bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B05: Investigating the role of STK3/4 kinases in cancer
Authors: Bata Nicole , Limpert Allison , Lambert Lester J. , Chaikuad Apirat , Hansen Malene , Knapp Stefan , Cosford Nicholas D.P. 
Published: September 2020

Abstract
The serine/threonine-protein kinases 3 (STK3, MST2) and 4 (STK4, MST1) are the “core kinase cassette” of the Hippo signaling pathway, directing cell proliferation and differentiation through control of the downstream transcription factors, YAP and TAZ. In cancer, the ability of the Hippo pathway to regulate growth and differentiation provides a potential target for therapeutic intervention. Interestingly, it has been proposed that STK3/4 have a role in autophagy, a cellular, self-degradative process important for generating sources of energy in response to nutrient stress. These functions for STK3/4 are likely to be both cell type and context dependent. For example, we show that knocking down STK3 in prostate tumor cells in vitro decreases proliferation, suggesting that targeting STK3 with small-molecule inhibitors could be effective in the treatment of prostate cancer. However, current chemical probes for STK3/4 are suboptimal with respect to selectivity, potency, and drug-like properties. Better tools are required to obtain a detailed mechanistic understanding of the biologic roles of STK3/4. Thus, we propose to identify small-molecule modulators of STK3 and STK4 that could be used as chemical probes of the Hippo pathway or autophagy and ultimately lead to novel therapies for cancer. With this objective we established an in-house expression of both STK3 and STK4 protein and performed a pilot screen of &gt;90 small molecules against purified STK3/4 using the ADP-Glo in vitro kinase assay. From this pilot screen, we identified nine STK3/4 inhibitors with low nanomolar potency and confirmed these hits as bona fide STK3/4 inhibitors using both protein-thermal shift and enzymatic kinetic assays. In addition, breast tumor cells treated with a selective STK3/4 inhibitor, PF-06447475, showed a concentration-dependent increase in microtubule-associated proteins 1A/1B light chain 3 (LC3) flux. In the future, we plan to further optimize our small-molecule hits and conduct a high-throughput screen to identify novel modulators of STK3/4.
Citation Format: Nicole Bata, Allison Limpert, Lester J. Lambert, Apirat Chaikuad, Malene Hansen, Stefan Knapp, Nicholas D.P. Cosford. Investigating the role of STK3/4 kinases 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 B05.
Abstract B11: Computational insights on the druggability of TEAD YAP-binding domain
Authors: Li Yiping , Zhou Wei , Li Chenglong 
Published: September 2020

Abstract
Transcriptional enhanced associate domain (TEAD) proteins are the downstream effectors of the Hippo signaling pathway that regulate cell proliferation and stem cell functions. The expression of TEAD family is upregulated in many cancer types including pancreatic, colorectal, breast, and prostate cancers, which is correlated with poor survival in patients. Pharmacologic modulators of TEADs could therefore find application in cancer treatment and regenerative medicine. In this presentation, we report our exploration of the TEAD2 Yap-binding domain conformational ensemble and its binding interaction characteristics with peptides and small molecules, using both molecular dynamics simulation and experimental binding studies with FP probes. We carried a series of conventional, cosolvent, and Gaussian-biased MD studies and discovered that the binding subsites II and III possess considerable flexibility as the free energy calculations indicate that multiple low-energy states exist with only about 1.4 Kcal/mol barriers among them. Together with the binding results, our study points to additional “hot spots”/pharmacophores for fresh design of novel small-molecule inhibitors disrupting YAP/TEAD protein-protein interactions.
Note: This abstract was not presented at the conference.
Citation Format: Yiping Li, Wei Zhou, Chenglong Li. Computational insights on the druggability of TEAD YAP-binding domain [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 B11.
Abstract B12: High-throughput screening platform to discover TEAD modulators
Authors: Moon Sungho , Park Hyun Woo 
Published: September 2020

Abstract
The TEAD family of transcription factors play critical roles during development, cell growth, proliferation, regeneration, and tissue homeostasis. TEADs are key downstream transcription factors of the evolutionarily conserved Hippo pathway, which binds Yes-associated protein (YAP) and transcriptional activator with PDZ-binding domain (TAZ) transcriptional coactivators through their transactivation domains. Despite TEAD being the key transducer of the Hippo signaling, most research have been focused on Hippo kinases and YAP/TAZ, whereas the Hippo-dependent and -independent regulators and regulations governing TEAD emerged only recently. Previously, we identified that environmental stress promotes TEAD cytoplasmic translocation via p38 MAPK-dependent, Hippo-independent mechanism, which overrides YAP-driven oncogenic growth in cancer cells. Here, we present a platform for high-throughput screening to identify chemical compounds that modulate TEAD cellular localization and activity. We designed cancer cells stably expressing a TEAD-GFP lentiviral vector and carried out a comprehensive comparative analysis of TEAD4 by GFP-fluorescence, immunoblotting, and transcript activities. Chemical compound screening to discover TEAD modulators will reveal novel anticancer drugs.
Citation Format: Sungho Moon, Hyun Woo Park. High-throughput screening platform to discover TEAD modulators [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 B12.
Abstract B21: Proteomic profiling of tandem affinity purified MAP4K family kinases
Authors: Seo Gayoung , Han Han , Yang Bing , Vargas Rebecca , Chen Yuxuan , Wang Wenqi 
Published: September 2020

Abstract
MAP kinase kinase kinase kinases (MAP4Ks) belong to the mammalian Ste20-like family of serine/threonine kinases and recently have been reported to regulate Hippo pathway via LATS1/2 activation. However, the diverse roles of MAP4Ks in biologic process are still unclear. To identify the MAP4K family kinase interaction network, we employed a tandem affinity purification-mass spectrometry (TAP-MS) approach using SFB tag-conjugated MAP4K1-7. Through a proteomic analysis, we could guess that MAP4K family kinases, especially MAP4K2, may regulate autophagy or interact with striatin-interacting phosphatase and kinase (STRIPAK) components. These results offer a framework for further studies on Hippo pathway and biologic processes involving MAP4Ks.
Note: This abstract was not presented at the conference.
Citation Format: Gayoung Seo, Han Han, Bing Yang, Rebecca Vargas, Yuxuan Chen, Wenqi Wang. Proteomic profiling of tandem affinity purified MAP4K family kinases [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 B21.
Abstract B23: A novel model of neurofibroma that deciphers its developmental origin and susceptibility to modification by the Hippo pathway
Authors: Chen Zhiguo , Mo Juan , Brosseau Jean-Philippe , Shipman Tracey , Wang Yong , Liao Chung-Ping , Cooper Jonathan M. , Allaway Robert J. , Gosline Sara J.C. , Guinney Justin , Carroll Thomas J. , Le Lu Q. 
Published: September 2020

Abstract
The neurocutaneous tumor predisposition disorder neurofibromatosis Type I (NF1) results from deregulation of RAS signaling in the MAPK pathway that leads to a wide spectrum of clinical presentations. Dermal or cutaneous neurofibromas (cNF), a Schwann cell tumor in the skin, affect more than 95% of individuals with NF1 and are a major source of emotional, physical, and social distress as NF1 patients can have thousands of these tumors covering most of their skin. Thus, patients with NF1 often identify these tumors as their greatest burden. To date, there is no available medical treatment for cNF and no known way to prevent them from developing. The major barriers that impede progress in this field are the lack of accurate models of these common cNF tumors for drug evaluation and a limited understanding of their pathogenesis as well as the identity of specific cell of origin that directly gives rise to cNF and signaling pathways essential for tumor development. We take advantage of genetic labeling for cell lineage tracing to identify mouse neural crest Cre lines that are expressed in the subpopulation of Schwann cell lineage that give rise to cNF when NF1 is deleted. We discovered that the Homeobox B7 transcription factor serves as the lineage marker to trace the developmental origin of cNF neoplastic cells that completely recapitulates human neurofibromatosis, generating a novel mouse model that spontaneously develops both cutaneous and plexiform neurofibroma. In addition, we discovered that modulation of the Hippo pathway acts as a modifier that enhances the MAPK pathway activation by NF1 loss to promote neurofibromagenesis, suggesting that dampening the Hippo pathway may serve as part of the comprehensive treatment approach for neurofibroma. This novel mouse model has begun to yield vital clues to neurofibroma pathogenesis and now opens the doors for deciphering the evolution of cNF to identify effective therapies, where none exist today.
Citation Format: Zhiguo Chen, Juan Mo, Jean-Philippe Brosseau, Tracey Shipman, Yong Wang, Chung-Ping Liao, Jonathan M. Cooper, Robert J. Allaway, Sara J.C. Gosline, Justin Guinney, Thomas J. Carroll, Lu Q. Le. A novel model of neurofibroma that deciphers its developmental origin and susceptibility to modification by the Hippo 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 B23.
Abstract B30: Joint control of epidermal cell fate by Yorkie and Bonus
Authors: Zhao Heya , Zhang Can , Moberg Kenneth , Veraksa Alexey 
Published: September 2020

Abstract
Dysregulation of the Hippo pathway results in organ overgrowth and contributes to carcinogenesis in humans. Although the Hippo pathway has been intensively studied for its regulation of cell proliferation and organ growth, its role beyond growth control remains elusive. To explore possible novel functions of the Hippo pathway, we carried out an affinity purification-mass spectrometry (AP-MS) analysis in Drosophila embryos and cultured cells, using transcriptional coactivator Yorkie (Yki, YAP1 homolog) as bait. Prominent groups of identified interactors included all of the core pathway components and known accessory regulators, as well as subunits of RNA polymerase II and components of the Trithorax-related (Trr) complex. Among putative novel interactors we found Bonus (Bon), the Drosophila homolog of the mammalian transcriptional intermediary factor-1/tripartite motif containing (TIF1/TRIM24/TRIM33) family of proteins. Protein interaction between Bon and Yki requires the WW domains in Yki and PPxY motifs in Bon. Interestingly, Bon overexpression leads to formation of epidermal extensions (trichomes) on the surface of adult eyes. This phenotype requires Yki and Scalloped (Sd, TEAD homolog), as well as Bon-Yki interaction. To obtain a mechanistic understanding of this apparent switch towards an epidermal cell fate, we searched for novel genes that may be jointly regulated by Bon and Yki, and identified several candidates based on published ChIP-seq and RNA-seq analyses. These putative target genes are not canonical Hippo pathway effectors, but include factors involved in early eye specification as well as genes controlled by steroid hormone signaling. Loss or gain of function of a subset of these genes modified the trichome phenotype, suggesting that they are under the control of Bon and Yki and are involved in establishing a choice between a “generic” epidermal cell fate and eye field specification. In summary, our study reveals a novel function of the Hippo pathway in the regulation of epidermal cell differentiation. This regulation occurs through the interaction between Yki and Bon as well as their joint transcriptional control of nonclassical target genes. This work broadens our understanding of the Hippo pathway beyond its role in growth control.
Citation Format: Heya Zhao, Can Zhang, Kenneth Moberg, Alexey Veraksa. Joint control of epidermal cell fate by Yorkie and Bonus [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 B30.
Abstract B39: The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ
Authors: Cordenonsi Michelangelo , Chang Lei , Azzolin Luca , Di Biagio Daniele , Zanconato Francesca , Battilana Giusy , Xiccato Romy Lucon , Panciera Tito , Aragona Mariaceleste , Piccolo Stefano 
Published: September 2020

Abstract
Inactivation of ARID1A and other components of the nuclear SWI/SNF protein complex occurs at very high frequencies in a variety of human malignancies, suggesting a widespread role for the SWI/SNF complex in tumor suppression. However, the underlying mechanisms remain poorly understood. Here we show that ARID1A-containing SWI/SNF complex (ARID1A-SWI/SNF) operates as an inhibitor of the pro-oncogenic transcriptional coactivators YAP and TAZ. Using a combination of gain- and loss of-function approaches in several cellular contexts, we show that YAP/TAZ are necessary to induce the effects of the inactivation of the SWI/SNF complex, such as cell proliferation, acquisition of stem cell-like traits, and liver tumorigenesis. We found that YAP/TAZ form a complex with SWI/SNF; this interaction is mediated by ARID1A and is alternative to the association of YAP/TAZ with the DNA-binding platform TEAD. Cellular mechanotransduction regulates the association between ARID1A-SWI/SNF and YAP/TAZ. The inhibitory interaction of ARID1A-SWI/SNF and YAP/TAZ is predominant in cells that experience low mechanical signaling, in which loss of ARID1A rescues the association between YAP/TAZ and TEAD. At high mechanical stress, nuclear F-actin binds to ARID1A-SWI/SNF, thereby preventing the formation of the ARID1A-SWI/SNF-YAP/TAZ complex, in favor of an association between TEAD and YAP/TAZ. We propose that a dual requirement must be met to fully enable the YAP/TAZ responses: promotion of nuclear accumulation of YAP/TAZ, for example, by loss of Hippo signaling, and inhibition of ARID1A-SWI/SNF, which can occur either through genetic inactivation or because of increased cell mechanics. This study offers a molecular framework in which mechanical signals that emerge at the tissue level together with genetic lesions activate YAP/TAZ to induce cell plasticity and tumorigenesis. (Published as Chang et al., Nature 2018.)
Citation Format: Michelangelo Cordenonsi, Lei Chang, Luca Azzolin, Daniele Di Biagio, Francesca Zanconato, Giusy Battilana, Romy Lucon Xiccato, Tito Panciera, Mariaceleste Aragona, Stefano Piccolo. The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ [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 B39.
Abstract IA11: Hippo signaling Is Intrinsically regulated during cell cycle progression
Authors: Yang Yingzi , Kim Wantae , Wang Xiaohui 
Published: September 2020

Abstract
The Hippo-YAP/TAZ signaling pathway plays a pivotal role in growth control during development and regeneration, and its dysregulation is widely implicated in various cancers. Hippo signaling has been recently identified as a major oncosuppressive pathway that plays critical roles in inhibiting hepatocyte proliferation, survival, and hepatocellular carcinoma (HCC) formation. We have found that Hippo/YAP signaling cell-autonomously inhibits HCC proliferation by interacting with Wnt and Notch signaling. We have also found that Hippo/YAP signaling cell-nonautonomously inhibits HCC by shaping its inflammatory microenvironment. To further understand the cellular and molecular mechanisms underlying Hippo signaling regulation, we have found that activities of core Hippo signaling components, LATS kinases and YAP/TAZ transcription factors, are regulated during cell cycle progression by core cell cycle machinery components. Furthermore, we show in Drosophila eye and wing development that cell cycle is required in vivo to regulate Hippo signaling with a conserved mechanism. Cell cycle control of Hippo signaling represents a previously unappreciated and evolutionarily conserved new layer of Hippo signaling regulation.
Citation Format: Yingzi Yang, Wantae Kim, Xiaohui Wang. Hippo signaling Is Intrinsically regulated during cell cycle progression [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 IA11.
Abstract IA15: Growth control and Hippo signaling in the Drosophila abdomen
Authors: Tapon Nicolas 
Published: September 2020

Abstract
To unravel the mechanisms of tissue size determination, we have established quantitative biology tools to study the growth of the Drosophila abdominal histoblasts (HBs), the precursor cells of the adult abdominal epidermis. HBs are organized in nests located in the abdominal segments, surrounded by larval epithelial cells (LECs). HBs are quiescent throughout larval development, then proliferate extensively during abdominal morphogenesis at the pupal stage, replacing the surrounding LECs, which undergo apoptosis. To cover the entire abdominal surface, the HBs undergo eight cell cycles (three synchronous cleavage divisions followed by five asynchronous cycles), then cease proliferating at 31-33hr after puparium formation and differentiate. A major advantage of this system is its amenability to long-term live imaging, allowing us to visualize proliferation/growth of the HBs and death of the LECs. I will present our ongoing work on the role and regulation of Hippo signaling in this system.
Citation Format: Nicolas Tapon. Growth control and Hippo signaling in the Drosophila abdomen [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 IA15.
Abstract IA16: Regulation of SAV1-STRIPAK antagonism by YSK1-dependent phosphorylation
Authors: Luo Xuelian “Sue” 
Published: September 2020

Abstract
The Hippo pathway is critical for tissue homeostasis and tumor suppression in multicellular organisms. Through cell-surface receptors and cytoskeletal complexes, extracellular signals, including cell-cell contact, activate a core kinase cascade formed by the Hippo kinases MST1/2, the NDR family kinases LATS1/2, and the adaptor proteins SAV1 and MOB1. Activated LATS1/2 phosphorylate and prevent the nuclear accumulation of the transcription factors YAP/TAZ. Activation of MST1/2 initiates Hippo signaling and requires trans-autophosphorylation in the T-loop (MST2 T180). We have recently shown that the PP2A complex STRIPAK blocks MST2 activation through feedback inhibition. SAV1 promotes MST2 activation by suppressing STRIPAKSLMAP-mediated dephosphorylation of MST2 pT180. Our preliminary results show that YSK1 (the kinase component of STRIPAK) phosphorylates SAV1 and blocks its ability to inhibit PP2A. We hypothesize that upstream signals impinge on the SAV1-STRIPAK antagonism through YSK1 to regulate MST1/2 activation.
Citation Format: Xuelian “Sue” Luo. Regulation of SAV1-STRIPAK antagonism by YSK1-dependent phosphorylation [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 IA16.
Abstract IA24: YAP in cancer and inflammation
Authors: Wang Guocan , Lu Xin , Chakravarti Deepavali , Kapoor Avnish , Yao Wantong , Ying Haoqiang , Dey Prasenjit , Wu Chiachin , Spring Denise , Hou Pingping , Deng Pingna , Zhao Di , Hu Baoli , Xizeng Mao , Logothesis Christopher , McArthur Michael , Chin Lynda , Wang Alan , Hua Sujun , Xia Hongai , Chu Gerald C , Lim Carol , Vilar Eduardo , Blutt Sarah , DePinho Ronald A. 
Published: September 2020

Abstract
Many common instigators drive the processes of inflammation and carcinogenesis. We have found such a common node in Yap1. In the context of cancer, YAP-TEAD complex is important in modulating the immune microenvironment, such that Yap 1-mediated transcriptional upregulation of CXCL5 by the prostate cancer cells in a PTEN/SMAD4 deficient mouse model leads to the recruitment of MDSCs through the interaction with CXCR2 on them. Depletion of MDSCs or pharmacologic inhibition of CXCR2 leads to impediment of cancer progression. In another well-established pancreatic cancer model (PDAC), Yap1/Tead2 governs escape from mutant Kras (G12D) inhibition through cooperative upregulation of E2F transcription factors to activate a cell cycle and DNA replication program. In the context of inflammation, specifically inflammatory bowel disease, telomere dysfunction is shown to activate pAtm/c-Abl-mediated phosphorylation and stabilization of Yap1 upregulating pro-IL-18, a major proinflammatory factor in IBD. This signaling axis cooperates with the gut microbiome stimulating cytosolic receptors causing activation of caspase-1 cleaving pro-IL-18 into mature IL-18. Epithelial IL-18 leads to recruitment of IFNγ-secreting T cells and other immunocytes provoking classical IBD pathology. Consistent with a role for DNA damage signaling driving IBD, newly diagnosed IBD patient samples exhibited elevated expression of pγH2AX, YAP1, Caspase-1, and IL-18 and significantly reduced telomere lengths. Telomerase reactivation in intestinal epithelium or pharmacologic inhibition of Atm, Yap1, or caspase-1 as well as antibiotic treatment of mice dramatically reduced IL-18 and inflammation. Thus, telomere dysfunction-induced activation of the Atm-Yap1-pro-IL-18 pathway identifies DNA damage signaling as a key instigator and promoter of IBD, illuminating novel therapeutic strategies.
Citation Format: Guocan Wang, Xin Lu, Deepavali Chakravarti, Avnish Kapoor, Wantong Yao, Haoqiang Ying, Prasenjit Dey, Chiachin Wu, Denise Spring, Pingping Hou, Pingna Deng, Di Zhao, Baoli Hu, Mao Xizeng, Christopher Logothesis, Michael McArthur, Lynda Chin, Alan Wang, Sujun Hua, Hongai Xia, Gerald C Chu, Carol Lim, Eduardo Vilar, Sarah Blutt, Ronald A. DePinho. YAP in cancer and inflammation [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 IA24.