signaling networks may converge to phosphorylate core Hippo pathway components to activate YAP1 in cancer will be also discussed.
Citation Format: J. Silvio Gutkind. Regulation of YAP by tyrosine phosphorylation of core Hippo pathway components: Lessons learned from the GNAQ oncogene and FAK [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr IA08.
Abstract IA09: The crosstalk between Hippo-YAP/TAZ and PTEN-AKT signaling in liver metabolic dysregulation and tumorigenesis
Authors: Jeong Sun-Hye , Lim Dae-Sik 
Published: September 2020

Abstract
Several in vitro studies have suggested that Hippo-YAP/TAZ signaling regulates the AKT pathway components PI3K and PTEN. Increased YAP expression in human liver tumors is associated with high levels of phosphorylated AKT. This suggests that crosstalk between the Hippo and AKT pathways may be important in the maintenance of functional liver homeostasis. The nature of such crosstalk has thus far remained unclear. Here, we investigated the possible role of crosstalk between Hippo-YAP/TAZ and PTEN-AKT pathways in the liver. Deletion of both Pten and Sav1 in the liver (DKO) accelerates the development of nonalcoholic fatty liver disease (NAFLD) and liver cancer in mice through excessive activation of AKT. At the molecular level, activation of YAP and TAZ amplifies AKT signaling through direct upregulation of IRS2 expression. Deletion of YAP/TAZ or activation of Hippo attenuated development of fatty liver in these DKO mice by downregulating IRS2. Notably, increased YAP/TAZ expression was also associated with high level of IRS2-pAKT in the patient. Moreover, treatment with the AKT inhibitor MK-2206 attenuated NAFLD development and tumorigenesis in DKO mice. Our findings suggest that crosstalk between Hippo and AKT pathways at the level of YAP/TAZ-IRS2 contributes to the development and progression of NAFLD to liver cancer, and they therefore provide a basis for the development of new therapeutic interventions.
Citation Format: Sun-Hye Jeong, Dae-Sik Lim. The crosstalk between Hippo-YAP/TAZ and PTEN-AKT signaling in liver metabolic dysregulation and tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr IA09.
Abstract IA17: Hippo pathway deregulation in cancers
Authors: Dey Anwesha 
Published: September 2020

Abstract
The Hippo signaling pathway is an evolutionarily conserved pathway that plays a key role in the development and homeostasis of tissues and organs. The TEAD family of the transcription factors (TEAD1-4) are the major transcription factors, and YAP/TAZ are the transcription activators/ key effectors of the Hippo pathway. TEADs regulate many biologic processes, including development, tissue homeostasis, and tumorigenesis by regulating target genes involved in cellular proliferation and survival. Amplification or upregulation of YAP/TAZ/TEADs correlates with poor prognosis in cancer patients. While data over the past few years have demonstrated that the pathway is dysregulated in a spectrum of cancers, the underlying molecular mechanisms of regulation and localization are areas of active investigation. One such focus area that I will discuss during my talk is the regulation and localization of TEADs. TEADs contain a highly conserved nuclear localization signal (NLS) embedded in the DNA binding domain (DBD). Overexpression of an NLS mutant TEAD in a Hippo-dependent cancer cell line is dominant negative and suppresses cellular proliferation and tumor growth. Additionally, we have identified physiologic conditions where TEADs are expressed in the cytoplasm and the nucleus. By performing comparative immunoprecipitation-mass spectrometry between WT and NLS mutant TEAD, we found novel interacting partners for cytoplasmic and nuclear TEAD, thus uncovering novel roles for TEADs in cancer.
Citation Format: Anwesha Dey. Hippo pathway deregulation in cancers [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr IA17.
Abstract IA18: Targeting the Hippo pathway for candidate cancer therapy
Authors: Hong Wanjin 
Published: September 2020

Abstract
My lab has been working on the Hippo pathway and its regulators in cancer. Our earlier works defined the oncogenic role of TAZ/WWTR1 and the importance of TEAD in mediating TAZ-driven oncogenesis. We also resolved the crystal structure of YAP-TEAD and Vgll1-TEAD complexes offering the structural basis for their role in the Hippo pathway. Amot proteins, Wbp2, and USP9X were identified to be regulators of the Hippo pathway. Due to the importance of YAP/TAZ-TEAD complex in driving transcriptional program that is implicated in diverse human cancers, targeting TAZ, YAP, TEAD, and their complexes represents an attractive opportunity for novel cancer drug discovery. We recently reported the discovery of a central hydrophobic pocket in the YAP/TAZ-binding domain of TEAD proteins that is targetable by small-molecule inhibitors. Flufenamic acid, a nonsteroidal anti-inflammatory drug (NSAID), was shown to bind to the central pocket of TEAD and modulate its function. Studies from other labs have also shown that this pocket is physiologically occupied by palmitate via autopalmitoylation of TEAD. We therefore developed a target-based, TEAD-palmitate interaction screen that was used to select compounds occupying the palmitate-binding pocket (PBP) in TEADs. Interestingly, we identified some candidates as TEAD-binding compounds that augment YAP/TAZ-TEAD activity. The enhancement of YAP/TAZ-TEAD activity by these compounds accelerates in vivo wound closure in a cutaneous wound-healing mouse model. These results suggest that the class of TEAD-activating compounds could be exploited for use in regenerative medicine, while future search for inhibitors will serve as candidates for cancer drugs.
Citation Format: Wanjin Hong. Targeting the Hippo pathway for candidate cancer therapy [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr IA18.
Abstract IA20: LATS1 and LATS2 suppress breast cancer progression by maintaining cell identity and metabolic state
Authors: Furth Noa , Pateras Ioannis , Rotkopf Ron , Schmitt Ina , Bakaev Deborah , Gershoni Anat , Johnson Randy , Gorgoulis Vassilis , Oren Moshe , Aylon Yael 
Published: September 2020

Abstract
Deregulated activity of the LATS tumor suppressors has broad implications on cellular and tissue homeostasis. We examined the consequences of downregulation of either LATS1 or LATS2 in breast cancer. Consistent with their proposed tumor-suppressive roles, expression of both paralogs is significantly downregulated in human breast cancer, and loss of either paralog accelerated mammary tumorigenesis in mice. However, each paralog had a distinct impact on breast cancer. LATS2 depletion in luminal B tumors resulted in metabolic rewiring, with increased glycolysis and reduced PPARg signaling. Furthermore, pharmacologic activation of PPARg elicited LATS2-dependent death in luminal B-derived cells. In contrast, LATS1 depletion augmented cancer cell plasticity, skewing luminal B tumors towards increased expression of basal-like features, in association with increased resistance to hormone therapy. Hence, these two closely related paralogs play distinct roles in protection against breast cancer; tumors with reduced expression of either LATS1 or LATS2 may rewire signaling networks differently and thus respond differently to anticancer treatments.
Citation Format: Noa Furth, Ioannis Pateras, Ron Rotkopf, Ina Schmitt, Deborah Bakaev, Anat Gershoni, Randy Johnson, Vassilis Gorgoulis, Moshe Oren, Yael Aylon. LATS1 and LATS2 suppress breast cancer progression by maintaining cell identity and metabolic state [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr IA20.
Abstract IA25: Adult deletion of Lats1/2 leads to sarcomatoid renal cell carcinoma
Authors: Reginensi Antoine , Jain Sanjay , Humphreys Benjamin , Shen Jess , Hodzic Didier , Wrana Jeff , McNeill Helen 
Published: September 2020

Abstract
Alterations of the Hippo signaling pathway have been found in patients with sarcomatoid renal cell carcinoma, a highly aggressive kidney disease with rapid progression and poor prognosis. It is unclear whether deregulated Hippo pathway is a primary cause of sarcomatoid cancers. To investigate whether conditional (kidney-specific) Hippo knockout leads to renal cancer development and/or sarcomatoid dedifferentiation, we conditionally inactivated both Lats1 and Lats2 from the adult renal proximal tubule epithelial cells. Mosaic deletion of Lats1 and Lats2 in the adult proximal tubules results in cell-autonomous sarcomatoid renal cell carcinoma ((54%) as early as 8 weeks after gene deletion) and lung metastasis. RNA sequencing of tumors compared to control renal cortices revealed massive transcriptional changes, with 2,292 genes significantly upregulated (FC&gt;2) and 2261 genes significantly downregulated (FCË‚0.5). To visualize the cellular onset and progression of renal defects, we conducted histologic examination at different time points after induction of Lats1/2 deletion. Mutant kidneys displayed tubular atrophy with glomerular cysts. Loss of proximal tubule epithelial markers, and de novo expression of the mesenchymal marker vimentin, indicated that kidney epithelial cells had undergone an epithelial-to-mesenchymal transition (EMT). These studies demonstrate that loss of Lats1/2 rapidly leads to aggressive, metastatic sarcomatoid renal cell carcinoma.
Citation Format: Antoine Reginensi, Sanjay Jain, Benjamin Humphreys, Jess Shen, Didier Hodzic, Jeff Wrana, Helen McNeill. Adult deletion of Lats1/2 leads to sarcomatoid renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr IA25.
Abstract IA26: Oncogenic LncRNA promotes escape from intrinsic Hippo tumor suppression
Authors: Hu Qingsong , Lin Chunru , Yang Liuqing 
Published: September 2020

Abstract
How tumor cells genetically lose antigenicity and evade intrinsic tumor suppression barriers has been uncertain for decades. Here, we report that tissue-specific expression of a human long noncoding RNA LINK-A in mouse mammary gland initiates metastatic breast tumor, which models human basal-like breast cancer morphologically, genetically, transcriptionally, and metabolically. LINK-A expression facilitates crosstalk between PIP3 and inhibitory GPCRs pathways, leading to decreased cAMP level and protein kinase A (PKA)-mediated phosphorylation of E3 ubiquitin ligase TRIM71. This leads to enhanced K48-polyubiquitination-mediated degradation of tumor suppressor MST1 as well as LATS1. Treatment with LINK-A antisense oligonucleotides or Rauwolscine (a Galphai antagonist) stabilizes Hippo tumor suppressor pathway, sensitizing breast tumors to immune checkpoint blockers. PD-1 blockade-resistant TNBC patients exhibited elevated LINK-A and downregulated Hippo tumor suppressors. We demonstrate an lncRNA-dependent escape from intrinsic tumor suppression and immunosurveillance, which provides a regimen of combinational immunotherapy and effective early prevention for TNBC.
Citation Format: Qingsong Hu, Chunru Lin, Liuqing Yang. Oncogenic LncRNA promotes escape from intrinsic Hippo tumor suppression [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr IA26.
Abstract PR01: Regulation of TEAD by p38 MAPK-induced cytoplasmic translocation
Authors: Park Hyun Woo 
Published: September 2020

Abstract
The Hippo pathway controls organ size and tissue homeostasis, with deregulation leading to cancer. The core Hippo components in mammals are composed of the upstream kinases Mst1/2, MAPK4Ks, and Lats1/2. Inactivation of these upstream kinases leads to dephosphorylation, stabilization, nuclear translocation, and thus activation of the major functional transducers of the Hippo pathway, YAP and its paralogue TAZ. YAP/TAZ are transcription coactivators that regulate gene expression primarily through interaction with the TEA domain DNA-binding family of transcription factors (TEAD). The current paradigm for regulation of this pathway centers on phosphorylation-dependent nucleocytoplasmic shuttling of YAP/TAZ through a complex network of upstream components. However, unlike other transcription factors, such as SMAD, NF-kB, NFAT, and STAT, the regulation of TEAD nucleocytoplasmic shuttling has been largely overlooked. In the present study, we show that environmental stress promotes TEAD cytoplasmic translocation via p38 MAPK in a Hippo-independent manner. Importantly, stress-induced TEAD inhibition predominates YAP-activating signals and selectively suppresses YAP-driven cancer cell growth. Our data reveal a mechanism governing TEAD nucleocytoplasmic shuttling and show that TEAD localization is a critical determinant of Hippo signaling output.
This abstract is also being presented as Poster A33.
Citation Format: Hyun Woo Park. Regulation of TEAD by p38 MAPK-induced cytoplasmic translocation [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr PR01.