bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA30: Population-level problems require system level solutions: Using collective impact approaches to solving cancer disparities
Authors: Rhoads Kim F. 
Published: September 2020

Abstract
Disparities in cancer incidence and mortality are longstanding and tenacious. The disproportionate burden of disease is borne by racial/ethnic minority groups, as well as those living in economically depressed conditions, regardless of race/ethnicity. Although there is no physiologic or genetic link between some of these disparate populations, the similarities in the experience of cancer outcomes suggests that they may be driven by socioeconomic conditions and inequities that underpin the US health care system. Despite the multilevel nature of the drivers of disparate outcomes, public health facing solutions have largely focused on interventions aiming to change individual level health behaviors, such as risk reduction, increasing screening, and early detection. Historically, much less attention and intervention have been directed toward addressing systemic factors, either inside or outside of the health care system, that contribute. Accordingly, gaps in cancer survival have persisted over time, and in some cases those gaps have widened. More recent discourse on cancer and other health disparities has emphasized the importance of the Social Determinants of Health (SDOH); in doing so have made clear the necessity for a multilevel, multisectoral approach to eliminate these differences. “Collective impact” is one such approach. Collective impact is defined as the commitment of a group of key actors from different sectors to a common agenda for solving a specific social problem. The five conditions of a collective impact approaches include a common agenda, shared measurement systems, mutually reinforcing activities; continuous communication, and backbone support organizations. This presentation will review some successes and lessons learned from well-established collective impact activities addressing noncancer conditions at our institution. We will then explore the establishment of a collective impact approach to addressing the burden of cancer in San Francisco and other surrounding counties. We will emphasize early successes in both big “P” as well as small “p” policy realms and highlight the role of the Comprehensive Cancer Centers in supporting system-level solutions to this longstanding population-level challenge.
Citation Format: Kim F. Rhoads. Population-level problems require system level solutions: Using collective impact approaches to solving cancer disparities [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr IA30.
Abstract IA34: The impact of ancestry on mutational signatures in population with African ancestry
Authors: Polak Paz 
Published: September 2020

Abstract
Mutational processes generate variations in DNA that fuel tumor devolvement. These processes include DNA damage due to exposure to environmental carcinogens and DNA repair. Different processes may lead to varying rates and types of mutations in cancers. Mutational processes can be inferred from whole-exome sequencing data using a computational method called mutational signatures framework. Sequencing tumors across populations can reveal population-specific signatures that can be mapped to specific environmental exposures or genetics. Knowing how mutational processes lead to tumor formation is key to understating the etiology of cancer. We analyzed The Cancer Genome Atlas data and discovered a mutational signature characteristic of homologous recombination deficiency (HRD). We found that this HRD signature was mainly attributed to germline mutations in BRCA1/BRCA2 in whites and promoter methylation of BRCA1/RAD51C in patients of African ancestry. Patients with BRCA mutation will likely benefit from cisplatin inhibitors in both neoadjvant and at time of recurrence. Clinical trials suggest TNBC patients with methylation of BRCA1 are less likely to benefit from cisplatin at the time of recurrence. Hence our initial observation might indicate that black TNBC patients might benefit from other treatment strategies.
Citation Format: Paz Polak. The impact of ancestry on mutational signatures in population with African ancestry [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr IA34.
Abstract PR15: Intratumoral heterogeneity in Latino gastric adenocarcinomas
Authors: Toal Ted , Echeverry Guadalupe P. , Sahasrabudhe Ruta , Bohorquez Mabel , Torres Javier , Urayama Shiro , Kirane Amanda , Echeverry Magdalena , Carmona Luis G. Carvajal 
Published: September 2020

Abstract
The goal of this study was to examine gastric (stomach) cancer mutational intratumoral heterogeneity (ITH) in Latinos using multiregion sequencing (MSEQ). Gastric cancer is the 2nd leading cause of cancer-related death worldwide. It is diagnosed in 25,000 Americans each year, with Latinos twice as likely to succumb as Whites. Treatment is currently limited to a few molecularly guided therapies, but TCGA data show that 70% of GC patients have a mutation in a gene targetable with existing drugs. Significant ITH has been identified in a variety of tumor types to date, although a GC study has yet to be published. ITH is an important consideration for personalized therapy. Driver gene mutations are frequently found to be nonclonal, a crucial factor when assessing effective druggability. In this study, two to five tumor biopsies and adjacent normal tissue were obtained from 33 Latino patients, totaling 120 tumor (T) biopsies and 33 normal (N) samples. DNA was extracted from the tissues and the coding regions of 762 cancer-related genes were sequenced using Agilent target enrichment and Illumina sequencing. For each biopsy, estimates were made of sample purity and ploidy, somatic mutations were called using joint analysis of all T and N sequence data for each patient, cancer cell fraction (CCF) was estimated for each mutation, and copy number variation (CNV) was called across the genome. Somatic mutations and copy number changes were analyzed for clonality in each patient. We found a high degree of heterogeneity, both intratumoral and interpatient, with the fraction of functional somatic mutations that are clonal ranging from 0 to 68%, the fraction private to one biopsy ranging from 32% to 100%, and the fraction shared between multiple but not all biopsies ranging from 0 to 42%. For 10 of the 33 samples there was at least one gene, containing a clonal functional mutation, for which there is an FDA-approved targeted therapy. In summary, our study is the first to assess ITH in GC. Our results are important to understand the genetic diversity and clonal architecture of these tumors and to improve molecular diagnostics.
This abstract is also being presented as Poster D107.
Citation Format: Ted Toal, Guadalupe P. Echeverry, Ruta Sahasrabudhe, Mabel Bohorquez, Javier Torres, Shiro Urayama, Amanda Kirane, Magdalena Echeverry, Luis G. Carvajal Carmona. Intratumoral heterogeneity in Latino gastric adenocarcinomas [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr PR15.
How Drosophila Can Inform the Emerging Paradigm of the Role of Antioxidants in Cancer
Authors: Saucedo Leslie J. , Triolo Rosalie E. , Segar Kate E. 
Published: September 2020

Abstract
Drosophila melanogaster has proven to be an effective model system in uncovering both genetic and cellular contributions to human cancer. Many elusive genes and signaling pathways that control oncogenic growth were first identified using flies. In many cases, these discoveries were not driven by a direct search for novel genes involved in cancer but rather stemmed from research programs to uncover mechanisms that control growth and development. However, the bounty of genetic tools and the shared evolution of multicellular organisms places Drosophila in a powerful position to purposefully elucidate observations seen in human cancers. In the past decade, the role of antioxidants in cancer progression has shifted dramatically. This review highlights major findings driving this change in perspective and underscores an array of existing work and resources in laboratories using Drosophila that can make significant contributions to how the redox environment affects cancer progression.
Abstract A01: YAP1 drives ependymoma-like tumor formation in the brain
Authors: Eder Noreen , Dolmart Marie-Charlotte , Claxton Suzanne , Cotton Jennifer , Mao Jun-Hao , Snijders Bram , Roncaroli Federico , Thompson Barry , Ultanir Sila 
Published: September 2020

Abstract
Ependymoma is the third most common pediatric brain cancer. YAP1 gene fusions have been observed in a subset of pediatric ependymomas. Here we show that increased YAP1 activity has a causative role in ependymoma-like tumor formation. YAP1 protein is strongly expressed and localized in the nucleus in a subset of human ependymomas. In the developing brain, YAP1 expression is normally found in subventricular zone neural progenitor cells, and NEX/NeuroD6-Cre induced conditional expression of active nuclear YAP1 (YAP1-5SAnls) is sufficient to drive brain tumor formation. YAP1 drives tumor formation by maintaining a nestin positive neural stem cell-like specification and preventing hippocampal neuronal differentiation. Dual conditional deletion of LATS1 and LATS2 kinases in the NEX-Cre lineage also generates similar tumors. Genetic rescue experiments in mice show that either YAP1 or its homolog TAZ can drive tumor formation downstream of LATS1/2 kinases. YAP1/TAZ activity causes tumors that display histologic and molecular characteristics of ependymoma, including ultrastructural features microvilli and tight junctions. Our results show that disruption of YAP1/TAZ activity in neuronal precursor cells leads to ependymoma-like tumors.
Citation Format: Noreen Eder, Marie-Charlotte Dolmart, Suzanne Claxton, Jennifer Cotton, Jun-Hao Mao, Bram Snijders, Federico Roncaroli, Barry Thompson, Sila Ultanir. YAP1 drives ependymoma-like tumor formation in the brain [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 A01.
Abstract A05: RAS signaling promotes ERMS cell viability via sustaining TAZ expression and protein stability
Authors: Lin Liz Yi-Tzu , Linardic Corinne 
Published: September 2020

Abstract
Rhabdomyosarcoma (RMS) is a pediatric cancer characterized by skeletal muscle histogenesis, with the embryonal histologic variant (ERMS) being the most common. Mutations of the RAS pathway are found in 40-60% of ERMS patient specimens, and as in other human cancers the RAS protein is currently not druggable, and inhibition of downstream RAS effector pathways fails due to compensating signaling. Thus, there is an urgent need to understand the dysregulated signaling in RAS-driven ERMS (rERMS). Hippo signaling was originally identified for its role in controlling organ size and tissue homeostasis, but it is now known to also have a critical role in cancer initiation and progression. In ERMS patients, higher YAP1 gene expression correlates with a poor prognosis, and in vitro and in vivo studies using ERMS cell lines and mouse models also show that YAP1 supports ERMS cell and tumor growth. Whether and how the YAP1 paralog WWTR1 (TAZ) contributes to rERMS tumorigenesis remains understudied. Our initial studies examining ERK suppression (genetic inhibition via shRNA or pharmacologic inhibition via trametinib) showed that this slowed rERMS cell growth and proliferation, and induced rERMS cell differentiation. However, we also found CTGF and CYR61 (downstream targets of YAP1/TAZ) significantly repressed upon trametinib treatment. While YAP1 appeared unaffected, trametinib treatment significantly suppressed TAZ at both the mRNA and protein levels in a dose-dependent manner. Suppression of TAZ with shRNA decreased rERMS cell growth and proliferation, suggesting that sustained TAZ expression is crucial for rERMS cell viability. Interestingly, there was no change in the activity of MST and LATS. Our next focus will be on the mechanism of ERK-mediated TAZ expression, with a potential role for glycogen synthase kinase 3 beta as a mediator of TAZ degradation. In summary, these studies identify a new role for RAS signaling in promoting rERMS cell survival via TAZ expression.
Citation Format: Liz Yi-Tzu Lin, Corinne Linardic. RAS signaling promotes ERMS cell viability via sustaining TAZ expression and protein stability [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 A05.
Abstract A10: Taz regulates aging of hematopoietic stem cells
Authors: Mura-Meszaros Anna , Heidel Florian , von Eyss Bjoern 
Published: September 2020

Abstract
During aging, several tissues display a progressive functional decline potentially leading to malfunction of whole organ systems. This phenomenon can also be observed in the hematopoietic system since aged hematopoietic stem cells (HSCs) display several cell-intrinsic defects, e.g., a strongly reduced self-renewal capacity as well as a skewing towards myeloid differentiation. To investigate a potential involvement of the Hippo pathway in the aging of HSCs, we performed RNA-sequencing in several stem and progenitor populations of young and aged mice, respectively. Here, we identified Taz as one of the most strongly upregulated genes, specifically in long-term hemtatopoietic stem cells (LT-HSCs), those cells that are at the apex of the hematopoietic system. Further analyses revealed that Taz actively contributes to the aging-specific gene expression changes in LT-HSCs and that Tazhigh cells accumulate over time in the LT-HSC compartment. Furthermore, we identified a novel surface marker as a Taz target gene, which allows us to trace Taz activity in the aging mouse and separate Tazhigh from Tazlow cells. Strikingly, our functional characterization revealed that Tazlow cells closely resemble young LT-HSCs whereas Tazhigh cells display a gene expression program that is found in aged LT-HSCs. Consistent with these observations, Tazhigh cells are functionally impaired, e.g., during cell cycle re-entry. Our observations demonstrate that Taz is potently induced during aging of the blood system and most prominently in the LT-HSC compartment where it contributes to age-dependent gene expression changes and functional decline of hematopoietic stem cells.
Citation Format: Anna Mura-Meszaros, Florian Heidel, Bjoern von Eyss. Taz regulates aging of hematopoietic 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 A10.
Abstract A12: YAP and cancer stem cells in basal-like breast cancer
Authors: Quinn Hazel M. , Vogel Regina , Birchmeier Walter 
Published: September 2020

Abstract
Cancer stem cells (CSCs) are responsible for minimal residual disease tumor relapse. Appearing as the optimal target for therapy, these cells are very difficult to target due to their ability to resist proapoptotic stimuli. In order to overcome this evolutionary stem cell property, elucidation of the mechanistic regulation of these survival pathways is crucial. Previously we identified the CSC population in our model of basal-like breast cancer. Using targeted therapies directed at the tumor-driving pathway (Wnt and Met), we have shown that tumors initially respond to this therapy; however, they quickly become resistant. We have now confirmed that the Hippo transducer, Yap, is active in Wnt-Met tumors. The activity in the CSC population was increased compared to that of bulk tumor cells, indicating that Yap could be an option for anti-CSC therapy. Based on this, we utilized an inhibitor of Yap, verteporfin (VP). Treatment of 3D cultured Wnt-Met cells with VP inhibited CSC survival, showing that Yap is essential for tumor initiation. qPCR analysis of treated, self-renewing spheres showed that Yap and Wnt control distinct sets of stem cell genes. Only combination treatments sufficiently inhibited these genes. We now investigate the relationship between Wnt and Yap to understand how they cooperate and to identify a targetable bottleneck between the two pathways.
Citation Format: Hazel M. Quinn, Regina Vogel, Walter Birchmeier. YAP and cancer stem cells in basal-like 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 A12.
Abstract A18: Location, location, location: Avenues to regulating Hippo
Authors: Calses Philamer C. , Pham Victoria , Verschueren Erik , Kljavin Noelyn , Chang Matt , Seidel Kerstin , Haley Benjamin , Pham Trang , Noland Cameron , Hinkle Trent , Hagenbeek Thijs , Lill Jennie , Dey Anwesha 
Published: September 2020

Abstract
The TEAD family of the transcription factors (TEAD1-4) are the major transcription factors for YAP/TAZ transcription activators in the Hippo pathway. TEADs regulate many biologic processes, including development, tissue homeostasis, and tumorigenesis by regulating target genes involved in cellular proliferation and survival. Amplification or upregulation of YAP/TAZ/TEAD correlates with poor prognosis in cancer patients. The mechanisms of TEADs regulation and localization remain largely unknown. TEADs contain a highly conserved nuclear localization signal (NLS) embedded in the DNA binding domain (DBD). Overexpression of an NLS mutant TEAD in a Hippo-dependent cancer cell line is dominant negative and suppresses cellular proliferation and tumor growth. These results suggest that TEAD nuclear expression is regulated by a highly conserved NLS that may be important in the development of cancer. In light of these results, we have identified physiologic conditions where TEADs are expressed in the cytoplasm and the nucleus. By performing comparative immunoprecipitation-mass spectrometry between WT and NLS mutant TEAD, we found novel interacting partners for cytoplasmic and nuclear TEAD, thus uncovering novel roles for TEADs in cancer.
Citation Format: Philamer C. Calses, Victoria Pham, Erik Verschueren, Noelyn Kljavin, Matt Chang, Kerstin Seidel, Benjamin Haley, Trang Pham, Cameron Noland, Trent Hinkle, Thijs Hagenbeek, Jennie Lill, Anwesha Dey. Location, location, location: Avenues to regulating Hippo [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 A18.
Abstract A34: Identification of a MAP kinase that regulates YAP abundance
Authors: Park Sanghyun , Kim Joon 
Published: September 2020

Abstract
Purpose: Recent evidence suggests that YAP and its paralog TAZ play key roles in tumoriogenesis, tumor progression, and chemotherapeutic resistance. Although verteporfin is known to inhibit YAP by suppressing its interaction with the transcription factor TEAD, it has low efficacy and adverse effects including photosensitivity. Therefore, identification of other molecular targets is essential for developing anticancer drugs to treat YAP-driven cancers.
Method: Image-based whole-genome siRNA library screening was performed to identify genes that regulate the abundance of nuclear YAP protein. LATS1/2-null RPE1 cells were used to exclude the influence of cell density that controls the Hippo pathway. Several kinases were identified as positive regulators of nuclear YAP/TAZ intensity. Among them, a member of the MAP kinase family was selected for further study to investigate its YAP-regulating mechanism and its role in BRAF inhibitor-resistant cutaneous melanoma, which has high YAP/TAZ activity. Direct phosphorylation of YAP by the MAP kinase was detected by in vitro kinase assay and LC-MS/MS. Roles of the kinase in BRAF inhibitor-resistant melanoma cells were evaluated by CCK assay, scratch assay, tumor xenograft, and apoptosis analysis.
Results: We found that RNAi-mediated inhibition of the MAP kinase decreases total YAP/TAZ protein levels and their transcriptional activity. The MAP kinase physically interacts with and phosphorylates YAP. This phosphorylation influences ubiquitination and lysosomal degradation of YAP. Knockdown of the MAP kinases decreases proliferation, migration, and tumor formation of BRAF inhibitor-resistant melanoma cells. In addition, inhibition of the kinase reverses BRAF inhibitor resistance.
Conclusion: These results suggest that the MAP kinase is a novel positive regulator of YAP acting independently of the Hippo pathway. We propose that inhibition of the kinase is an efficient way of suppressing YAP/TAZ and the kinase can serve as a therapeutic target for YAP/TAZ-driven cancers.
Citation Format: Sanghyun Park, Joon Kim. Identification of a MAP kinase that regulates YAP abundance [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 A34.
Abstract A40: Hippo signaling in cancer development
Authors: Han Han , Seo Gayoung , Vargas Rebecca , Wang Wenqi 
Published: September 2020

Abstract
The Hippo pathway is known to control cell growth and stimulates cell apoptosis, two key events that are frequently dysregulated in tumorigenesis. Long-term YAP activation results in cell transformation and tumor development, suggesting the power of the Hippo pathway in control of cancer initiation and progression. Genetic mouse models fully support an oncogenic role for YAP and a tumor-suppressive function for the Hippo pathway components. Given the enormous implications of the Hippo pathway in cancer, great efforts have been made in dissecting the genetic mutations of the Hippo pathway components in cancer development and searching for effective approaches to target YAP for therapeutic intervention. Actually, elevated YAP expression and nuclear enrichment have been observed in many types of cancers including liver, breast, lung, ovary, colon, brain, and others. Interestingly, our recent study demonstrated that Hippo signaling deficiency enables the development of an active YAP addiction in cancer cells, which provides an opportunity to develop new targeted strategies for the cancers with deficient Hippo signaling.
Citation Format: Han Han, Gayoung Seo, Rebecca Vargas, Wenqi Wang. Hippo signaling in cancer development [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr A40.