bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PR02: Spatial resets modulate YAP-dependent transcription
Authors: Franklin Matt , Ghosh Raja , Shi Quanming , Liphardt Jan 
Published: September 2020

Abstract
Despite the emergence of YAP as an important regulator of cell proliferation and oncogenesis, a clear picture of the relationship between YAP localization dynamics and downstream transcription is missing. Using live-cell imaging of CRISPR-knockin breast epithelial lines, we show that YAP displays dramatic spatial resets characterized by bulk exit from the nucleus followed by re-entry. These localization resets were upregulated by inhibiting Src-kinase and dampened by Ras transformation. After monolayer wounding, we found that edge-cells exhibited a synchronized localization reset. Lastly, induction of store-operated Ca2+ release and chromatin condensation during mitosis were found to also cause YAP localization resets. We relate these spatiotemporal YAP localization changes to transcriptional outputs from endogenous YAP targets using nascent-transcription reporter-cassette knockins. Maximal transcriptional responses were strictly correlated to the induction of localization resets through targeting Src-kinase, inducing Ca2+ release, and mitosis. By blocking the response to Ca2+ release using a PKC inhibitor, we show that the large transcriptional response is dependent on the ability of YAP to transiently localize to the cytoplasm. We found that Ras transformation, which suppressed YAP localization resets, caused upregulated import and export, reduced overall chromatin binding, and increased target gene expression. Untransformed cells, on the other hand, show relatively high nuclear retention through increased binding and slower nuclear export. This suggests that Ras transformation allows an escape from the compartmentalization-based control shown in untransformed cells. Our results suggest a new perspective on YAP-dependent transcription, revealed through the application of real-time imaging of native YAP dynamics and nascent transcription of YAP target genes.
This abstract is also being presented as Poster A21.
Citation Format: Matt Franklin, Raja Ghosh, Quanming Shi, Jan Liphardt. Spatial resets modulate YAP-dependent transcription [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 PR02.
Abstract PR03: YAP/TAZ requirement in mesenchyme-originated intestinal hamartomatous polyposis
Authors: Cotton Jennifer L. , Dang Kyvan , Li Qi , Johnson Randy L. , Ip Y. Tony , Wu Xu , Mao Junhao 
Published: September 2020

Abstract
Hamartomatous polyposis syndromes (HPS) are rare genetic syndromes, including Peutz-Jeghers syndrome (PJS) and PTEN hamartoma tumor syndrome (Cowden and Bannayan-Riley-Ruvalcaba syndromes), which are caused by germline mutations of STK11 (LKB1) and PTEN genes, respectively. HPS is characterized by the development of hamartomatous polyps in the GI tract; however, the cellular origins and molecular mechanism underlying hamartomatous polyposis remain poorly understood. Here we demonstrate that specific disruption or deletion of Stk11 or Pten in mouse GI mesenchyme, but not in the epithelium, generates hamartomatous polyps histologically resembling GI polyps observed in PJS and Cowden syndrome patients. Genetically, we show that mTOR activity is essential for Pten but not Stk11 deletion-driven hamartomatous polyposis. Furthermore, we show that AMPK1/2 deletion is not able to initiate PJS polyp formation. However, we find significant upregulation of mesenchymal YAP/TAZ activity in PJS polyps and demonstrate that YAP/TAZ in gut mesenchyme are required for Stk11 deletion-induced PJS hamartomatous polyposis. Our studies suggest a mesenchymal origin of GI polyps in HPS and reveal the distinct roles of YAP/TAZ and mTOR in gut mesenchyme during hamartomatous polyposis, which likely have important therapeutic implication for treating these HPSs.
This abstract is also being presented as Poster A06.
Citation Format: Jennifer L. Cotton, Kyvan Dang, Qi Li, Randy L. Johnson, Y. Tony Ip, Xu Wu, Junhao Mao. YAP/TAZ requirement in mesenchyme-originated intestinal hamartomatous polyposis [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 PR03.
Abstract PR04: Integrin-mediated mechano-transduction controls HER2 oncogenic signaling and activation of YAP in breast cancer
Authors: Wang Shimin , Kim Young-Mi , Garippa Ralph , Norton Larry , Giancotti Filippo G. 
Published: September 2020

Abstract
Integrin-mediated adhesion and signaling via focal adhesion kinase is required for mammary tumorigenesis in the PyMT mouse model. Moreover, PTK2 encoding FAK is amplified in a substantial fraction of human breast cancers. We have investigated the mechanism through which integrin signaling controls mammary tumorigenesis and found that integrin-mediated mechano-transduction controls invasive growth in stiff 3D matrices through activation of YAP/TAZ. Mechanistic studies revealed that integrin signaling induces—via activation of FAK and Src family kinases (SFKs) —tyrosine phosphorylation and inactivation of LATS. The ensuing activation of YAP/TAZ is necessary for invasive growth of HER2+ breast cancer cells. Engagement of HER2/HER3 with neuregulin impinges on SFKs to amplify activation of YAP/TAZ in HER2+ breast cancer cells, suggesting that integrin-mediated mechano-transduction functions as a rheostat to regulate HER2 oncogenic signaling. Finally, administration of dasatinib significantly increases the efficacy of HER2 inhibition in the MMTV-Neu mouse model of HER2+ breast cancer. These findings reveal a major mechanism through which the Hippo pathway is disabled in breast cancer and suggest that targeting HER2 and SFKs simultaneously may be a rational strategy in selected cases of breast cancer.
This abstract is also being presented as Poster A22.
Citation Format: Shimin Wang, Young-Mi Kim, Ralph Garippa, Larry Norton, Filippo G. Giancotti. Integrin-mediated mechano-transduction controls HER2 oncogenic signaling and activation of YAP in 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 PR04.
Abstract PR05: Genome-wide screening identifies novel YAP modulators
Authors: Elster Dana , Tollot Marie , Schlegelmilch Karin , Ori Alessandro , Rosenwald Andreas , Sahai Erik , von Eyss Björn 
Published: September 2020

Abstract
The transcriptional coactivator YAP is the key downstream effector of the Hippo pathway, which is a central regulator of organ size, stem cell/progenitor cell expansion, and tissue regeneration. Diverse studies have shown the importance of a precise regulation of this pathway and its key downstream regulator YAP for tissue homeostasis. To achieve new insights in the Hippo-independent transcriptional regulation of YAP in breast cancer, we set out to identify new YAP modulators using a genome-wide CRISPR screen and Perturb-Seq. We identified the transcriptional repressor protein Trichorhinophalangeal Syndrome 1 (TRPS1) as a potent repressor of YAP-dependent transactivation, using a genome-wide CRISPR screen. TRPS1 globally regulates YAP-dependent transcription by binding to a large set of joint genomic sites, mainly enhancers. Moreover, TRPS1 antagonizes activating YAP/TEAD complexes by recruiting corepressor complexes to joint sites. Loss of TRPS1 leads to activation of enhancers due to increased H3K27 acetylation and an altered promoter-enhancer interaction landscape. TRPS1 is commonly amplified in breast cancer, suggesting that restrained YAP activity favors tumor growth. Combined, we uncover TRPS1 as an epigenetic regulator of YAP activity in breast cancer. Additionally, we developed a Trps1-deficient mouse line that we will use to test the in vivo role of Trps1 in mammary gland physiology and breast cancer. Furthermore, we combined CRISPR-based gene perturbation with droplet-based single-cell RNA sequencing (Perturb-Seq), to perform a second large-scale analysis on potential YAP modulators. To this end, we used a CRISPR-library containing 158 previously from us in a Bio-ID assay identified YAP interactors. Together, we uncover several novel YAP modulators, contributing to a better understanding of the Hippo-independent transcriptional regulation of YAP.
This abstract is also being presented as Poster B40.
Citation Format: Dana Elster, Marie Tollot, Karin Schlegelmilch, Alessandro Ori, Andreas Rosenwald, Erik Sahai, Björn von Eyss. Genome-wide screening identifies novel YAP 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 PR05.
Abstract PR07: Targeting the Hippo-YAP pathway with small-molecule compounds
Authors: Tang Tracy T. , Konradi Andrei W. , Feng Ying , Peng Xiao , Qiao Sofie , Post Leonard 
Published: September 2020

Abstract
The Hippo-YAP pathway is involved in the regulation of cell proliferation, survival, and cell migration. It functions normally to control tissue regeneration and homeostasis and limit organ size/shape. Genetic alterations of pathway components resulting in YAP activation have been reported in a variety of human malignancies. YAP activity is also linked to resistance to targeted therapies and cancer relapse. Through high-throughput phenotypic screens, we have identified novel classes of small-molecule compounds that target the Hippo-YAP pathway. Using different assays, we determined whether the screen hits specifically inhibit YAP-TEAD transcription activity and examined their effects on YAP phosphorylation, YAP nuclear and cytoplasmic localization, and YAP-TEAD interaction. To map the target points in the Hippo pathway, we analyzed the effects of the compounds in cells deficient for various pathway components. Lead optimization resulted in highly potent inhibitors that block YAP-TEAD transcription activity at single-digit nM, and we have identified the molecular targets of some chemical series. In all, we have discovered different classes of pathway inhibitors: 1) compounds that induce YAP phosphorylation and cytoplasmic translocation, 2) compounds that induce YAP cytoplasmic translocation without affecting its phosphorylation, and 3) compounds that work in the nucleus to block YAP-TEAD transcription activity without affecting YAP phosphorylation or nuclear localization. Examples of a few classes will be presented to illustrate that we now have a way to target the Hippo-YAP pathway that thus far has been undruggable and is dysregulated in many cancers and critically associated with targeted therapy resistance.
This abstract is also being presented as Poster B15.
Citation Format: Tracy T. Tang, Andrei W. Konradi, Ying Feng, Xiao Peng, Sofie Qiao, Leonard Post. Targeting the Hippo-YAP pathway with small-molecule compounds [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 PR07.
Abstract PR08: Systematic pan-cancer analyses of Hippo pathway deregulation in cancer
Authors: Chang Matthew T. , Hagenbeek Thijs J. , Lacap Jennifer , Modrusan Zora , Klijn Christiaan , Dey Anwesha 
Published: September 2020

Abstract
Hippo signaling is a highly conserved, pleiotropic pathway that is recurrently deregulated across many cancers. With large-scale cancer genomics data, several efforts have been undertaken to quantify Hippo pathway activity in an unbiased manner. However, identifying a comprehensive catalog of Hippo pathway genes can be difficult due to the heterogenous nature of the disease and the limitations of any given study. Here we show the high concordance between different methods of quantifying Hippo pathway activity in cancers. Furthermore, we establish a first-principled approach by experimentally deriving a lineage-independent quantification by leveraging the transcriptomic profiles of nearly 900 cell lines from 28 tissue types. We applied these signature(s) to the genomic profiles of over 11,000 primary human cancer patients to identify several statistically significant biomarkers associated with Hippo pathway dysregulation, including NF2 mutations and deletions, SOX2 amplifications, and CDH1 mutations. To further assess therapeutic implications of pathway inhibition, we applied machine learning approaches to predict a tumor’s sensitivity to Hippo pathway inhibition based on its genomic profile, revealing that Hippo pathway inhibition may be a tractable approach in a wide spectrum of cancers.
This abstract is also being presented as Poster B38.
Citation Format: Matthew T. Chang, Thijs J. Hagenbeek, Jennifer Lacap, Zora Modrusan, Christiaan Klijn, Anwesha Dey. Systematic pan-cancer analyses of Hippo pathway deregulation 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 PR08.
Abstract PR10: Hippo regulates intestinal regeneration by inducing revival stem cells
Authors: Ayyaz Arshad , Wrana Jeff 
Published: September 2020

Abstract
The mechanisms underlying intestinal regeneration and initiation of adenomas have been obscure. Here we profiled the single-cell transcriptomes of regenerating intestines and identify revival stem cells. Revival stem cells are dependent on Yap signaling, are transiently induced by a variety of damage, and are required to reconstitute the intestinal crypt. These studies reveal a unique pathway to regenerate damaged tissues.
This abstract is also being presented as Poster A14.
Citation Format: Arshad Ayyaz, Jeff Wrana. Hippo regulates intestinal regeneration by inducing revival stem 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 PR10.
Abstract A02: The feedback loop among miR-449b-3p/ADAM17/NF-κB promotes metastasis in nasopharyngeal carcinoma
Authors: Fei Qian , Du Ming-Yu , Jiang Ning , Yin Li , He Xia 
Published: September 2020

Abstract
Emerging pieces of evidence have proved an important role of miRNAs in tumorigenesis and progression. However, the function of miRNAs in nasopharyngeal carcinoma (NPC) development remains poorly elucidated. Quantitative reverse transcription-polymerase chain was used to detect the expression level of miR-449b-3p in NPC cell lines and tissues. We performed cell viability assay, colony formation, flow cytometric, transwell assay, and wound-healing assay to assess the ability of cell proliferation, apoptosis, invasion, and migration in vitro, respectively. NPC xenograft tumor and lymph node metastatic mice model were conducted to validate the function of miR-449b-3p in vivo. Luciferase reporter assay, ChIP assay, and Western blot analysis were actualized to explore the mechanism underlying the miR-449b-3p on NPC metastasis. Here we showed that miR-449b-3p was downregulated in NPC specimens (p&lt;0.001) and cells (p&lt;0.05), and most of the patients with advanced-stage NPC had an impaired expression of miR-449b-3p, on the contrary, early-stage NPC patients had a high level of miR-449b-3p (p&lt;0.001). Moreover, miR-449b-3p inhibited NPC metastasis both in vitro and in vivo. Further investigation revealed that a disintegrin and metalloproteinase 17 (ADAM17) was the direct target of miR-449b-3p. Rescue experiments suggested that the downregulation of ADAM17 in miR-449b-3p inhibited cells partially reversed the inhibition of cell invasion and migration. We also found that ADAM17 could conversely suppress the promoter activity and expression of miR-449b-3p via inducing NF-κB transcriptional activity. In conclusion, our study provides new insights into the mechanism underlying the invasion and metastasis in NPC. The novel miR-449b-3p/ADAM17/NF-κB feedback loop in NPC could potentially be a target for clinical treatment in NPC.
Citation Format: Qian Fei, Ming-Yu Du, Ning Jiang, Li Yin, Xia He. The feedback loop among miR-449b-3p/ADAM17/NF-κB promotes metastasis in nasopharyngeal carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr A02.
Abstract A04: Tumor development trajectories for exploring differences between cancer subtypes
Authors: Leshchiner Ignaty , Rosebrock Daniel , Spiro Oliver , Mroz Edmund , Livitz Dimitri , Rocco James W. , Getz Gad 
Published: September 2020

Abstract
We have employed PhylogicNDT, our computational method for timing somatic events and subclonal architecture reconstruction, to explore the association of tumor development trajectory (from normal cell to malignant state) with cancer subtype and genetic landscape. Previous attempts to understand the order of somatic events that lead to the formation of cancers are mostly based on studies of premalignant samples, which are often hard or impossible to obtain due to small size or inaccessible location. Our approach allows us to use information from whole-exome and whole-genome data to computationally reconstruct the order of events preceding malignant transformation of the tissue. We show that this approach yields accurate reconstruction of premalignant events in lung, colorectal, and head and neck cancers based on previous exploration of premalignant lesions. We explored the association between the developmental trajectories, treatment outcome, and survival in several cancer types. PhylogicNDT can be used to infer the order of clonal driver events (including in precancerous stages), subclonal populations of cells and their phylogenetic relationships, and dynamics of cell populations. This methodology will enable a systematic study of tumor initiation and progression across cancer types and therapies.
Citation Format: Ignaty Leshchiner, Daniel Rosebrock, Oliver Spiro, Edmund Mroz, Dimitri Livitz, James W. Rocco, Gad Getz. Tumor development trajectories for exploring differences between cancer subtypes [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr A04.
Abstract A10: Treatment of squamous cell carcinoma by alpha radiation-based brachytherapy (Alpha DaRT)
Authors: Mizrachi Aviram , Popovtzer Aron , Rosenfeld Eli , Ben-Hur Ran , Kelson Itzhak , Keisari Yona 
Published: September 2020

Abstract
Objective: The first clinical trial in humans with skin and oral cavity squamous cell carcinoma (SCC) was performed in order to evaluate the effect of a unique intratumoral alpha radiation-based tumor ablation treatment termed Diffusing Alpha-emitters Radiation Therapy (DaRT).
Methods: Radium-224 loaded sources (DaRT seeds) were inserted into solid tumors and released by recoil short-lived alpha-emitting atoms (Rn-220, Po-216, Pb-212, Bi-212, Po-212, Tl-208). These atoms disperse in the tumor and spray it with highly destructive alpha radiation. The decay products diffuse in the tumor mass to a distance of at least 5 mm.
Results: A feasibility and safety clinical study is ongoing and currently 28 patients were treated at the Rabin Medical Center (Israel) and IRST (Italy). Patients with histopathologic confirmed skin or head and neck SCC, and tumor size ≤5 centimeters in the largest diameter, were enrolled. Treatment was delivered based on a CT-simulation pretreatment plan. The seeds (1 cm long and 0.7 mm in diameter), each carrying a dose of 2 μCi, were placed up to 5 millimeters from each other. CT was used in order to confirm the position of the radioactive seeds. Two weeks after implantation the seeds were removed, and six weeks after treatment a CT scan was performed to assess the effect of treatment. Study results are available for 18 cases that were treated per protocol and reached the 30-day follow-up period. Age of the patients ranged from 60 to 102 years (median 80 years). Ten patients had oral cavity SCC and 18 were diagnosed with cutaneous SCC. Thirteen subjects were treated within prior radiation failure fields (radiation dosage &gt;60Gy). All tumors responded to the treatment; 13 tumors exhibited a complete response and five tumors showed partial response. No major toxicity was noted.
Conclusions: In this first feasibility and safety human study we demonstrated that alpha-based treatment (DaRT) resulted in enhanced radiobiologic potential. Furthermore, the treatment was effective against radioresistant SCC tumors without any major side effects.
Citation Format: Aviram Mizrachi, Aron Popovtzer, Eli Rosenfeld, Ran Ben-Hur, Itzhak Kelson, Yona Keisari. Treatment of squamous cell carcinoma by alpha radiation-based brachytherapy (Alpha DaRT) [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr A10.