bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A43: Identification of novel YAP/TAZ regulators in metastatic cancer
Authors: Xiao Yuxuan , Norton Emily , Warren Janine , Lamar John 
Published: September 2020

Abstract
Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the downstream effectors of the Hippo tumor inhibition pathway. Studies from us and others show that inappropriate activation of YAP and/or TAZ promotes tumor growth and metastasis. Increased YAP and/or TAZ expression and nuclear localization is observed in many human cancers and often predict poor prognosis. Mutations in Hippo-YAP/TAZ pathway exist but are not common enough to explain the frequently observed increase of YAP/TAZ expression and activity in cancer. Therefore, we hypothesize that other cancer-associated pathways cause aberrant YAP/TAZ activation in cancer cells, and identifying such pathways would provide targets for treatment of YAP/TAZ-driven cancers. Furthermore, transcriptional cofactors are often difficult to target and YAP/TAZ have important functions in adult tissues. Therefore, targeting YAP/TAZ regulators may provide a nonsystemic path of targeting YAP/TAZ that could avoid severe adverse effects. To identify novel YAP/TAZ regulators in metastatic cancer cells, we screened a lentiviral shRNA library that targets 124 cancer-associated genes in A375 MA2 (MA2) cells using a YAP/TAZ-TEAD (TEA domain family members) transcriptional reporter assay. We found that 62 genes are able to regulate YAP/TAZ activity in MA2, 24 of which are already established YAP/TAZ regulators, which supports the effectiveness of our approach. The other 38 genes have not been reported previously, which are potential novel YAP/TAZ regulators. We subsequently validated these candidate YAP/TAZ regulators by examining the expression of the YAP/TAZ target gene CTGF by qPCR and phosphorylation of YAP and TAZ by Western blot in MA2 and other metastatic cell lines. We are currently pursuing several of these novel YAP/TAZ regulators to determine the mechanism through which they regulate YAP/TAZ activity and test their role in metastasis. Our results suggest that YAP/TAZ regulators are cell type and context specific and may also functionally compensate for each other. Therefore, it is critical to identify a “core” group of YAP/TAZ regulators that are important in multiple cancer types. This could provide new strategies to more effectively inhibit YAP/TAZ activation and treat metastatic cancer.
Citation Format: Yuxuan Xiao, Emily Norton, Janine Warren, John Lamar. Identification of novel YAP/TAZ regulators in metastatic 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 A43.
Abstract A45: In silico drug discovery targeting Hippo pathway and YAP-TEAD protein-protein interactions for small-molecule anticancer agent
Authors: Jongwan Kim , Lim Hocheol , No K.T. 
Published: September 2020

Abstract
The Hippo pathway is one of the important pathways regulating tissue growth and proliferation. Dysregulation of this pathway can result in overgrowth of phenotypes because of a malfunction of stem cell proliferation, differentiation, and apoptosis, which are directly involved with components to cancer cell developments. Protein-protein interaction (PPI) in YAP (Yes-associated protein) and TEAD (transcriptional enhancer associate domain) is a key interaction that regulates cancer cell growth in the Hippo pathway. Regulating YAP-TEAD protein-protein interaction by small molecules could play an important role in cancer therapy. In this study, we identified small molecules inhibiting YAP-TEAD interactions by an in silico approach. Molecular hits were identified by pharmacophore-based virtual screening. The hit compounds from virtual screening were tested by surface plasmon resonance (SPR), Luciferase activity test. As a result, several hit compounds were identified to inhibit YAP-TEAD protein-protein interactions. These selected hit compounds were also evaluated by molecular docking study and FMO (fragment molecular orbital) binding energy calculations. In our overall results, we identified hit compounds to inhibit YAP-TEAD PPIs and also analyzed hit compounds’ binding interaction energy to TEAD protein.
Citation Format: Kim Jongwan, Hocheol Lim, K.T. No. In silico drug discovery targeting Hippo pathway and YAP-TEAD protein-protein interactions for small-molecule anticancer agent [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 A45.
Abstract B04: Hepatic cholesterol upregulates TAZ in nonalcoholic steatohepatitis
Authors: Wang Xiaobo , Radhakrishnan Arun , Covey Douglas , Horton Jay , Schwabe Robert , Tontonoz Peter , Guan Kun-Liang , Tabas Ira 
Published: September 2020

Abstract
Nonalcoholic steatohepatitis (NASH) has emerged as the leading cause of chronic liver disease worldwide and is rapidly increasing in prevalence owing to the obesity epidemic. Incomplete understanding of the mechanisms of NASH progression, particularly fibrosis, has limited the design of therapeutic strategies. My previous published study indicated that a transcription factor in hepatocytes called TAZ (WWTR1) contributes to steatosis-to-NASH progression. However, the mechanism that induces high TAZ expression in NASH liver remains unknown. The objective of this study is to understand the mechanism of hepatocyte TAZ upregulation in NASH, which may suggest novel therapeutic strategies to prevent NASH and its comorbidities. We hypothesize that hepatic cholesterol upregulates TAZ through PKA-Ca2+-RhoA mediated Hippo pathway inactivation. In vitro, we use liposome to deplete and replete cholesterol in hepatocyte cells and check downstream signaling pathway that includes cholesterol translocation, Ca2+ signaling, RhoA activity, Hippo pathway, and E3 ligase activity. In vivo, we used different concentration cholesterol diet to build the correlation between increased TAZ/liver fibrosis and cholesterol, and AAV8-H1 mediated hepatic-gene silencing to prove the functions of the molecules in the pathway, including AsterB/C, RhoA, and Trcp. My data suggest that hepatic cholesterol accumulation is associated with liver fibrosis and increased TAZ. In addition, cholesterol loading of hepatocytes increases TAZ, and cholesterol depletion decreases TAZ in a proteasome/Trcp-dependent manner. Mechanistically, Hippo pathway kinase-Lats2 inhibits TAZ expression on the post-transcriptional level through TAZ phosphorylation. Moreover, intracellular cholesterol increases cytosolic Ca2+ and activates RhoA signaling, then represses Lats2 activity, so TAZ degradation is inhibited and total protein level increases. Finally, blocking cholesterol translocation from cell membrane to intracellular suppresses the pathway and inhibits TAZ level. We conclude that hepatic cholesterol induces high-level TAZ in NASH through PKA-Ca2+-RhoA mediated Hippo pathway inactivation, and cholesterol transportation plays an important role during this process. These data provide a plausible mechanism underlying liver cholesterol as a risk factor for NASH fibrosis and suggest new therapeutic interventions to block NASH fibrosis and to prevent NASH-associated HCC.
Citation Format: Xiaobo Wang, Arun Radhakrishnan, Douglas Covey, Jay Horton, Robert Schwabe, Peter Tontonoz, Kun-Liang Guan, Ira Tabas. Hepatic cholesterol upregulates TAZ in nonalcoholic steatohepatitis [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 B04.
Abstract B06: Development of selective LATS1/LATS2 inhibitors for the pharmacologic modulation of the Hippo signaling pathway
Authors: Ceribelli Michele , Morris Patrick , Duveau Damien , Tosto Frances A. , Hoyt Scott , Thomas Craig J. 
Published: September 2020

Abstract
We performed a large-scale profiling of currently available kinase inhibitors (KI) to identify “off-targets” that could be repurposed/repositioned as the starting point for the rational development of novel and selective kinase inhibitors against underdrugged targets. We profiled 257 KI at a single dose against a panel of 365 wild-type kinases tested individually, for a total of about 100,000 in vitro drug/kinase data points. After unsupervised hierarchical clustering of this dataset based on percent inhibition values, we identified a well-resolved subcluster driven by 5 KI with limited polypharmacology and a clean kinase-inhibition profile, mostly targeting AGC group kinases. These inhibitors were the AKT inhibitors GSK-690693, AZD-5363, and AT-7867; the MSK inhibitor SB-747651-A; and the Rho kinases (ROCK) inhibitor GSK-269962A. Notably, the AGC and hippo kinases LATS1 and LATS2 were part of this subcluster and were both inhibited to significant extents by these 5 compounds. With the regenerative potential of a candidate LATS1/2 inhibitor in mind, we next developed several orthogonal biochemical and cellular assays to prioritize compounds that possessed the desired activity against LATS1/2 without the burden of cytotoxic “off-targets,” such as those resulting from strong AKT inhibition. Based on the results of these assays, we prioritized one of the initially identified kinase inhibitors as the starting point for an ongoing, rational structure-activity relationship (SAR) effort to develop novel, 1st-in-class, highly selective LATS1 and LATS2 inhibitors. We will present data showing how such novel LATS1/2 inhibitors efficiently block LATS1/2-dependent YAP phosphorylation, induce YAP nuclear translocation in a high cell-density setting, and promote the transcription of bona fide YAP target genes such as AMOTL2, CTGF, and CYR61. Finally, consistently with the activation of a YAP-dependent transcriptional program, small-molecule inhibitors of LATS1/2 kinases promoted proliferation/regeneration in an in vitro wound-healing assay. Altogether, we identified novel small molecules that can be used as chemical probes to acutely inactivate the Hippo signaling pathway and validated LATS1 and LATS2 kinases as novel druggable kinases whose inhibition could be exploited for several indications, spanning from regenerative medicine to cancer immunotherapy.
Citation Format: Michele Ceribelli, Patrick Morris, Damien Duveau, Frances A. Tosto, Scott Hoyt, Craig J. Thomas. Development of selective LATS1/LATS2 inhibitors for the pharmacologic modulation of the Hippo signaling pathway [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 B06.
Abstract B09: Selective depletion of YAP1 with next-generation (constrained ethyl-cEt) antisense oligonucleotides results in tumor regression in mouse models of HCC with YAP1 activation
Authors: Kim Youngsoo , Schmidt Joanna , Jo Minji , Yi Jing , Luo Xiaolin , Fleming Rachel , Yim Sun Young , Lee Ju-Seog , Mornia Brett P. , Johnson Randy L. , Mills Gordon , MacLeod A. Robert 
Published: September 2020

Abstract
The Hippo pathway plays important roles in tissue homeostasis. When dysregulated in adult tissues, however, it contributes to the development of a variety of cancers including hepatocellular carcinoma (HCC). YAP1 is the final regulator of the Hippo pathway and is associated with poor prognosis of HCC patients, and more recently has been suggested to be involved in tumor immune evasion. Here, we employed next-generation constrained ethyl (cEt) antisense oligonucleotides (ASOs) to selectively target YAP1 in the genetically engineered mouse (GEM) model of HCC (Salvador KO mice) as well as in a spontaneous carcinogen-induced model of HCC (diethylnitrosamine, DEN-induced HCC). In YAP1-activated Salvador KO mice with established HCC tumors, systemic treatment with YAP1 ASO at 25 mg/kg resulted in a marked reduction in YAP1 protein level in tumor (&gt;90%) and regression of existing tumors, in contrast to the tumors in vehicle or control ASO-treated animals that significantly increased in size. In the DEN-induced HCC model, YAP1 was strongly activated in tumors as demonstrated by nuclear localization of YAP1 protein and the gene signature we previously identified (SOH). YAP1 ASOs produced either complete tumor stasis when DEN tumors were grown in immune-deficient mice, or complete regressions when tumors were grown in immune-competent animals. In accordance with this, YAP1 ASO treatment resulted in significant infiltration of T cells and myeloid lineage cells in the tumors in immune-competent mice. Importantly, when tumor-bearing animals were taken off the treatment after tumor regression was observed with YAP1 ASO, the antitumor response was sustained for more than 1 year, with 4 out of 16 animals remaining tumor-free in YAP1 ASO group. Furthermore, YAP1 ASO in combination with anti-PD1 antibody led to enhanced antitumor activity in the same tumor model. Collectively, these results suggest a potential therapeutic use of YAP1 ASO in the treatment of HCC with YAP1 activation as a single agent or in combination with immuno-oncology drugs. Broad screens have identified the human YAP1 ASO clinical development compound YAP1RX.
Citation Format: Youngsoo Kim, Joanna Schmidt, Minji Jo, Jing Yi, Xiaolin Luo, Rachel Fleming, Sun Young Yim, Ju-Seog Lee, Brett P. Mornia, Randy L. Johnson, Gordon Mills, A. Robert MacLeod. Selective depletion of YAP1 with next-generation (constrained ethyl-cEt) antisense oligonucleotides results in tumor regression in mouse models of HCC with YAP1 activation [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 B09.
Abstract B13: Cancer metabolism sensitizes metformin treatment by targeting the Hippo-YAP/TAZ pathway
Authors: Park Jae Hyung , Park Hyun Woo 
Published: September 2020

Abstract
The biologic significance and deregulation of the Hippo pathway during organ growth and tumorigenesis have received a surge of interest in the past decade. The Hippo pathway core kinases, MST1/2 and LATS1/2, are tumor suppressors that inhibit the oncogenic nuclear function of YAP/TAZ and TEAD. Dysregulation of Hippo pathway leads to tumorigenesis via hyperactivation of YAP/TAZ. In this study, we focused on how differential metabolic stress response (DMSR) between normal and cancer cells, such as the Warburg effect, could synergize with the anticancer effect of metformin to regulate the Hippo pathway. Surprisingly, metformin treatment combined with low glucose concentration activates the Hippo pathway, which induces YAP/TAZ phosphorylation, loss of cell adhesion, and cell death in a cancer cell-specific manner. Using CRISPR KO cells, we show that YAP/TAZ inhibition by metformin in combination with glucose restriction is AMPK and p38 MAPK-independent, but Hippo-dependent. Therefore, these results demonstrate that DMSR-based glucose restriction and metformin cotreatment can be a novel therapeutic approach to treat cancer via inhibition of cancer cell-specific YAP/TAZ activity.
Citation Format: Jae Hyung Park, Hyun Woo Park. Cancer metabolism sensitizes metformin treatment by targeting the Hippo-YAP/TAZ pathway [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 B13.
Abstract B16: Silence of Hippo pathway induces protumoral immunity: New therapeutic target of glioblastomas
Authors: Kim Eui Hyun , Kang Seok-Gu , Lee Ju-Seog 
Published: September 2020

Abstract
The Hippo pathway plays a critical role in various cancers, but its role in glioblastoma (GBM) has not been properly addressed. To assess the clinical relevance of the Hippo pathway in GBM, we generated a core gene expression signature reflecting silence of the Hippo pathway (SOH), and validated it in GBM patient samples from The Cancer Genome Atlas (TCGA) and in a separate cohort, revealing that SOH signature was associated with poor prognosis in GBM in both cohorts. Expression levels of CTGF and CYR61, the most reliable and well-known downstream targets of YAP1 (a target of the Hippo pathway), were markedly increased in GBM with the SOH signature. GBM showing the SOH signature was associated with an increased Immune signature score (ISS), suggesting that these patients might be good potential candidates for immunotherapy. Genes differentially expressed between samples with the SOH signature and samples with an active Hippo signature showed that many inhibitory immune checkpoint genes, such as CTLA4, PD-1, and PD-L2, were upregulated in the SOH subgroup, suggesting that YAP1/TAZ may induce resistance of cancer cells to host immune response in GBM. Also, many M2-polarized microglial markers and innate immune pathways were activated in the SOH subgroup. The SOH signature was strongly correlated with the TGF-β signature, which was also associated with a high ISS and mesenchymal features. In summary, SOH induces protumoral immunity in various ways, which may be new immunotherapeutic targets of GBM.
Note: This abstract was not presented at the conference.
Citation Format: Eui Hyun Kim, Seok-Gu Kang, Ju-Seog Lee. Silence of Hippo pathway induces protumoral immunity: New therapeutic target of glioblastomas [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 B16.
Abstract B29: AXL Inhibitor TP-0903 attenuates TGFβ-Hippo signaling in lung adenocarcinoma cells
Authors: Taverna Josephine A. , Hung Chia-Nung , Lin Chun-Lin , Osmulski Pawel A. , Gaczynska Maria E. , Wang Chiou-Miin , Lucio Nicholas D. , Chen Meizhen , Chou Chih-Wei , Nazarullah Alia , Lampkin Shellye R. , Qiu Lianquin , Bearss David J. , Warner Steve , Mouritsen Lars , Wade Mark , DeArmond Daniel , Mesa Ruben , Kirma Nameer , Huang Tim H.-M. 
Published: September 2020

Abstract
Background: Non-small cell lung cancer (NSCLC) is a molecularly heterogeneous disease with a high propensity for drug resistance and metastasis. AXL, a member of the Tyro3-AXL-Mer (TAM) family of receptor tyrosine kinases, is a central regulator of epithelial-to-mesenchymal transition (EMT) and enables tumor cells to invade and acquire drug resistance. AXL is overexpressed in NSCLC and its expression correlates positively with tumor invasion, drug resistance, and negatively predicts overall survival. We mechanistically interrogated the effects of the AXL inhibitor, TP-0903, on EMT in NSCLC cells using transcriptomic and proteomic profiling.
Methods: Atomic force microscopy, Western blot analysis, RNA sequencing, and mass cytometry (CyTOF) were used to evaluate the phenotypic, transcriptomic, and proteomic profiles of A549 cells treated with 40 nM TP-0903 or shAXL knockdown. A549 and H1650 NSCLC xenograft models were used to explore the consequences of AXL inhibition in vivo.
Results: As expected, TP-0903 treatment attenuated AXL signaling and downstream phosphorylation in the A549 cells. Interestingly, the treatment also reduced gene expression responses to TGFβ-Hippo signaling by disrupting the transcriptional complexes formed by SMAD2/3, SMAD4, YAP1, and TAZ. Consistent with AXL inhibition, TP-0903 reversed the mesenchymal phenotype in A549 and H2009 cell lines and decreased their migratory potential in culture. The CyTOF analysis on TP-0903-treated cells identified resistant clones overexpressing TGFβ receptor II (TGFBR2) and TAZ proteins and displaying hybrid EMT phenotypes. TP-0903 was also active in suppressing A549 or H1650 tumor growth in vivo.
Conclusions: We are the first to report the interplay between AXL and TGFβ-Hippo signaling axis. TP-0903 has excellent therapeutic promise in NSCLC and we speculate that TP-0903 can target mesenchymal transitional states in NSCLC, possibly through the inhibition of the AXL-TGFβ-Hippo signaling axis.
Citation Format: Josephine A. Taverna, Chia-Nung Hung, Chun-Lin Lin, Pawel A. Osmulski, Maria E. Gaczynska, Chiou-Miin Wang, Nicholas D. Lucio, Meizhen Chen, Chih-Wei Chou, Alia Nazarullah, Shellye R. Lampkin, Lianquin Qiu, David J. Bearss, Steve Warner, Lars Mouritsen, Mark Wade, Daniel DeArmond, Ruben Mesa, Nameer Kirma, Tim H.-M. Huang. AXL Inhibitor TP-0903 attenuates TGFβ-Hippo signaling in lung adenocarcinoma cells [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 B29.
Abstract B41: Role of AIB1 in YAP-TEAD signaling in the progression of early-stage breast cancer
Authors: Kushner Max Harley , Graham Garrett , Sharif Ghada , Kietzman Will , Glasgow Eric , Sangupta Surojeet , Wellstein Anton , Riegel Anna Tate 
Published: September 2020

Abstract
AIB1 is an oncogenic transcription coactivator that is overexpressed and amplified in breast cancer and is known to interact with TEAD. AIB1, like YAP, is critical to the development and progression of triple-negative breast cancer, yet it is unclear to what extent the AIB1-TEAD interaction promotes the progression of triple-negative breast cancer. Herein, we confirm by ChIP and ChIP-seq that AIB1 is recruited to the chromatin with TEAD in complex with the YAP oncogene. In doing so, AIB1 potentiates YAP activity on a subset of TEAD target genes known to be critical to driving epithelial-to-mesenchymal and invasive behaviors in early-stage and advanced triple-negative breast cancer. Loss of AIB1 reverts the oncogenic phenotype conferred by YAP and attenuates 3D matrix invasion, migration, and endothelial extravasation, suggesting AIB1 may act as an oncogene in triple-negative breast cancer through YAP-TEAD. We find AIB1-YAP coregulation of a subset of oncogenic target genes that is determined by relative enrichment and global proximity of Oct1/POU2F1 binding motifs within target promoters. Thus, AIB1 is critical to maintaining YAP driven EMT and invasive phenotypes during the development and progression of triple-negative breast cancer.
Citation Format: Max Harley Kushner, Garrett Graham, Ghada Sharif, Will Kietzman, Eric Glasgow, Surojeet Sangupta, Anton Wellstein, Anna Tate Riegel. Role of AIB1 in YAP-TEAD signaling in the progression of early-stage breast 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 B41.