bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A16: The α-arrestin ARRDC3 functions as a metastasis suppressor by regulating GPCR activation of the Hippo pathway
Authors: Arakaki Aleena K.S. , Pan Wen-An , Wedegaertner Helen , Trejo JoAnn 
Published: September 2020

Abstract
G protein-coupled receptors (GPCRs) are key regulators of the Hippo pathway, a well-established mediator of tumorigenesis and cancer progression. The Hippo pathway is a promising therapeutic target, yet developing inhibitors for the core pathway components has proven difficult. As critical regulators of the Hippo pathway, GPCRs represent a potential upstream therapeutic target for cancer. However, despite the success and promise of GPCRs as therapeutic targets, there are currently no FDA-approved drugs targeting GPCRs for cancer. Protease-activated receptor-1 (PAR1) is a GPCR that has been shown to activate the Hippo pathway and also promote breast cancer progression. PAR1 is overexpressed in breast cancer patient tissue biopsies and in breast carcinoma cell lines and correlates with increased rates of metastasis and poor prognosis and increased invasion and metastatic potential, respectively. One mechanism that leads to PAR1 aberrant overexpression is defective lysosomal trafficking and degradation of the receptor, leading to persistent signaling. We recently showed that arrestin domain containing protein-3 (ARRDC3), an adaptor protein for E3 ubiquitin ligases, functions as a tumor suppressor by controlling proper PAR1 trafficking and degradation in highly aggressive, triple-negative breast carcinoma cells. The dysregulation of PAR1 trafficking due to loss of ARRDC3 expression leads to persistent signaling and promotes breast cancer invasion. However, the mechanism by which ARRDC3 specifically regulates PAR1-stimulated Hippo signaling to promote breast cancer metastasis remains unknown. Here, we show that ARRDC3 regulates GPCR activation of the Hippo pathway in basal-like breast cancer, where the transcriptional coactivators YAP and TAZ play differential roles in GPCR-mediated signaling and invasive capacity. ARRDC3 re-expression in invasive breast carcinoma cells attenuates PAR1-mediated activation of the Hippo pathway through regulation of TAZ but not YAP activation. Furthermore, siRNA knockdown of TAZ inhibits PAR1-stimulated Hippo signaling and invasion, whereas YAP siRNA knockdown has no effect. Our studies suggest a crucial role for ARRDC3 and TAZ in PAR1-Hippo pathway signaling in breast carcinoma invasion and metastasis. A better understanding of the mechanisms by which the Hippo pathway is regulated by GPCRs may lead to new potential therapeutic targets for the treatment or prevention of metastatic breast cancer.
Citation Format: Aleena K.S. Arakaki, Wen-An Pan, Helen Wedegaertner, JoAnn Trejo. The α-arrestin ARRDC3 functions as a metastasis suppressor by regulating GPCR activation of 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 A16.
Abstract A27: Increasing proximity triggers Mst2 autophosphorylation
Authors: Tran Thao , Kavran Jennifer M. 
Published: September 2020

Abstract
The Hippo pathway limits cell number and differentiation by blocking the transcriptional activity of YAP. The fidelity of signal transduction relies on the coordinated activity of a core kinase cassette that includes the kinases Mst1/2 and Lats1/2 and the accessory proteins Mob1 and hSalvador. Mst1/2 contains a kinase domain, linker region, and a C-terminal coiled-coil domain termed SARAH and is responsible for the phosphorylation of downstream components. Activation of Mst1/2 requires phosphorylation of the activation loop, a process believed to be a consequence of trans-autophosphorylation that is promoted by SARAH-domain mediated homodimerization. We aimed to understand what mechanistically triggers Mst1/2 autophosphorylation. Using purified proteins, we show that the kinase domain of Mst2 is sufficient for autophosphorylation but full-length Mst2 undergoes autophosphorylation faster than variants lacking the SARAH domain. This increased autophosphorylation could arise from either a specific contribution of a SARAH-domain mediated homodimer (allostery) or the increased proximity of kinase domains following homodimerization (effective local concentration). We investigated both possibilities using a series of biochemical assays and revealed that autophosphorylation of Mst2 variants lacking a SARAH domain could be stimulated by either chemically induced dimerization or increased localization following recruitment to the surface of a lipid-vesicle. Our results suggest that SARAH-domain mediated homodimerization is not the only event that promotes autophosphorylation of Mst1/2 and, instead, supports a more inclusive model that relies on colocalization. Any cellular event that increases the proximity of Mst1/2 could activate the kinase such as SARAH-domain mediated homodimerization, higher-order complex formation with hSalvador, or membrane recruitment.
Citation Format: Thao Tran, Jennifer M. Kavran. Increasing proximity triggers Mst2 autophosphorylation [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 A27.
Abstract A29: Genome-wide CRISPR/Cas9 screens for the identification of novel YAP1/TAZ modulators
Authors: Naujoks Jan , Potze Lisette , Kuehnlenz Julia , Kamburov Atanas , Nevedomskaya Ekaterina , Steffen Andreas , Luther Claudia , Anurin Anna , Buttgereit Anne , Prechtl Stefan , Bader Benjamin , Lesche Ralf , Staller Peter , Lange Martin , Nicke Barbara 
Published: September 2020

Abstract
Aberrant activation of the Hippo pathway effectors YAP1/TAZ promotes cell proliferation and tumorigenesis. To identify novel regulators of YAP1/TAZ in cancer, we established a FACS-based screening system monitoring YAP1/TAZ activity in MDA-MB-231 breast cancer cells. Using these cells, we performed pooled genome-wide CRISPR/Cas9 knockout and CRISPR activation/interference (a/i) screens. The list of hits included previously known YAP1/TAZ modulators such as LATS2, AJUBA, and TAZ itself, demonstrating the robustness of the screen. Moreover, we identified about 30 novel candidate genes with potential inhibitory activity on YAP1/TAZ and about 50 candidate genes that may play a role in YAP1/TAZ activation. These genes represent diverse cellular functions such as regulation of actin cytoskeleton, integrin signaling, and ER protein processing, among others. Modulation of endogenous YAP1/TAZ target genes was assessed by individual gene knockout using crRNAs. Functional characterization of the novel potential YAP1/TAZ modulators will aid to the further understanding of YAP1/TAZ biology in health and disease.
Citation Format: Jan Naujoks, Lisette Potze, Julia Kuehnlenz, Atanas Kamburov, Ekaterina Nevedomskaya, Andreas Steffen, Claudia Luther, Anna Anurin, Anne Buttgereit, Stefan Prechtl, Benjamin Bader, Ralf Lesche, Peter Staller, Martin Lange, Barbara Nicke. Genome-wide CRISPR/Cas9 screens for the identification of novel YAP1/TAZ 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 A29.
Abstract A30: Super-enhancer-associated long noncoding RNA UCA1 interacts directly with AMOT to inhibit Hippo signaling pathway in epithelial ovarian cancer
Authors: Lin Xianzhi , Spindler Tassja J. , de Souza Fonseca Marcos A , Corona Rosario I. , Seo Ji-Heui , Dezem Felipe S , Li Lewyn , Lee Janet M. , Long Henry W. , Sellers Thomas A. , Karlan Beth Y. , Noushmehr Houtan , Freedman Matthew L. , Gayther Simon A. , Lawrenson Kate 
Published: September 2020

Abstract
Long noncoding RNAs (lncRNAs) have emerged as critical regulators of tumorigenesis and yet their mechanistic role remains challenging to characterize. Here, we present LncRNA Interpreter, a strategy integrating functional proteomics with interacting proteins to characterize lncRNAs. Its robustness is exemplified by lncRNA Urothelial Cancer Associated 1 (UCA1), a driver of ovarian cancer development. Reverse phase protein array (RPPA) analysis indicates that UCA1 inhibits Hippo signaling pathway and in vivo RNA antisense purification (iRAP) of UCA1 interacting proteins identified angiomotin (AMOT), a known YAP regulator, as direct binding partner. Loss-of-function experiments show that AMOT mediates Hippo signaling pathway inhibition by UCA1. UCA1 enhances the AMOT-YAP interaction to prevent YAP phosphorylation and facilitate its nuclear translocation. Together, our LncRNA Interpreter pipeline identified UCA1 as an lncRNA regulator of the Hippo signaling pathway and highlighted the UCA1-AMOT-YAP signaling axis in ovarian cancer development. LncRNA Interpreter can readily be applied to other lncRNAs implicated in complex diseases.
Citation Format: Xianzhi Lin, Tassja J. Spindler, Marcos A de Souza Fonseca, Rosario I. Corona, Ji-Heui Seo, Felipe S Dezem, Lewyn Li, Janet M. Lee, Henry W. Long, Thomas A. Sellers, Beth Y. Karlan, Houtan Noushmehr, Matthew L. Freedman, Simon A. Gayther, Kate Lawrenson. Super-enhancer-associated long noncoding RNA UCA1 interacts directly with AMOT to inhibit Hippo signaling pathway in epithelial ovarian 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 A30.
Abstract A44: PR55α regulatory subunit of PP2A inhibits the MOB1/LATS cascade and activates YAP in pancreatic cancer cells
Authors: Hein Ashley L. , Brandquist Nichole D. , Ouellette Caroline Y. , Seshacharyulu Parthasarathy , Enke Charles A. , Ouellette Michel M. , Batra Surinder K. , Yan Ying 
Published: September 2020

Abstract
PP2A holoenzyme complexes constitute the majority of Ser/Thr phosphatase activities in human cells. Each PP2A consists of a catalytic subunit (C), a scaffold subunit (A), and a regulatory subunit (B). While the A and C subunits are highly conserved, a large number of B subunits share no homology, which determines PP2A substrate specificity and/or cellular localization. Although different PP2A complexes play distinct roles in cell signaling networks, PP2A has been defined only as a putative tumor suppressor, mostly based on loss-of-function studies using inhibitors (pharmacologic or biologic) for the highly conserved A or C subunit of PP2A. Many studies of specific pathways indicate that PP2A also possesses tumor-promoting function. We have reported an essential role of PR55α, a PP2A regulatory subunit, in supporting oncogenic phenotypes and in vivo tumorigenicity and metastasis of pancreatic cancer cells. In this study, we investigated a novel mechanism by which PR55α activates the YAP oncoprotein that plays an essential role in oncogenesis and metastasis of solid tumors including pancreatic cancer, resulting in its stabilization and nuclear retention. This mechanism involves PR55α’s inhibition of the MOB1-mediated LATS1/2 autoactivation, which otherwise would suppress YAP activation, and its direct activation of YAP itself. However, this mechanism does not involve the inhibition of upstream MST1/2 kinases and their subsequent T1079/T1041-phosphorylation of the LATS1/2 kinases. Furthermore, PR55α has the predominant effect on YAP activation, and the effect cannot be substituted by the depletion of either LATS1/2 or MOB1. Accordingly, PR55α is essential for YAP-promoted gene transcription, as well as for the anchorage-independent growth of cancer cells. In summary, current studies demonstrate a novel pancreatic cancer promoting mechanism through the PR55α-regulated PP2A.
Citation Format: Ashley L. Hein, Nichole D. Brandquist, Caroline Y. Ouellette, Parthasarathy Seshacharyulu, Charles A. Enke, Michel M. Ouellette, Surinder K. Batra, Ying Yan. PR55α regulatory subunit of PP2A inhibits the MOB1/LATS cascade and activates YAP in pancreatic cancer 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 A44.
Abstract B01: Understanding the LATS1 pro-apoptotic signaling network in melanoma
Authors: Garcia-Gutierrez Lucia , McKenna Stephanie , Badrock Andrew , Hurlstone Adam , Matallanas David 
Published: September 2020

Abstract
The tumor suppressor LATS1 is a core kinase of the MST2 pathway that regulates many cellular processes such as proliferation, cell growth, differentiation, and apoptosis. The MST2 pathway has been reported to interact with the MAPK pathway at the level of MST2 through RAF1, blocking MTS2 signaling. Our group has reported that, upon a proapoptotic signal, the tumor suppressor RASSF1A disrupts RAF1-MST2 complexes, leading to activation of MST2 and further LATS1-mediated phosphorylation of YAP, which triggers YAP translocation to the nucleus together with p73, leading to apoptosis. Apart from this mechanism, our group has found evidence showing that LATS1 could act as a signaling hub integrating proliferative and apoptotic signals and thus deciding cell fate. Several lines of evidence have shown that LATS1 crosstalks with several proteins of the apoptotic pathways including Mdm2, Omi, and p53. To get a better knowledge of the signaling network mediating LATS1 proapoptotic signaling, we have performed a proteomics screening. In this screening we have identified a cluster of proteins that are part of the intrinsic apoptotic pathway. Here we present validation experiments of these novel interactions and characterize the molecular mechanisms mediated by LATS1 proapoptotic network. We focus in melanoma cells, a cancer type where loss of function of the RASSF1A/MST2/LATS1 seems to be common. Thus, the main driving mutation of melanoma mutant BRAF has been shown to inhibit MST2; loss of expression of RASSF1A by promotor methylation is rather frequent and our analysis show that LAST1 is also downregulated. Our results indicate that the silencing of LATS1 crosstalk with the intrinsic pathway results in the evasion of apoptotic signals in melanocytes and can lead to cell transformation.
Citation Format: Lucia Garcia-Gutierrez, Stephanie McKenna, Andrew Badrock, Adam Hurlstone, David Matallanas. Understanding the LATS1 pro-apoptotic signaling network in melanoma [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 B01.
Abstract B03: Differential YAP expression in glioma cells induces cell competition and promotes tumorigenesis
Authors: Liu Zhijun , Yee Patricia P. , Wei Yiju , Liu Zhenqiu , Kawasawa Yuka Imamura , Li Wei 
Published: September 2020

Abstract
Intratumor heterogeneity associates with cancer progression and may account for a substantial portion of therapeutic resistance. Although extensive studies have focused on the origin of the heterogeneity, biologic interactions between heterogeneous malignant cells within a tumor are largely unexplored. Glioblastoma (GBM) is the most aggressive primary brain tumor. Here, we found that the expression of Yes-associated protein (YAP) is intratumorally heterogeneous in GBM. In a xenograft mouse model, differential YAP expression in glioma cells promotes tumorigenesis and leads to clonal dominance by cells expressing more YAP. Such clonal dominance also occurs in vitro when cells reach confluence in the two-dimensional culture condition or grow into tumor spheroids. During this process, growth of the dominant cell population is enhanced. In tumor spheroid, such enhanced growth is accompanied by increased apoptosis in cells expressing less YAP. The cellular interaction during clonal dominance appears to be reminiscent of cell competition. RNA-seq analysis suggested that the interaction induces expression of tumorigenic genes, which may contribute to the enhanced tumor growth. These results suggested that tumorigenesis benefits from competitive interactions between heterogeneous tumor cells.
Citation Format: Zhijun Liu, Patricia P. Yee, Yiju Wei, Zhenqiu Liu, Yuka Imamura Kawasawa, Wei Li. Differential YAP expression in glioma cells induces cell competition and promotes 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 B03.
Abstract B24: Identification of YAP modulators using genome-wide gain-of-function screening
Authors: Cramer Paul , von Eyss Björn 
Published: September 2020

Abstract
The Hippo pathway is a signaling pathway that is crucial to regulate tissue homeostasis and organ growth. The core of the Hippo pathway consists of the MST1/2 and LATS1/2 kinase cascade that regulates the activity of the transcriptional coactivators YAP/TAZ by phosphorylation. Unphosphorylated YAP/TAZ display nuclear localization and interact with TEAD proteins to regulate gene expression. A tight regulation is crucial, since deregulated YAP/TAZ can lead to several organismal defects including cancer development. To ensure robustness of the signaling pathway to perturbations, many Hippo components are organized in a redundant manner, e.g., redundancy of LATS kinases. This feature aggravates the identification of new Hippo signaling components using loss-of-function screens since a knockout of one factor could potentially be compensated for by its redundant counterpart. To discover novel potential regulators of YAP, we performed a genome-scale gain-of-function CRISPR/Cas9 screening in MCF10A cells using the synergistic activation mediator (SAM) system. SAM is an adaptation of CRISPR/Cas9 to overexpress endogenous genes by targeting the proximal promoter with sgRNAs rather than knocking out target genes. Using the nuclear localization of YAP as a measure of YAP activity, we could identify several genes as positive regulators of YAP. One of the best screening hits is ISOC1 (Isochorismatase domain-containing protein 1). We validated the screening by using single sgRNAs to induce the endogenous ISOC1 locus by SAM. The expression of YAP-target genes as ANKRD1, CTGF, and IGFBP3 was increased upon ISOC1 overexpression. Main goals in the future will be to understand the biochemical mechanism by which ISOC1 modulates YAP activity and the biologic role of ISOC1. Since ISOC1 is reported to localize to peroxisomes and is induced upon dietary restriction in mice, we hypothesize that ISOC1 acts as a central hub to connect peroxisomal metabolism and YAP/TAZ activity.
Citation Format: Paul Cramer, Björn von Eyss. Identification of YAP modulators using genome-wide gain-of-function screening [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 B24.
Abstract B26: A tumor specific molecular network promotes tumor growth by enforcing a JNK-YKI feed forward loop
Authors: Kango-Singh Madhuri 
Published: September 2020

Abstract
Cancer cells expand rapidly in response to altered cell-cell interactions among tumor and their surrounding cells; however, the molecular mechanisms by which alterations in these interactions promote aggressive metastatic tumor growth remain unclear. Earlier studies showed that increased oncogenic signaling and deregulation of inflammatory cytokines may be underlying tumor growth and progression. To study the nature of these interactions, we made mosaic clones expressing oncogenic forms of Yorkie (Yki) or Ras in polarity deficient cells (RasV12, scrib- or Yki3SA, scrib-) that are marked with GFP in Drosophila imaginal discs. This mosaic system recapitulates the clonal origins of human cancer and provides a distinct advantage in analyzing cell-cell (intratumoral and tumor-surrounding cell) interactions affecting tumor growth. Using these models of oncogenic cooperation, we show that tumor cells grow by activation of a previously unidentified network comprising Wingless (Wg), Dronc (Drosophila Caspase 9 ortholog), Jun N-terminal kinase (JNK), and Yki. Further, Toll-like receptor (TLR) component Cactus is highly expressed in the tumor cells. We show that Wg, Dronc, JNK, and Yki signaling are all required for the growth of tumors (RasV12, scrib-, and other tumor models), and downregulating Cactus affects both tumor progression and invasion. It is notable that Wg, Dronc, JNK, and Yki play a signaling and patterning role in normal development, and act as regulators of cell-cell interactions like cell competition and compensatory proliferation. JNK was previously shown to undergo a paradoxical signaling switch from proapoptosis to proproliferation that leads to activation of Yki. We report that Yki not only regulates the TLR component Cactus, but also positively regulates JNK in the tumor cells to form a JNK-Yki self-reinforcing positive feedback signal-amplification loop downstream of Wg and Dronc. We further demonstrate that the Wg-Dronc-JNK-Yki signaling network promotes tumor growth in other contexts of oncogenic cooperation. Overall, the identification of the Wg-Dronc-Yki-JNK molecular network and the organization of the signaling elements provide novel insights into how altered cell-cell interactions and signaling promote tumorigenesis. Our findings suggest that identification of molecular networks may provide significant insights about the key biologically meaningful changes in signaling pathways and paradoxical signals that promote tumorigenesis.
Citation Format: Madhuri Kango-Singh. A tumor specific molecular network promotes tumor growth by enforcing a JNK-YKI feed forward loop [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 B26.
Abstract IA04: Regulation of the Hippo pathway in cancer
Authors: Guan Kun-Liang 
Published: September 2020

Abstract
The Hippo pathway is crucial in organ size control and its dysregulation contributes to tumorigenesis. Core components of the Hippo pathway include the protein kinases of MST1/2, MAP4Ks, LATS1/2, the transcription co-activators YAP/TAZ, and their DNA binding partners TEADs. LATS phosphorylates YAP/TAZ to promote cytoplasmic localization and degradation, thereby inhibiting YAP/TAZ and cell growth. The Hippo pathway is regulated by a wide range of signals, including cell density, GPCR, cellular energy levels, and mechanical cues. We will present our recent progresses on Hippo pathway regulation and its role in cancer. The emerging role of the Hippo pathway in tumorigenesis suggests the potential therapeutic value of targeting this pathway for cancer treatment.
Citation Format: Kun-Liang Guan. Regulation of the Hippo pathway 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 IA04.