bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A009 Single cell transcriptomic signature of Li-Fraumeni Syndrome soft tissue sarcomas
Authors: Kissoondoyal Ashby , Malkin David 
Published: September 2024

Abstract
Li-Fraumeni Syndrome (LFS) is a genetic predisposition disorder associated with pathogenic germline Tp53 mutations. A subset of LFS-associated neoplasms occurs at an increased risk within the first 5 years of life, with the most common being soft tissue sarcomas (STS). Histological characterization of STS is one of the primary approaches to guiding treatment. However, the heterogeneity of STS has necessitated a further understanding of the molecular etiology of these tumors. Examining sarcomas using a single-cell transcriptomic approach has shown unique subsets of cells with dysregulations in cell fate and differentiation. Within LFS-associated tumors, including LFS-STS a major event in tumorigenesis is the copy-neutral loss of heterozygosity (LOH). LOH was determined to occur much earlier than cancer onset in LFS, suggesting a dormancy period from the LOH until tumorigenesis; cancer-defining events in LFS are likely occurring prenatally. During embryogenesis, Tp53 is involved in differentiation and pluripotency regulation, as well as cell cycle control and apoptosis. Here we hypothesize that the emergence of STS in LFS mice is associated with distinct disturbances in the cell fate and differentiation pathways. Specifically, there will be deficits in cell fate determination and the organization of cells across multiple cell types in LFS-Sarcomas. Single-cell RNAseq was performed on spontaneous tumors and healthy matched muscle tissue from male and female C57BL/6J Trp53R172H/WT mice. Cell types were determined based on differential gene expression between clusters defined by principal component analysis. Despite tumor heterogeneity between mice, there were consistent disruptions of developmental pathways among tumor cells. Moreover, when comparing matched cell types across tumor and healthy muscle tissue we observed dysregulation of pathways promoting tumorigenesis, and cell fate determination in cells originating from tumor tissue. For the first time to our knowledge, this study examines the single-cell transcriptome of LFS-STS. Current literature has speculated on the presence of an early precancer state of LFS-associated tumors. This study will provide evidence to determine whether this precancer state can be determined in tumor samples, and identify elements that constitute this state. Moreover, we will determine changes in supporting non-tumor cells and whether they also exhibit dysregulations in cell state and differentiation. Together these findings will hopefully contribute to improvements in molecular subtyping across STS, and particularly within LFS individuals.
Citation Format: Ashby Kissoondoyal, David Malkin. Single cell transcriptomic signature of Li-Fraumeni Syndrome soft tissue sarcomas [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A009.
Abstract A043 Plasma circulating proteomic markers are associated with metastatic spread and outcome in osteosarcoma
Authors: Audinot Baptiste , Drubay Damien , Da Costa Maria Eugenia , Beaudry Gael Moquin , Jimenez Marta , Geoerger Birgit , Gaspar Nathalie , Abbou Samuel , Marchais Antonin 
Published: September 2024

Abstract
Background: Osteosarcoma is the most frequent bone cancer in children and young adults. Histological response and control of primary metastases are the main prognostic clinical factors, but are insufficient to identify the ∼30% of hard-to-treat patients and are not predictive of the response to combinations of chemotherapies or biological treatments. Our aim was to evaluate if circulating proteomic analyses could predict tumor progression. Methods: 88 plasma samples from newly diagnosed patients with osteosarcoma in the OS2006 trial were sequenced using the OLINK Explore panel (3072 proteins) and 88 more coming from the SARCOME13 trial will be used as a validation cohort. Results: Principal component analysis defined co-circulating proteins associated to critical biological pathways involved in osteosarcoma oncogenesis, such as cell adhesion, cell survival/growth, bone formation and extracellular matrix organization. Cox survival analysis associated circulating bone formation pathway with OS(HR=1.10 [1.03;1.17], p=0.006) and PFS(HR=1.12 [1.05;1.19], p=&lt;0.001). These circulating pathways were also associated with presence of metastases at diagnosis (odd ratio = 1.33 [1.12;1.72], p=0.006). These results are being validated on SARCOME13 data. Conclusion: Proteomic plasma markers quantification in patients with osteosarcoma at diagnosis capture a biological signal significantly associated to prognosis and the presence of metastasis at diagnosis.
Citation Format: Baptiste Audinot, Damien Drubay, Maria Eugenia Da Costa, Gael Moquin Beaudry, Marta Jimenez, Birgit Geoerger, Nathalie Gaspar, Samuel Abbou, Antonin Marchais. Plasma circulating proteomic markers are associated with metastatic spread and outcome in osteosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A043.
Abstract A062 Therapeutic targeting of the SAGA KAT module impairs MYCN-amplified neuroblastoma growth through reduction of the MYCN oncogenic gene expression program
Authors: Mabe Nathaniel W. , Malone Clare F. , Forman Alexandra B. , Alexe Gabriela , Engel Kathleen L. , Chen Ying-Jiun C. , Soeung Melinda , Salhotra Silvi , Basanthakumar Allen , Liu Bin , Dent Sharon YR , Stegmaier Kimberly 
Published: September 2024

Abstract
Pediatric cancers are frequently driven by genomic alterations that result in aberrant transcription factor activity. While direct targeting of transcription factors is difficult, one method to circumvent this problem is to target co-factors and chromatin complexes that are necessary for their oncogenic function. To evaluate protein complex dependencies enriched in MYCN-amplified neuroblastoma, a disease of dysregulated development driven by aberrant expression of an oncogenic expression program, we curated a list of protein complexes using the CORUM database and mined the Dependency Map using single sample gene set enrichment analysis. This analysis identified the KAT module of the transcriptional coactivator Spt-Ada-Gcn5-acetyltransferase (SAGA) complex as a selective dependency in MYCN-amplified neuroblastoma. Loss of SAGA complex activity in neuroblastoma through both genetic knockout and induced protein degradation of the lysine acetyltransferase (KAT) module subunit TADA2B resulted in a global reduction of histone lysine acetylation and impaired neuroblastoma cell growth. Genetic knockout of TADA2B did not impair the growth of pediatric sarcoma cell lines, suggesting that SAGA loss-of-function is not broadly deleterious. Furthermore, SAGA loss-of-function reduced MYCN binding to chromatin, resulting in suppression of the MYCN-driven gene expression program and impaired cell cycle progression. Importantly, the SAGA complex is pharmacologically targetable in vitro and in vivo with GSK-699, a PROTAC that induces proteolysis of both KAT2A and KAT2B paralogs. As observed with genetic knockout studies, loss of SAGA activity through KAT2A/B degradation reduced the MYCN-driven transcriptional signature and impaired cell cycle progression. Our findings expand our understanding of the chromatin complexes that maintain the oncogenic transcriptional state in MYCN-amplified neuroblastoma and suggest therapeutic potential for inhibitors of SAGA KAT activity in MYCN-amplified neuroblastoma.
Citation Format: Nathaniel W. Mabe, Clare F. Malone, Alexandra B. Forman, Gabriela Alexe, Kathleen L. Engel, Ying-Jiun C. Chen, Melinda Soeung, Silvi Salhotra, Allen Basanthakumar, Bin Liu, Sharon YR Dent, Kimberly Stegmaier. Therapeutic targeting of the SAGA KAT module impairs MYCN-amplified neuroblastoma growth through reduction of the MYCN oncogenic gene expression program [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A062.
Abstract A073 Epigenetic control of neuroblastoma differentiation through inhibition of the histone acetyltransferases KAT6A and KAT6B
Authors: Weichert-Leahey Nina , Look Thomas 
Published: September 2024

Abstract
Retinoic acid re-organizes the enhancers regulating the expression of these key transcription factors in neuroblastoma and establishes a new differentiated cell state characterized by MYCN downregulation and proliferative arrest. However, the epigenetic and growth suppressing effects of retinoic acid are completely reversible in vitro, leading to cell proliferation. We sought to determine if retinoid-induced differentiation can be forced to progress to terminal neuronal maturation by the addition of inhibitors of enzymes modifying the epigenome. We conducted a drug screen using more than 450 epigenetic modifiers to treat neuroblastoma cells either with each compound alone or in combination with retinoic acid to determine whether any compound augments the antiproliferative effects of retinoic acid. We found that an inhibitor of the histone acetyltransferases KAT6A/B synergistically inhibits neuroblastoma growth in combination with retinoic acid in vitro and enhances neuroblastoma differentiation. We used a xenograft model of retinoid-sensitive neuroblastoma cells in mice to test if the combination treatment with isotretinoin and a KAT6 inhibitor is more effective than isotretinoin alone to induce permanent neuroblastoma differentiation in vivo. We found that isotretinoin is very effective in suppressing neuroblastoma proliferation, however its effects are completely reversible upon drug removal leading to rapid tumor re-growth. In contrast, when isotretinoin is combined with a KAT6 inhibitor, tumors cannot re-grow after isotretinoin removal and remain differentiated. In conclusion, our studies nominate KAT6A/B inhibition combined with isotretinoin as a promising approach to improve outcome for patients with neuroblastoma.
Citation Format: Nina Weichert-Leahey, Thomas Look. Epigenetic control of neuroblastoma differentiation through inhibition of the histone acetyltransferases KAT6A and KAT6B [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A073.
Abstract A080 PRC1/BMI1 activity alters chromatin accessibility to regulate differentiation in atypical teratoid rhabdoid tumors
Authors: Alimova Irina Irina , Murdock Gillian , Pierce Angela M. , Wang Dong , Dahl Nathan , Venkataraman Sujatha , Vibhakar Rajeev 
Published: September 2024

Abstract
Atypical Teratoid Rhabdoid Tumor (ATRT) is a highly aggressive pediatric brain tumor and characterized by SMARCB1 deletion. SMARCB1 is a member of the SWI/SNF chromatin remodeling complex that is responsible for determining cellular pluripotency and lineage commitment. We performed an RNAi-based functional genomic screen to identify key epigenetic regulators that co-operate with SMARCB1 loss and contribute to tumorigenesis in ATRT. 406 genes associated with epigenetic regulation in patient derived ATRT cell lines were targeted. This screen identified BMI1, a component of the Polycomb Repressive Complex 1 (PRC1), as one of the top targets essential for ATRT cell growth. Using RNA-seq and ChIP-Seq analysis we demonstrated that BMI1 co-operates with SMARCB1 deletion to suppress transcription of pro-differentiation pathways and promote self-renewal of tumor stem cells. In SMARCB1 deficient cells BMI1 forms a partial PRC1 complex devoid of DNA binding components. We found that genetic inactivation of BMI1 suppresses ATRT cell clonogenicity in vitro and decreases S-phase length. By Doxycycline-inducible SMARCB1 re-expression system we revealed activation of proapoptotic proteins p16 and p21. With immunoprecipitation for BMI1, followed by mass spectrometry analysis we demonstrated that re-expression of SMARCB1 activates two PRC1 chromatin localizing components CBX4 and CBX8. Moreover, inhibition of BMI1 significantly prolongs mice survival and decreases tumor size as evaluated by IVIS imaging system and T2-MRI. Thus, we demonstrated that SMARCB1 deletion results in reprograming of BMI1 chromatin occupancy away from lineage specification by altering the components of the PRC1 complex and that PRC1/BMI1 inhibition is a novel therapeutic approach in ATRT.
Citation Format: Irina Irina Alimova, Gillian Murdock, Angela M. Pierce, Dong Wang, Nathan Dahl, Sujatha Venkataraman, Rajeev Vibhakar. PRC1/BMI1 activity alters chromatin accessibility to regulate differentiation in atypical teratoid rhabdoid tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A080.
Abstract B008: Decoding the primary site-specific regulation of rhabdomyosarcoma metastasis
Authors: Hebron Katie E. , Isanogle Kristine , Edmondson Elijah F. , James Amy , Difilippantonio Simone , Yohe Marielle E. 
Published: September 2024

Abstract
The prognosis for patients with high-risk rhabdomyosarcoma (RMS), a pediatric sarcoma characterized in part by defective skeletal muscle (myogenic) differentiation, has remained stagnant at &lt;30% for over forty years. With &gt;15% of patients presenting at diagnosis with metastasis, a defining factor of high-risk disease, there is an urgent need for new therapies. Some primary tumor locations are associated with a higher incidence of metastasis and poorer outcomes. However, the biology (and potential for therapeutic intervention) driving this prognostic factor is poorly defined.To analyze the influence of the primary tumor location on RMS invasion and metastasis, we evaluated cell line xenografts (CDX) implanted in a favorable site, the tongue, versus an unfavorable site, the hindlimb. We evaluated invasion and metastasis from each primary tumor site by histopathology and measured gene expression changes by bulk RNAseq.Despite the tongue being deemed a favorable primary site, perineural invasion or intravascular tumor emboli (60% versus 0%), sentinel lymph node metastasis (25-100% versus 0%), and clinically significant lung metastases (&gt;10% lung area or symptomatic mice; 20% versus 0%) were observed more frequently in tongue xenograft-bearing mice than hindlimb xenograft-bearing mice. The expression of myogenic differentiation markers is higher in tongue CDX than in hindlimb CDX, but expression of these markers is reduced upon metastasis. These phenotypes are maintained when cells are returned to 2D culture, suggesting a stable shift in the differentiation state. Interestingly, CDX of sentinel lymph node metastasis-derived cells were more invasive and metastatic than parental CDX when implanted in the tongue, but not when implanted in the hindlimb.Our work, the first direct evaluation of RMS invasion and metastasis by primary tumor location, demonstrates that the primary tumor location influences RMS metastasis and that tumor cell-intrinsic properties alone are insufficient to increase invasion and metastasis. Ongoing work aims to identify the mechanisms by which the primary tumor microenvironment regulates invasion, enhancing our understanding of the biology of RMS metastasis and offering an opportunity to employ a precision medicine-based approach to targeting metastasis.
Citation Format: Katie E. Hebron, Kristine Isanogle, Elijah F. Edmondson, Amy James, Simone Difilippantonio, Marielle E. Yohe. Decoding the primary site-specific regulation of rhabdomyosarcoma metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B008.
Abstract B046: Addressing inequities in pediatric solid tumors: Insights from Hispanics in Puerto Rico
Authors: Ruiz-Perez Carolyn M. , Rivera-Valentín Rocío K. 
Published: September 2024

Abstract
Introduction: Pediatric solid tumors are a diverse group of rare cancers that occur in children. Recent advancements in therapy, such as immunotherapy, targeted therapy, and precision medicine, have shown promise in improving treatment outcomes for these cancers. Moreover, health disparities in the incidence and mortality rates of pediatric solid tumors have been reported between US racial/ethnic groups, where Hispanics and African ethnicities present higher rates of incidence and metastatic disease. Despite disparities observed in pediatric solid tumors among US Hispanics, no information exists for Puerto Rican Hispanic children with cancer. Thus, this study aims to understand and describe the epidemiology of a Hispanic population of pediatric patients diagnosed with solid tumors living in Puerto Rico. Methods: Age-adjusted incidence rates (IR) and mortality rates (MR) for specific childhood cancers (ages 0-19) were estimated using data obtained from the Incidence Case File from the Puerto Rico Central Cancer Registry for the period 2009-2020. Results: During this period, 666[MS1]pediatric patients were diagnosed with cancer, with malignant bone tumors comprising 4.7% of cases and with an age-adjusted incidence rate of 6.0 cases per million. Among pediatric patients with malignant bone tumors, 34.6% presented with regional disease and 23.1% presented with distant metastatic disease at diagnosis. The mortality rate for pediatric cancers involving bone and joints was 2.4 cases per million. Conclusions: This is a first-of-its-kind analysis in a Hispanic cohort of pediatric solid tumor patients in Puerto Rico. Understanding the disparities in solid pediatric tumors within this Hispanic population is crucial for developing targeted interventions that improve diagnosis, treatment, and survival rates for these children who face other disparities, including limited access to specialized care and economic barriers, among others. Publishing this data is essential as it raises awareness, guides resource allocation, and informs policy decisions to address healthcare inequities. Future studies should explore risk factors and differential gene expression. Acknowledgement: The authors extend gratitude to the Biostatistics and Bioinformatics Core of the UPR Comprehensive Cancer Center and the PR Central Cancer Registry for collaborating in our research.
Citation Format: Carolyn M. Ruiz-Perez, Rocío K. Rivera-Valentín. Addressing inequities in pediatric solid tumors: Insights from Hispanics in Puerto Rico [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B046.
Abstract B078: Rapid PTEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy
Authors: Walker Faye M. , Sobral Lays Martin , Danis Etienne , Sanford Bridget , Balakrishnan Ilango , Wang Dong , Pierce Angela , Karam Sana , Serkova Natalie J. , Foreman Nicholas K. , Venkataraman Sujatha , Dowell Robin , Vibhakar Rajeev , Dahl Nathan A. 
Published: September 2024

Abstract
Background: Dynamic regulation of gene expression is fundamental for cellular adaptation to exogenous stressors. PTEFb-mediated promoter proximal pause-release of Pol II is a conserved regulatory mechanism for synchronous transcriptional induction best described in response to heat shock, but this pro-survival role has not been examined in the applied context of cancer therapy. Design/Method: In order to examine the dynamics of chromatin reorganization following radiotherapy, we performed a combination of ChIP-, ATAC-, and RNA-seq in model systems of diffuse intrinsic pontine glioma (DIPG) and other pediatric high-grade gliomas (pHGG) following IR exposure. We interrogated IR-induced gene expression in the presence or absence of PTEFb blockade, including both mechanistic and functional consequences of concurrent inhibition or genetic depletion. We utilized culture models with live cell imaging to assess the therapeutic synergy of PTEFb inhibition with IR, as well as the therapeutic index of this intervention relative to normal controls. Finally, we employed orthotopic models of pHGG treated with conformal radiotherapy and CNS-penetrant PTEFb inhibitors in order to assess tolerability and anti-tumor effect in vivo. Results: Rapid genome-wide redistribution of active chromatin features and PTEFb facilitates Pol II pause-release to drive nascent transcriptional induction within hours of exposure to therapeutic ionizing radiation. Concurrent inhibition of PTEFb imparts a transcription elongation defect, abrogating canonical adaptive programs such as DNA damage repair and cell cycle regulation. This combination demonstrates a potent, synergistic therapeutic potential agnostic of glioma subtype, leading to a marked induction of tumor cell apoptosis and prolongation of xenograft survival.Conclusion: These studies reveal a central role for PTEFb underpinning the early adaptive response to radiotherapy, opening new avenues for combinatorial treatment in these lethal malignancies.
Citation Format: Faye M. Walker, Lays Martin Sobral, Etienne Danis, Bridget Sanford, Ilango Balakrishnan, Dong Wang, Angela Pierce, Sana Karam, Natalie J. Serkova, Nicholas K. Foreman, Sujatha Venkataraman, Robin Dowell, Rajeev Vibhakar, Nathan A. Dahl. Rapid PTEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B078.