tbuckley/cabot-search huggingface dataset:
Abstract 5514: Crosstalk between prostatic epithelial cells and the tumor microenvironment drives cancer progression and metastasis
Authors: Darya Yanushko, Beatriz German Falcon, Céline Keime, Tao Ye, Christelle Thibault-Carpentier, Daniel Metzger, Gilles Laverny
Journal: Cancer Research (2024)

Abstract Prostate cancer is a heterogeneous disease with a slow progression and a highly variable clinical outcome. Recent advances in the clinical handling of localized prostate cancers resulted in an almost 100% 10-year survival, but no curative treatment is currently available for metastatic disease. Thus, understanding the molecular mechanisms of progression of primary tumors to metastasis is crucial to develop new therapeutic strategies. While tumorigenesis initiates in prostatic epithelial cells, various cell types, including cancer associated fibroblasts (CAFs), immune and endothelial cells produce extra-cellular matrix and secrete signaling molecules that might contribute to tumor progression. However, the complex communication network driving tumor progression is poorly characterized. As the tumor suppressors PTEN and TP53 are among the most frequently altered genes in prostate cancer, we generated genetically engineered mice with Pten and Trp53 selective inactivation in prostatic epithelial cells at adulthood. Their analysis revealed that they develop precancerous lesions that progress to invasive and metastatic tumors. Spatial transcriptomic and single-cell analyses of Pten- and Trp53-deficient prostatic tumors identified the presence of a cancer cell population exhibiting cell plasticity driven by Jak/Stat3 signaling and induced by CAF-produced IL6. In addition, these tumors exhibit a hypoxic core and an immune infiltrate dominated by neutrophils. Inhibition of the hypoxic signaling reduced immune infiltration in primary tumors and their metastatic potential, but did not induce apoptosis of Pten- and Trp53- deficient epithelial cells, in contrast to those of Pten-deficient tumors. These results underline the importance of the tumor genomic background for therapeutic intervention. Taken together, our work highlights the key role of the tumor microenvironment in driving prostate cancer progression and uncovers new vulnerabilities of this disease. Citation Format: Darya Yanushko, Beatriz German Falcon, Céline Keime, Tao Ye, Christelle Thibault-Carpentier, Daniel Metzger, Gilles Laverny. Crosstalk between prostatic epithelial cells and the tumor microenvironment drives cancer progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5514.
Abstract 152: Exploring the impact of heat shock protein 90 on the antitumor efficacy and stemness in medulloblastoma cells
Authors: Shu-Mei Chen, Hsieng-Yun Huang, Chien-Kai Wang, Yi-Yuan Yang, Sy-Jye Leu, Ying-Ying Li
Journal: Cancer Research (2024)

Abstract Background: Medulloblastoma (MB) is the most common children’s malignant brain tumor. Although MB can be treated with conventional chemotherapies, chemoresistance has been frequently developed and thereby hampers their therapeutic effectiveness. The preliminary reports of our research showed that some heat shock proteins have higher levels in MB cells. Among these heat shock proteins, HSP70 and HSP90 expressions are particularly high in MB CD133+ cancer stem cells (CSCs), which arouses our attention and interest. Numerous studies demonstrated that heat shock proteins are prominent in some chemotherapy-resistant cancer cells and CSCs. As known HSP90 and its client proteins are required for the maintenance of self-renewal/stemness and regulation of cell cycle, synergistic killing of cancer cells by simultaneous inhibition of HSP90 expression and activity may be a considerable good therapeutic strategy for treating MB. The purpose of this study is to verify the regulatory function of HSP90 in chemoresistance and stemness of MB. Materials and Methods: The levels of HSP90, its client proteins (P13K/pAKT, Erk, NFκB, and c-Myc), and stemness makers were detected using immunoblotting and immunoprecipitation after the treatment of HSP90 inhibitor (17-AAG) or knockdown of HSP90 by siRNA in MB and MB CSCs. The antitumor effects of HSPs inhibitors or knockdown of HSPs on these cells were evaluated by MTT assay, Annexin V/PI analysis and cell cycle analysis. Results: Our findings revealed elevated expression of HSP90 and its target client proteins in MB cells compared to normal astrocytes. Silencing or inhibiting HSP90 expression induced cell cycle arrest in MB cells. Notably, CD133+ MB CSCs exhibited higher HSP90 levels than parental MB cells. Inhibition of HSP90 led to reduced sphere formation and expression of stemness markers in CD133+ MB CSCs. Treatment with 17-AAG demonstrated antitumor activity in CD133+ MB CSCs, and a synergistic effect was observed when combining conventional chemotherapeutic agents with 17-AAG in MB cells Conclusion: These results illustrated that inhibition of HSP90 could eliminate CSCs, and thereby overcome resistance to chemotherapeutic agents in MB. Chemotherapies in combination with HSP90 blockade may be an emerging MB therapy in the future. Citation Format: Shu-Mei Chen, Hsieng-Yun Huang, Chien-Kai Wang, Yi-Yuan Yang, Sy-Jye Leu, Ying-Ying Li. Exploring the impact of heat shock protein 90 on the antitumor efficacy and stemness in medulloblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 152.
Abstract 6599: 3D genomic analysis reveals novel enhancer hijacking mechanisms caused by complex structural alterations that drive oncogene overexpression
Authors: Katelyn L. Mortenson, Courtney Dawes, Emily R. Wilson, Nathan E. Patchen, Hailey Johnson, Jason Gertz, Swneke D. Bailey, Yan Liu, Katherine E. Varley, Xiaoyang Zhang
Journal: Cancer Research (2024)

Abstract Enhancer hijacking, caused by structural alterations on chromosomes as well as extrachromosomal DNA (ecDNA), is a common cancer driver event. The complexity and ubiquity of structural alterations in cancer genomes make it difficult to identify enhancer hijacking with genome sequencing alone. Here we describe a 3D genomics-based analysis called HAPI (Highly Active Promoter Interactions) to characterize enhancer hijacking caused by various types of structural alterations. Applying HAPI analysis to HiChIP data from 34 cancer cell lines, we identified novel enhancers hijacked through chromosomal rearrangements to activate both known and potentially novel oncogenes such as MYC, CCND1, ETV1, CRKL, and ID4, which we validated using CRISPRi assays and RNA-seq analysis. Furthermore, we found that ecDNAs often contain multiple oncogenes from different chromosomes, which cause nested enhancer hijacking among them. For instance, we found that MYC ecDNAs relocate additional oncogenes from other chromosomes such as CDX2, ERBB2, or CD44 near the MYC locus, co-opting MYC’s enhancers for their overexpression, which we validated using dual-color DNA FISH and CRISPRi assays. This multiple oncogenes-involved enhancer hijacking mechanism may suggest novel therapeutic strategies such as targeting either the co-opting oncogenes or the hijacked enhancers for ecDNAs. Our study provides a robust strategy to detect enhancer hijacking events using our publicly available HAPI analysis tool and reveals novel mechanisms underlying oncogene activation caused by chromosomal and extrachromosomal structural alterations. Citation Format: Katelyn L. Mortenson, Courtney Dawes, Emily R. Wilson, Nathan E. Patchen, Hailey Johnson, Jason Gertz, Swneke D. Bailey, Yan Liu, Katherine E. Varley, Xiaoyang Zhang. 3D genomic analysis reveals novel enhancer hijacking mechanisms caused by complex structural alterations that drive oncogene overexpression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6599.
Abstract 2317: Development and validation of a colorectal cancer prediction model: A nationwide cohort-based study
Authors: Samah Hayek
Journal: Cancer Research (2024)

Abstract Background: Colorectal cancer (CRC) ranks as the third most prevalent cancer globally and is a major cause of cancer-related mortality. Early diagnosis is critical to increase survival rates. While CRC screening has shown significant benefit, adherence remains low, and there is a need for better tools to identify high-risk patients. Risk prediction models were demonstrated to identify such patients. Aim: To establish an individualized risk prediction model for CRC diagnosis based on Electronic Health Records (EHR). Methods: This is a retrospective cohort study utilizing EHR data of Clalit Health Services (CHS) members aged 50-74 that were eligible for CRC screening, from January 2013 to January 2019. The model was trained to predict CRC diagnosis within two years using approximately 20,000 EHR features including socio-demographic information, laboratory results and medical history. Model performance, as a complementary screening method, was evaluated. Results: The study included 2679 subjects with CRC diagnosis and 1,133,713 subjects without CRC diagnosis. The model was trained on subjects from 2013-2017, and performance was validated on subjects from 2019 and a cohort of subjects that underwent fecal occult blood test (FOBT). Incidence values of CRC among subjects in the top 1% risk scores were higher than baseline (2.3% vs. 0.3%; lift 8.38; P-value &amp;lt;0.001). Characteristics of subjects by risk scores percentiles are presented in Table 1. Cumulative event probabilities increased with higher model scores, indicating a correlation between predicted and actual risk of CRC diagnosis. Model-based risk stratification among subjects with a positive FOBT, identified subjects with more than twice the risk for CRC compared to FOBT alone. Conclusions: We developed an individualized risk prediction model for CRC that can be utilized as a complementary decision support tool for healthcare providers to precisely identify patients at high risk for CRC and refer them to confirmatory testing. Citation Format: Samah Hayek. Development and validation of a colorectal cancer prediction model: A nationwide cohort-based study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2317.
Abstract 1787: The β3-adrenergic receptor as novel target of metabolic phenotype in Ewing sarcoma
Authors: Cristina Banella, Francesco Carrozzo, Laura Zocca, Amada Pasha, Gianluca Mattei, Marina Mola, Lara Ballerini, Nicla Lorito, Annalisa Tondo, Claudio Favre, Maura Calvani
Journal: Cancer Research (2024)

Abstract Purpose of study: Metabolic targeted therapies may represent an innovative strategy in Ewing sarcoma (ES). Introduction: Ewing sarcoma (ES) is highly aggressive round cell mesenchymal neoplasm, most often occurring in children and young adults. Metabolic peculiarities of ES cells are indeed involved in tumor growth, survival and resistance to therapy. We have further investigated apoptotic role of 𝜷;;3-adrenergic receptor (𝜷;;3-AR) SR59230A (SR) antagonist for its ability to reduce cells viability due increased oxidative stress, now we underline the metabolic role of SR. Materials &amp; Methods: The metabolic profile after SR administration in A673 ES cell model was studied using the Seahorse XF Analyzer. Viability was evaluated with MTS. Changes in gene expression was evaluated with RNA sequencing. Western blot analysis and Immunofluorescence was performed for redox signature and metabolic alteration. Ros production and cell death was assessed by flow cytometry. Results: Metabolic analysis reveals glucose and fatty acid dependency in A673 cells using the Fuel Flex Test of Seahorse XFe Analyzer. Quantification of transcript abundance using Salmon in A673 after SR treatment showed decrease in response to reactive oxygen species, increase of Thioredoxin Interacting Protein (TXNIP) inhibits the antioxidative function of thioredoxin, moreover reduced glucose uptake, consequently, decrease NADPH/NADP resulting in the accumulation of ROS coincident with a decrease of GLUT1, SOD2, TrDX an increase of LC3IIA protein expression. SR enhances A673 pyruvate dependency, and decrease glyco and mito ATP production rate, more over observed under glucose deprivation. Furthermore, apoptotic effect was significantly amplified when cells were under nutrient starvation, revealing a 56% apoptotic rate after 24 hours of SR treatment. Conclusion: SR antagonist of 𝜷;;3-AR and combination of SR with BUF could be an innovative therapeutic option to raise awareness ES. Citation Format: Cristina Banella, Francesco Carrozzo, Laura Zocca, Amada Pasha, Gianluca Mattei, Marina Mola, Lara Ballerini, Nicla Lorito, Annalisa Tondo, Claudio Favre, Maura Calvani. The β3-adrenergic receptor as novel target of metabolic phenotype in Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1787.
Abstract 1996: Novel mechanism of temozolomide resistance in glioblastoma
Authors: Yuet Yi Charmaine Hung, Mei Yee Karrie Kiang, Ka Kit Gilberto Leung
Journal: Cancer Research (2024)

Abstract Intrinsic expression of PD-1 has been discovered in different types of tumurs, exhibiting either oncogenic or tumor-suppressing function. In glioblastoma (GBM), intrinsic PD-1 has been found to play a role in promoting the proliferation and self-renewal of brain tumor-initiating cells through nuclear factor κB without involving PD-L1 ligation, with unknown factors activating this signalling pathway. Meanwhile, TMZ resistance significantly contributes to treatment failure and an extremely poor prognosis for GBM. This study investigated whether intrinsic PD-1 is also expressed in differentiated human GBM cell lines and its role in GBM proliferation and temozolomide (TMZ) resistance. In vitro studies demonstrated the presence of PD-1 in both U87 and U251 TMZ-sensitive and -resistant cell lines, with a higher expression on TMZ-resistant cell lines. PDCD1 knockdown led to decreased GBM progression, including cell proliferation, colony formation and cell migration, in TMZ-resistant U87 and U251 cell lines using cell viability assays. It also resensitizes these cell lines to TMZ. Overexpression of PDCD1 in the PDCD1-knockdown cell lines increases their proliferation and restores their resistance to TMZ. Treatment of U87 and U251 TMZ-resistant cell lines with TMZ upregulated PD-1 expression. An orthotopic xenograft mouse model is further deployed by injecting previously cultured U87 and U251 cell lines into the mouse brains. A smaller tumour size is observed in the model with PDCD1 knockdown model than the one without PDCD1 knockdown when treated with TMZ. This study reveals that intrinsic PD-1 expression contributes to TMZ resistance in GBM and TMZ may be a factor activating the PD-L1-independent PD-1 signalling. PD-1 and its downstream signalling pathway, such as SHP-2 and IKK, may be potential therapeutic targets for GBM patients with TMZ resistance. Co-administration of TMZ and agents inhibiting the intrinsic PD-1 signalling pathway can potentially produce synergistic therapeutic effects. The higher expression of PD-1 on TMZ-resistant GBM than on TMZ-sensitive GBM also suggests that the intrinsic PD-1 level can be a predictor of TMZ outcome. Citation Format: Yuet Yi Charmaine Hung, Mei Yee Karrie Kiang, Ka Kit Gilberto Leung. Novel mechanism of temozolomide resistance in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1996.
Abstract 6590: Novel WRN helicase inhibitors selectively target microsatellite unstable cancer cells
Authors: Gabriele Picco, Yanhua Rao, Angham Al Saedi, Sara F. Vieira, Yang Lee, Ray Shenje, Shriram Bhosle, Samantha Walker, Kieron May, Carmen Herranz-Ors, Cansu Dicer, Freddy Gibson, Ruby Banerjee, Thilo Werner, Josh Cottom, Yang Peng, Nanhua Deng, Phil Landis, Thomas Angel, Jacob Bush, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Howard Lightfoot, Francesca Zappacosta, Jonathan Pettinger, Syd Barthorpe, Chris Eberl, Brian Jones, Jess Schneck, Dennis Murphy, Josh Taygerly, Mike DeMartino, Matthew Coelho, Jon Houseley, Benjamin Schwartz, Mathew J. Garnett
Journal: Cancer Research (2024)

Abstract Microsatellite-unstable (MSI) cancers depend on the WRN helicase to resolve replication stress from expanded (TA)-dinucleotide repeats. WRN is a promising synthetic lethal target for MSI tumours and WRN inhibitors are being developed. Here, we used CRISPR-Cas9 base editing to map WRN residues critical for MSI synthetic lethality, validating the helicase domain as the primary target and guiding inhibitor discovery. Fragment-based screening led to the discovery of potent and highly selective WRN helicase covalent inhibitors from the same chemical series. These compounds strikingly and selectively suppressed MSI model growth in vitro and in vivo by mimicking genetic WRN loss, inducing DNA double-strand breaks at expanded TA repeats and DNA damage response. We characterized WRN inhibition across cancer cell lines and patient-derived tumour organoids, enabling biomarker assessment of TA-repeat expansions and MMR status to refine patient selection, with compound efficacy correlating with TA-repeat expansions in MSI cells. Efficacy was also confirmed in patient-derived organoids and PDX models refractory to immunotherapy. The discovery of potent and selective covalent WRN inhibitors provides proof-of-concept for targeting MSI cancers and provides tools to unlock the molecular dissection of the WRN biology and MSI synthetic lethality. Citation Format: Gabriele Picco, Yanhua Rao, Angham Al Saedi, Sara F. Vieira, Yang Lee, Ray Shenje, Shriram Bhosle, Samantha Walker, Kieron May, Carmen Herranz-Ors, Cansu Dicer, Freddy Gibson, Ruby Banerjee, Thilo Werner, Josh Cottom, Yang Peng, Nanhua Deng, Phil Landis, Thomas Angel, Jacob Bush, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Howard Lightfoot, Francesca Zappacosta, Jonathan Pettinger, Syd Barthorpe, Chris Eberl, Brian Jones, Jess Schneck, Dennis Murphy, Josh Taygerly, Mike DeMartino, Matthew Coelho, Jon Houseley, Benjamin Schwartz, Mathew J. Garnett. Novel WRN helicase inhibitors selectively target microsatellite unstable cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6590.
Abstract 1527: Exploring the role of tertiary lymphoid structure in the tumor microenvironment of cholangiocarcinoma
Authors: Shin-Yi Chung, Ming-Huang Chen, Yi-Chen Yeh, Yu-Chan Chang, Yu-Cha Wang
Journal: Cancer Research (2024)

Abstract Cholangiocarcinoma is the second most common hepatobiliary malignant tumor besides liver cancer, grows from bile duct epithelial cells. However, surgery is the only hope for most patients with cholangiocarcinoma, but the effectiveness of treatment is not outstanding. Even though other methods of treatment, such as chemotherapy and radiation therapy, have limited effects. The immunotherapy and precision treatment have become the latest expectations of patients. Here, we analyzed the TCGA and GEO database to classify the cold and hot tumor using hierarchical clustering. The MCP counter results demonstrated that two genes, MS4A1 and CD79A, could identify the hot and cold tumor subgroups after TCGA data training and similar results show in GEO database. We also performed the tissue array for 105 cholangiocarcinoma tissue samples and found patients with high expression levels of MS4A1 or CD79A have better disease free survival (DFS) and progression free survival (PFS) (p value =0.0131 and 0.0017). In addition, we tested the tertiary lymphoid structures (TLS) signatures in tissue array sections, which is associated with the present of MS4A1 and CD79A. The results shows that patients who received the immunotherapy with TLS signatures have longer overall survival (OS) and PFS (p value =0.017 and 0.006). Collectively, B cell lineages or TLS could be an ideal biomarker to lead the clinical treatment and wish can broader applications in other diseases. Citation Format: Shin-Yi Chung, Ming-Huang Chen, Yi-Chen Yeh, Yu-Chan Chang, Yu-Cha Wang. Exploring the role of tertiary lymphoid structure in the tumor microenvironment of cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1527.
Abstract 1521: Chromatin remodeler ACTL6A in CD8+ T cells promotes antitumor immunity
Authors: Bogang Wu, Win Thant, Elena Bitman, Ting Liu, Leif W. Ellisen
Journal: Cancer Research (2024)

Abstract Chromatin remodeling plays a pivotal role in dictating epigenetic and transcriptomic regulation governing cytotoxic T lymphocyte differentiation and effector function. However, the regulatory mechanisms underlying chromatin remodeler assembly and actions remains unclear. Actin-like gene family members have been implicated in the organization of chromatin landscapes, however their role in T cell functional regulation remains unknown. We identified Actin-like protein 6A/Actl6a as the most upregulated gene within actin-like family members upon CD8+ T cell activation across multiple species. Additionally, ACTL6A is highly expressed in human tumor-infiltrating CD8+ mitotic tissue-resident memory T cells, suggesting a functional importance of ACTL6A in this subset. Deletion of mouse Actl6a in mature T lymphocytes impairs immune responses to transplanted syngeneic mouse tumors. T cell-specific Actl6a deletion mice exhibit a reduced effector memory population and attenuated cytotoxicity in their tumor infiltrating CD8+ T cells. Heterozygous deletion of Actl6a displays an intermediate reduction of effector memory population and cytotoxicity between that of wildtype and homozygous knockout, indicating that ACTL6A acts in a dose-dependent manner to promote CD8+ effector cell fate. T cell adoptive transfer further corroborates a CD8+ T cell-intrinsic role of Actl6a on antitumor adaptive immunity. Currently, we are investigating the chromatin landscape and transcriptomic changes upon loss of Actl6a using ATAC-seq and RNA-seq. Furthermore, the dose dependency of Aclt6a on CD8+ T cell effector function suggests that pharmacological or genetic approaches to increase Actl6a expression in CD8+ T cells may have the potential to boost immune based anticancer therapies including CAR-T therapies. Citation Format: Bogang Wu, Win Thant, Elena Bitman, Ting Liu, Leif W. Ellisen. Chromatin remodeler ACTL6A in CD8+ T cells promotes antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1521.