bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5420: NLRX1 involves in prostate cancer cell growth, survival and migration
Authors: Lin Wan-Wan , Rathore Varsha 
Published: March 2024

Abstract
Prostate cancer (PCa) is one of the most common male cancer and is the second leading cause of death in men. The basic working components about its cause and progression are not surely known in the research as well as the practitioner community. The current curing therapies such as surgery, radiation therapy, cryotherapy, and hormone therapy are not very encouraging. Subsequently, there is a need to investigate new potential targets for focused treatment. NLRX1 (NOD9 or NLR family member X1) is one member among the NLRs and is a non-inflammasome forming NLR sub-group localized in mitochondria. Previous studies showed that NLRX1 is involved as a tumor suppressor in colorectal cancer and hepatocellular carcinoma. However, NLRX1 serves as tumor promoter in breast cancer and head and neck cancer sarcoma. The present study focuses on the role of NLRX1 in prostate cancer cells under stress conditions including serum-free and hydrogen peroxide (H2O2) to understand cell regulation and functions of NLRX1. We used human prostate cancer PC3 and LNCaP cell lines as the models and the following methods, including Annexin V/PI staining for cell viability, BrdU incorporation for cell proliferation, mitoSOX staining for mitochondrial ROS, wound healing assay for cell migration and Boyden chamber for cell invasion. First, we assessed the TCGA database via UCSC Xena and found that prostate cancer tumors have high NLRX1 expression than normal tissues. Next, we knock down the NLRX1 through lentivirus transduction. We found that silencing NLRX1 expression can decrease cell proliferation in PC3 cells. Furthermore, silencing NLRX1 can significantly decrease cell viability under H2O2 in PC3 cells and serum-free condition in both cancer cell lines. In addition, we found that H2O2-induced cell death is reversed by necroptosis inhibitor Nec-1. Moreover, NLRX1 silencing reduces cell migration in both PC3 and LNCaP cells and can inhibit cell invasion in both cell lines at 24 h. These results suggest that NLRX1 is a positive regulator of cell growth, migration and invasion in prostate cancer cells, and NLRX1 provides a cell-protective role in response to H2O2 and serum-free stress. Thus, this study will provide a potential target for the development of a therapeutic strategy for prostate cancer.
Citation Format: Wan-Wan Lin, Varsha Rathore. NLRX1 involves in prostate cancer cell growth, survival and migration [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 5420.
Abstract 5436: A therapeutically targetable dysadherin/YAP axis promotes cancer stem features and tumor aggressiveness in hepatocellular carcinoma
Authors: Jeon So-El , Jang Tae-Young , Lee Choong-Jae , Yun Hyeon-Ji , Cho Yeong-Hoon , Lim Da-Ye , Nam Jeong-Seok 
Published: March 2024

Abstract
Hepatocellular carcinoma (HCC) remains one of the most challenging tumors to treat. Cancer stem-like cells (CSCs) are believed to be important in HCC development, immune evasion, and treatment resistance. Dysadherin is a cell membrane glycoprotein linked to cancer progression by endowing HCC with CSC features. However, the underlying mechanism of increasing CSC characteristics in refractory advanced HCC is not entirely understood. A comprehensive bioinformatics study revealed that dysadherin-expressing HCC cells were associated with cancer stemness and the YAP signaling activation. Dysadherin knockdown or overexpression in liver cancer cell lines attenuated or increased cancer stemness and aggressiveness via YAP signaling, respectively. Correspondingly, dysadherin deficiency lowered cancer stemness and aggressiveness in the HCC mouse model by blocking the YAP pathway. Mechanistically, dysadherin promoted YAP nuclear localization, which activated stem cell transcription factors such as OCT4, KLF4, and MYC. Of note, our comprehensive gain and loss of function studies in CSCs demonstrated that targeting the dysadherin/YAP axis could boost sorafenib’s therapeutic effect and suppress PD-L1 expression, which helps tumor cells escape from immune surveillance. Thus, our results highlight that the dysadherin/YAP axis drives the aggressive phenotype of HCC, providing a potential therapeutic strategy for HCC.
Citation Format: So-El Jeon, Tae-Young Jang, Choong-Jae Lee, Hyeon-Ji Yun, Yeong-Hoon Cho, Da-Ye Lim, Jeong-Seok Nam. A therapeutically targetable dysadherin/YAP axis promotes cancer stem features and tumor aggressiveness in hepatocellular carcinoma [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 5436.
Abstract 544: Reverse engineering strategy for new targets identification
Authors: Xie Bin , Zhang Taimei , Li Le , Chen Hongkui , Liu Yang , Bi Lintao , Wen Danyi 
Published: March 2024

Abstract
The issue of drug resistance in cancer is very similar to the field of infectious disease, either existing before treatment (intrinsic) or generated during therapy (acquired), highly affected by cell endogenous factors and/or the surrounding environment. Acquired resistance can be occurred several months after targeted therapy via alternations of drug targets due to the genomic mutations of the targets, epigenetic transcriptional or translational changes, for example the C797S mutation impairs AZ9291 binding to the EGFR kinase domain. To overcome this, novel well-designed chemical compounds targeting new mutations would be urgently needed, as well as the potential new oncogenes/susceptible genes driving the resistance. Considering about the heterogeneity of primary tumor tissues, LIDE has established one functional cost-effective in vitro and in vivo screening method, named reverse engineering strategy for targets identification by using patients-derived conditional reprogramed cancer cell lines (CRs) and IO-FIVE (Immuno-Oncology drugs Five In Vivo Efficacy test). Basically, pro-siRNA library or CRISPR/sgRNA library is carried out in CRs for candidates hunting, alternatively drug-response evaluation among multiple clinical biopsies in mice cancer trials, after filtered with bioinformatic scanning from large groups of patients, and finally it is validated in vivo by CRISPR, shRNA silence or targeted compounds. In addition to these known factors (EGFR C797S, Her2/Met amplification, Ras and MAPK activation), we have discovered that epigenetic factors for DNA modification, protein translation kinases, mitochondrial/peroxisomal transporters and cell membrane lectins may contribute to AZ92921 resistance in vivo. And one previously unknown acyltransferase member has been identified as key driver gene for pan-cancer development by IO-FIVE, and patients with high expression level of this enzyme have had poor survival outcomes, accompany with uncontrolled tumor growth and immunotherapy resistance, which is becoming a promising therapeutic target.
Citation Format: Bin Xie, Taimei Zhang, Le Li, Hongkui Chen, Yang Liu, Lintao Bi, Danyi Wen. Reverse engineering strategy for new targets identification [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 544.
Abstract 5441: Down regulation of cysteine glutamate antiporter in ALDH1A1 expressing oral and breast cancer stem cells induced oxidative stress triggered ferroptosis
Authors: Bellala Ravishankar 
Published: March 2024

Abstract
Background: Sulfasalazine, an xCT inhibitor, is being used as a repurposed antineoplastic drug to induce ferroptosis. Ferroptosis is a regulated necrotic cell death pathway that is dependent on iron reserves. Interestingly, cancer stem cells (CSCs) that are regarded as major drivers of resistance to conventional therapies accompanied with tumor relapse and recurrence have bulk amount of iron reserves in the form of ferritin. This suggests that inducing ferroptosis might disrupt stemness and drug resistant mechanisms in cancer stem cells, thereby reducing the risk of drug resistance, cancer recurrence, and relapse.
Materials & Methods: In the present study, ALDH1A1 expressing oral (OCSCs) and breast (BCSCs) cancer stem cells were sorted and used to investigate the role of sulfasalazine to induce ferroptosis. To check the self-renewability of CSCs spheroid formation assay was performed and the resultant CSCs were treated with sulfasalazine (SAS) and subjected to gene expression analysis RT PCR and flow cytometry. FACS was performed to check stem cell marker expression, cell cycle arrest, and apoptosis.
Results: Our results suggest that the cells showed a gradual increase in sphere formation till S3 in the case of OCSCs and S2 in the case of BCSCs, with a gradual decrease in sphere forming efficiency from the respective generations. When treated with 0.6mM SAS, these cells induced ferroptosis by downregulating stem cell markers like ALDH1A1, SLC7A11, ferritin, and GPx 4 with a concomitant increase in transferrin and STEAP 3. Flow cytometry studies revealed that the cells have undergone mitochondrial dysfunction characterized by loss of membrane potential and the cell cycle progression was halted in the G2/M phase.
Conclusion: In the present study, we demonstrate that SAS potentially induced ferroptosis accompanied with oxidative stress in both OCSCs as well as BCSCs by lowering GPx 4 activity, a key enzyme that scavenges the products produced as a result of oxidative stress.
Citation Format: Ravishankar Bellala. Down regulation of cysteine glutamate antiporter in ALDH1A1 expressing oral and breast cancer stem cells induced oxidative stress triggered ferroptosis [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 5441.
Abstract 5449: Exploring signaling pathways essential for stemness and metastasis of colorectal cancer cells
Authors: Fujishita Teruaki , Taketo Makoto M. , Aoki Masahiro 
Published: March 2024

Abstract
The prognosis of colorectal cancer (CRC) patients with distant metastasis remains poor, requiring elucidation of molecular mechanisms and identification of therapeutic targets. While cancer stem cells have been implicated in metastasis, recurrence, and drug resistance, our understanding of the regulatory mechanisms governing the stemness of CRC stem cells remains largely incomplete. In this study, we utilized an innovative autochthonous metastatic mouse model of CRCs generated by the introduction of sporadic mutations in Ctnnb1, Kras, Trp53, and Smad4 genes (CKPS mice) and CRC cell lines derived from the mice (CKPS cells). Our investigation revealed that the cAMP/PKA/CREB and TGFβ/SMAD4 pathways play a positive and negative role, respectively, in the sphere-forming and metastasis-initiating ability of CRC cells. Treatment with the CREB inhibitor 666-15 or the genetic knockout of CREB significantly reduced the spheroid-forming and metastasis-initiating potentials of CKPS cells. Intriguingly, we observed that the irinotecan treatment induced CREB phosphorylation in liver metastases, and co-treatment of 666-15 greatly potentiated the inhibitory effect of irinotecan on liver metastasis. Furthermore, we found that the transition from 2D to 3D spheroid culture of CKPS cells led to the induction of RhoC expression. Notably, RhoC knockout in CKPS cells effectively suppressed spheroid formation in vitro and inhibited metastasis formation in an intrasplenic injection liver metastasis assay. Potential therapeutic implications of these findings will be discussed.
Citation Format: Teruaki Fujishita, Makoto M. Taketo, Masahiro Aoki. Exploring signaling pathways essential for stemness and metastasis of colorectal 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 5449.
Abstract 5452: AXIN2 differentially modulates stem cell subpopulations providing a potential therapeutic opportunity for targeting colorectal cancer stem cells
Authors: Zhang Chi , Facey Caroline O. , Opdenaker Lynn M. , Boman Bruce M. 
Published: March 2024

Abstract
Constitutively activated WNT-signaling promotes stem cell (SC) overpopulation which drives most colorectal cancer (CRC) development. It is not known, however, how WNT-signaling activity regulates different SC sub-populations. We previously reported that SC population size decreases as AXIN2 is knocked down, and increases when AXIN2 is overexpressed. Changes in cell cycle and apoptotic rate were also observed. Here, we present our recent results on changes between different SC subpopulations (ALDH+ vs. LGR5+) that occur due to AXIN2 modulation. We hypothesize that modulation of AXIN2 promotes differential expansion between different CRC SC subpopulations (ALDH+ and LGR5+). We observed that AXIN2 not only increases LGR5+ SC population size, but also expands the ALDH+ SC population to a greater extent as shown by an increased ALDH+-to-LGR5+ SCs ratio. This indicates that AXIN2, via WNT signaling, regulates SC population size, particularly ALDH+ SCs. Since the ALDH SC marker is also a key component in the retinoic acid (RA) signaling pathway, we surmised that increased AXIN2 would not only lead to elevated ALDH levels, but also upregulate the RA-signaling pathway components in CRC cells. To this end, we conducted NanoString mRNA profiling to study the effects of AXIN2 knockdown and overexpression in HT29 and SW480 CRC cells. The results showed that increased AXIN2 significantly up-regulated several key components of the RA-signaling pathway. Taken together, our results indicate that AXIN2 drives a shift in SC subpopulation sizes favoring the ALDH+ SCs. It also promotes the RA-signaling component expression - a pathway known to regulate SC differentiation. As a potential treatment strategy for CRC, therapeutically inducing high levels of AXIN2 could shift the balance between SC populations towards ALDH+ SCs, which may provide a way to target cancer SCs with retinoids to induce their differentiation.
Citation Format: Chi Zhang, Caroline O. Facey, Lynn M. Opdenaker, Bruce M. Boman. AXIN2 differentially modulates stem cell subpopulations providing a potential therapeutic opportunity for targeting colorectal cancer stem 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 5452.
Abstract 5471: Ribosome heterogeneity and RNA polI inhibition in osteosarcoma heterogeneity
Authors: Baud'huin Marc , Colleville Elvina , Thepault Rose Anne , Orgebin Emilien , Lamoureux Francois , Ory Benjamin 
Published: March 2024

Abstract
Osteosarcoma is the most common primary bone tumour in adolescents and young adults, with an incidence rate of 3.8 per million. These tumors affect the long bones of the body such as femur. Current standard therapy includes tumour resection associated with multi-drug chemotherapy. The 5-year survival rate can reach 65% but is significantly reduced to 30% when pulmonary metastases are detected at the time of diagnosis. As this rate has not improved in the last 50 years, it is necessary to identify new therapeutic strategies. Inhibition of ribosomal biogenesis is one of the strategies developed in many cancer studies. This can be obtained by inhibition of RNA pol I, and in particular by BMH-21. The objective of this study was to analyze the complexity and heterogeneity of osteosarcomas through the ribosomal spectrum. The effect of BMH-1 on survival was also studied in osteosarcoma cell lines. The data obtained showed that there was no difference in ribosome protein composition in the “core” ribosome in different osteosarcoma cell lines. In addition, BMH-21 decreased cell viability in all osteosarcoma and chemoresistant cell lines. However, any activation of the apoptotic pathway by caspases was detected, nor any impact on the formation of new colonies after treatment with BMH-21. These results suggest a rather cytostatic mechanism. Moreover, a G0/G1 arrest in cell cycle was shown for U2OS cells. Finally, BMH-21 does not appear to have any impact on migration in HOS and U2OS cells. The different molecular mechanisms involved in the regulation of proliferation need to be further investigated.
Citation Format: Marc Baud'huin, Elvina Colleville, Rose Anne Thepault, Emilien Orgebin, Francois Lamoureux, Benjamin Ory. Ribosome heterogeneity and RNA polI inhibition in osteosarcoma heterogeneity [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 5471.
Abstract 5479: Spatially resolved molecular features in the tumor-immune microenvironment of germline BRCA1/2 mutated versus BRCA wild type high grade serous ovarian cancers
Authors: Qian Jing , Roman Lynda D. , Bassiouni Rania , Rajpara Seeta , Neuman Monica , Khetan Varun , Craig David W. , Carlson Joseph W. , Carpten John D. 
Published: March 2024

Abstract
High-grade serous ovarian cancer (HGSC) is the most common and aggressive subtype of epithelial ovarian cancer. Importantly, germline mutations in BRCA1/2 give rise to HGSC. Because most HGSC are diagnosed at stage III/IV, outcomes are poor and more effective therapies are needed. Although immune checkpoint inhibitors show promise for a number of cancer types, efficacy has been variable in HGSC. To help provide new clues to the molecular features of HGSC, we set out to elucidate the tumor microenvironment of HGSC using spatial transcriptomics approaches. Specifically, we applied 10x Genomics Visium Spatial Transcriptomics (ST) technology to 48 samples representing primary HGSC tumors from 24 patients, including 15 BRCA1/2 mutated cases and 9 BRCA non-mutated cases. In addition to individual sample analysis, we normalized data from 64,784 total features across all sections and performed an integrated cluster analysis to get an overall picture of the cellular architecture of HGSC, but to also directly investigate differences in the tumor microenvironment based on BRCA mutation status. The resulting 17 integrated clusters were subjected to molecular annotation using GSEA, ESTIMATE, and CIBERSORTx, which revealed feature clusters representing important cell types defined by marker genes. Analysis of the entire dataset identified a primary tumor cluster defined by the expression of known ovarian cancer genes including WFDC2 and “don’t eat me” marker genes CD24 and CD47. However, the predominant tumor cell population in BRCA mutated cases was marked by the expression of MUC1, EPCAM, CLDN3, and CD24, while BRCA non-mutated tumor cell cluster was marked by EFNA1, ID1, LSR, and CD9. Importantly, both groups revealed the presence of a specialized monocyte derived macrophage cluster defined by the expression of LYZ and genes involved in cholesterol metabolism including APOE and APOC1. These lipid-associated macrophages are M2 polarized and shown to be associated with poor outcome. Additional analyses are underway to determine spatial dependencies of various tumor and immunological cell compartments. These data provide novel insights into the HGSC tumor microenvironment that may influence HGSC’s vulnerability to immunological therapies.
Citation Format: Jing Qian, Lynda D. Roman, Rania Bassiouni, Seeta Rajpara, Monica Neuman, Varun Khetan, David W. Craig, Joseph W. Carlson, John D. Carpten. Spatially resolved molecular features in the tumor-immune microenvironment of germline BRCA1/2 mutated versus BRCA wild type high grade serous ovarian cancers [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 5479.
Abstract 5504: Integrating ultrahigh-plex spatial phenotyping: From discovery to clinical applications
Authors: Pratapa Aditya , Ma Ning , Jhaveri Niyati 
Published: March 2024

Abstract
Background The journey from discovering predictive spatial biomarkers (known as spatial signatures) for immunotherapy responses to their clinical application necessitates a cohesive approach bridging ultrahigh-plex discovery experiments with high-throughput translational studies. This study focuses on integrating Akoya Biosciences spatial multiplexed imaging technologies with advanced data analysis techniques for comprehensive spatial phenotyping across the discovery-to-clinical continuum.
Methods Human formalin-fixed, paraffin-embedded (FFPE) cancer tissues were profiled using ultrahigh-plex PhenoCode™ Discovery panels to examine cell lineage, immune activation, and checkpoint markers via the PhenoCycler®-Fusion spatial biology platform. The subsequent use of PhenoCode™ Signature panels targeted specific biomarkers of immune profile, immune contexture, tumor-infiltrating lymphocytes (TIL), macrophage polarization, and T cell status via the PhenoImager® HT platform. Open-source whole slide image analysis software QuPath was employed for precise image analysis, including ROI segmentation, cell detection, classification, exploration of spatial interactions, and identification of distinct spatial signatures.
Results Our analysis revealed distinct spatial relationships within various tumor types, quantifying immune cell distributions and their interactions. The ultrahigh-plex data correlated with high-throughput signature panel analyses, thus paving a new simplified way for targeted identification and development of predictive spatial signatures for immunotherapy outcomes.
Conclusions The combined use of ultrahigh-plex discovery panels, high-throughput signature panels, and deep-learning image analysis provides a comprehensive understanding of cellular interactions in the tumor microenvironment. This integrated approach, utilizing Akoya's end-to-end workflows, accelerates the identification of predictive spatial biomarker signatures across various human tissue samples.
Citation Format: Aditya Pratapa, Ning Ma, Niyati Jhaveri. Integrating ultrahigh-plex spatial phenotyping: From discovery to clinical applications [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 5504.