bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B003: Systematic loss-of-function screens identify pathway-specific functional circular RNAs
Authors: Neve Matt , Liu Ling , Conn Simon , Goodall Gregory , Rosenbluh Joseph 
Published: November 2024

Abstract
Circular RNA (circRNA) is covalently closed, single-stranded RNA produced by back-splicing. A few circRNAs have been implicated as functional; however, we lack understanding of pathways that are regulated by circRNAs. Here we generated a pooled short-hairpin- RNA library targeting the back-splice junction of 3,354 human circRNAs that are expressed at different levels (ranging from low to high) in humans. We used this library for loss-of-function proliferation screens in a panel of 18 cancer cell lines from four tissue types harbouring mutations leading to constitutive activity of defined pathways. Both context-specific and non- specific circRNAs were identified. Some circRNAs were found to directly regulate their precursor, whereas some have a function unrelated to their precursor. We validated these observations with a secondary screen and uncovered a role for circRERE(4–10) and circHUWE1(22,23), two cell-essential circRNAs, circSMAD2(2–6), a WNT pathway regulator, and circMTO1(2,RI,3), a regulator of MAPK signalling. Our work sheds light on pathways regulated by circRNAs and provides a catalogue of circRNAs with a measurable function.
Citation Format: Matt Neve, Ling Liu, Simon Conn, Gregory Goodall, Joseph Rosenbluh. Systematic loss-of-function screens identify pathway-specific functional circular RNAs [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr B003.
Abstract B004: Ovarian cancer long intergenic noncoding RNA 1 is a potential therapeutic target in advanced ovarian cancer by promoting glycolytic pathway and hypoxic response
Authors: Horie Kuniko , Sato Wataru , Ikeda Kazuhiro , Inoue Satoshi 
Published: November 2024

Abstract
Ovarian cancer (OvC) is often diagnosed as an advanced disease because symptoms do not develop at earlier stages. Besides current treatments, alternative efficient therapies for OvC need to be established. We have previously identified that a novel long intergenic noncoding RNA (lincRNA) originated from chromosome 10q21 was predominantly expressed in clinical ovarian cancer tissues, designated as ovarian cancer lincRNA 1 (OIN1). Silencing of OIN1 in OvC cell lines substantially exhibited the inhibition of in vitro and in vivo cell proliferation, by upregulating apoptosis-related genes. In the present study, we aimed to evaluate whether OIN1 can be a therapeutic target in advanced OvC and how OIN1 drives the progression of OvC. We established long-term culturable spheroid cultures of OvC patient-derived cells (OvC-PDCs) from ascites of OvC patients as an advanced OvC model. The OvC-PDC spheroid cultures abundantly expressed OIN1 and stemness-related genes. OIN1-targeted siRNAs could suppress the spheroid growth and upregulate apoptosis-related genes such as RASSF5 and ADORA1 in OvC-PDC cultures. In a bloody ascites-generating xenograft in vivo model of mice intraperitoneally injected with OvC-PDC, OIN1-targeted siRNA treatment engineered by drug delivery system alleviated ascites production and prolonged the mice survival time. Based on transcriptomic analysis of OIN1 silencing in OvC-PDC cultures, we found that OIN1 inhibition exerts the downregulation of genes involved in glycolytic pathway and hypoxic response. We further demonstrated that OIN1 modulates HIF1a-mediated transcriptional regulation in OvC- PDCs. The present findings provide promising evidence that OIN1 can be a potential therapeutic target for advanced OvC.
Citation Format: Kuniko Horie, Wataru Sato, Kazuhiro Ikeda, Satoshi Inoue. Ovarian cancer long intergenic noncoding RNA 1 is a potential therapeutic target in advanced ovarian cancer by promoting glycolytic pathway and hypoxic response [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr B004.
Abstract B005: A robust NSCLC biomarker: miR-7-5p: in-silico validation and potential SPR- based probe for detection
Authors: Dhara Chandrajeet , Dhara Anindita , Gantayat Saumyatika 
Published: November 2024

Abstract
The abundance of micro RNAs as a specific biomarker for accurately detecting cancer metastasis has arisen recently. The expression levels of miRNA are analyzed to get insights into cancer tissue detection and subtypes. Similar to other cancer types, the miRNA shows high levels of target mRNA dysregulation in association with non-small cell lung carcinoma (NSCLC). Among many promising cancer biomarkers for NSCLC, miR-7-5p has shown significant downregulation in the NSCLC tissues and targets proto-oncogenes like PAK2 and NOVA2. The expression levels of different proto-oncogenes targeting the miR-7-5p in NSCLC show that the EGFR- mutated NSCLC has an experimental validation. And, the target validation of the miR-7-5p could be analyzed using SPR (Surface plasmon resonance) based sensors at a single nanoparticle level such as Au nanocube due to its high specificity and accountability. Despite being an accountable tool for cancer diagnosis, miRNA-based biomarkers sometimes cause poor diagnostic specificity and reproducibility due to their heterogenicity and immunogenicity in cancer detection. To overcome these shortcomings, the biomarkers need to be validated according to recent clinical studies.
Citation Format: Chandrajeet Dhara, Anindita Dhara, Saumyatika Gantayat. A robust NSCLC biomarker: miR-7-5p: in-silico validation and potential SPR- based probe for detection [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr B005.
Abstract B007: Unlocking antiviral immunity against endogenous retroviruses in skin squamous cell carcinomas
Authors: Lyu Ying , Ge Yejing 
Published: November 2024

Abstract
Known as molecular parasites that invaded our genome through ancestors, transposons (mainly retrotransposons) are interspersed genomic repeats that constitute ∼40% of the mammalian genome. Primarily residing in the heterochromatin, retrotransposons exhibit dynamic expressions to orchestrate embryonic development and shape adult functions. Although rare, a cohort of evolutionarily young retrotransposons resisted extinction, whose selfish activities underlie polymorphic variations and genetic diseases including cancer. While the extraordinary molecular and functional heterogeneity of retrotransposons has been long recognized, mechanistic dissection remains challenging. To tackle this challenge, we use murine skin as our model, given its well-characterized, abundant, and highly accessible adult stem cells, not only mediating postnatal remodeling and tissue repair, but also serving as cell of origin for squamous cell carcinomas. By analyzing a genetic model lacking a known retrotransposon suppressor, histone methyltransferase Setdb1, which we found to be essential in the adult skin, we saw hair loss and hair follicle stem cell exhaustion phenotype, accompanied by a robust and selective surge of endogenous retroviruses (ERVs). When combined with squamous cell carcinoma drivers, Setdb1 loss significantly blocked tumor progression in vivo. We detected abundant retroviral peptides originated from its full-length copies through mass spectrometry and viral-like particles through transmission electron microscopy that are immunoreactive to previously reported ERV surface envelope (env) antibody. Similar viral-like particles were broadly evident across several epithelial tissues beyond skin, implicating its conserved function across squamous cancers. Mechanistically, epithelial originated ERVs elicit tissue wide inflammatory response, and can be ameliorated by pharmacological or genetic inhibition of retroviral activity. Moreover, ERV reactivation induced replication stress functionally accounts for stem cell exhaustion, therefore serving as a specific therapeutic vulnerability in squamous cancers. As an evolutionary conundrum, viral-coding ERVs pose a threat to host fitness and yet, they’ve resisted extinction persisting in the mammalian genome. Our findings suggest ERVs wrestle with the host surveillance programs to regulate adult tissue physiology and pathology, thus providing a key target in eliciting innate immunity in squamous cell carcinomas.
Citation Format: Ying Lyu, Yejing Ge. Unlocking antiviral immunity against endogenous retroviruses in skin squamous cell carcinomas [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr B007.
Abstract B009: The RNA binding activity of the BRAF Kinase
Authors: Le Barch Alexia , Mennour Sabrina , Uguen Patricia , Vagner Stephan 
Published: November 2024

Abstract
Multiprotein complexes are key molecular switches of oncogenic signal transduction pathways that relay the flux of information coming from transmembrane receptors and distribute signals to a myriad of effectors. As such the regulation of protein-protein interactions is crucial in signal transduction pathways. For instance, activation of the mitogen-activated protein kinases pathway (MAPK) occurs through a cascade of phosphorylation and protein-protein interactions (PPIs) and is often deregulated in cancer. RNA-protein interactions play key roles in biological processes. More than a thousand RNA binding proteins (RBPs) influence the fate of mRNAs and non-coding RNAs in different ways. It is however less described how RNAs can in turn influence the functions of proteins to which they bind. Here we propose that RNAs scaffold PPIs in the MAPK pathway, thereby fine-tuning oncogenic signaling. We focused our study on cutaneous melanoma for which the MAPK is activated in more than 70% of the cases due to activating mutations in BRAF and NRAS. Using UV-CrossLinking ImmunoPrecipitation (CLIP) experiments, we found that several proteins of the MAPK pathway, including BRAF (but not MEK and ERK) interact with RNAs in RAS-activated melanoma cells. In addition, using a PLA- based imaging technique that allows the visualisation of the proximity of two given proteins, we showed that RNAs promote the stabilisation of BRAF-PPIs, suggesting a scaffolding role of RNAs in the MAPK pathway. Loss of BRAF RNA binding activity (achieved with a single point mutation) is associated with decreased BRAF dimerization and signaling. The oncogenic mutant protein BRAF (V600E) also interacts with RNA in a variety of melanoma cell lines including a BRAF inhibitor-resistant melanoma cell line in which the dimerization of BRAF and CRAF is partly dependent on RNA. Identifying BRAF-bound RNAs will open new therapeutic strategies targeting RNA-protein interactions. We also envision that the level of BRAF-RNA interactions could serve as a predictive marker of response to BRAF (V600E) inhibitors.
Citation Format: Alexia Le Barch, Sabrina Mennour, Patricia Uguen, Stephan Vagner. The RNA binding activity of the BRAF Kinase [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr B009.
Abstract B017: Discovery of cancer-specific small RNAs using a new unbiased analysis of cohort sequence data
Authors: Kalogeropoulos Panagiotis , Ulloa Maria Alejandra , Friedländer Marc 
Published: November 2024

Abstract
It is well-established that small RNAs such as microRNAs can have important roles as oncogenes or tumor suppressors. The majority of studies of small RNAs in cancer have focused on examining the often subtle deregulation of specific, well-characterized molecules, aiming to understand their role in tumorigenesis. However, these efforts have predominantly concentrated on known, well-annotated RNA sequences, potentially overlooking novel, cancer-specific molecules. In this study, we sought to apply a new computational approach to uncover small RNA molecules that are uniquely associated with cancer and are completely absent from all non- cancerous tissues. To achieve this, we developed an unbiased approach that can detect cancer- specific sequences even if they are lowly abundant, do not overlap with existing genome annotations and even if they do not map to the human reference genome. We applied our framework to hundreds of small RNA-seq samples across a diverse range of cancer types from two large-scale public resources: The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC). Through this comprehensive analysis, we identified a series of small RNA molecules that are exclusively present in tumor samples and completely absent in adjacent normal tissues across multiple cancer types. Furthermore, these molecules were not detected in a large cohort comprising over 2,500 non-cancerous public samples, underscoring their specificity to cancerous conditions. Some of these molecules are also associated with different patient metadata. For example, one of these candidates exhibited significant correlation with poor patient survival in both Lung Adenocarcinoma and Endometrial Carcinoma within both the TCGA and CPTAC datasets. The discovery of such cancer-specific small RNAs holds immense potential for clinical applications. These molecules could serve as highly specific diagnostic and prognostic biomarkers, aiding in the early detection and stratification of cancers. Moreover, their unique presence in cancer cells, positions them as promising targets for the development of novel therapeutic interventions. In summary, our findings highlight the importance of exploring the full spectrum of small RNAs in cancer research. By moving beyond the constraints of known annotations, we have uncovered previously unknown molecules that could improve cancer diagnostics, prognostics, and treatment.
Citation Format: Panagiotis Kalogeropoulos, Maria Alejandra Ulloa, Marc Friedländer. Discovery of cancer-specific small RNAs using a new unbiased analysis of cohort sequence data [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr B017.
Abstract B018: miRNA-130a promotes Breast cancer progression by inhibiting multiple tumour suppressor genes as a Gene-TF-miRNA network
Authors: Reddy Gayam Prasanna Kumar , Mathew A Jesil , SM Fayaz 
Published: November 2024

Abstract
Cancer is a disease that has implications worldwide, including in developing countries. It is known for its notorious ways of adapting and gaining resistance to the therapies available. Breast cancer (BC) majorly affects women and leading cause of death in women worldwide. Despite studying BC for many decades, we are not yet certain about a definitive therapy that can cure it with confidence. One of the challenges associated with treating BC is its metastasis and resistance to available therapies. Non-cancerous cells exhibit a tightly regulated transcription profile. An altered transcription profile is considered one of the main causes of the origin of cancers and their progression, including resistance and metastasis. Tumor suppressor genes are associated with mitigating any oncogenic signals induced by external factors or internal dysregulation in oncogenic genes. Changes in the expression profiles of tumour suppressor and oncogenic genes are associated with BC progression and metastasis. Transcription factors (TFs) play a significant role in marinating the tight regulation of transcription. In this study, we have analyzed Genes(N=1057), TFs(N =233) and miRNAs (N = 246) that are promoting BC from literature and publicly available databases; we have analyzed the regulation of Gene-Gene, miRNA-miRNA, TF-TF, miRNA-Gene, miRNA-TF, TF-Gene, TF-miRNA as a network of three node Feed Forward Loops (FFLs). Upon constructing 3, 4,5 and 6 node FFLs, we have identified that the miRNA130a is promoting BC by inhibiting crucial Tumor suppressor genes like TGFBR1, TGFBR2, SOD2, PTEN, SMAD4, RUNX3 etc.
Citation Format: Prasanna Kumar Reddy Gayam, Jesil Mathew A, Fayaz SM. miRNA-130a promotes Breast cancer progression by inhibiting multiple tumour suppressor genes as a Gene-TF-miRNA network [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr B018.
Abstract B020: The Ratio of Alternatively Spliced KRAS Isoforms Plays a Role in The Tumorigenesis of Colorectal Cancer
Authors: Pulipelli Harika Reddy , Hertel Dr. Klemens J. 
Published: November 2024

Abstract
One of the most frequently mutated oncogenes, KRAS, has two alternatively spliced isoforms, KRAS4A(4A) and KRAS4B(4B). The isoforms differ by the inclusion or exclusion of the fourth exon, resulting in 4A or 4B respectively. They undergo different post-transcriptional modifications, indicating the non-redundant nature of the two isoforms. Studies also show spatiotemporal regulation of 4A in the gastrointestinal tract of mice during development. Although 4B is considered the major isoform, the ratio of 4A to 4B is cell-type specific. We show 4A is more abundant in colorectal cancer (CRC) cells like CaCO2 and HCT116, compared to other cancer cell lines like HeLa cells and MDA-MB-468 cells. Differential splicing analysis on existing data from flow-sorted mouse colon-crypt cells (stem-like vs. differentiated) and murine intestinal organoids of colon cancer (WT vs. tumor) shows that while differentiated colon cells and WT organoids have decreased levels of 4A, stem-like cells and tumor cells show increased levels of 4A. This supports the stem-cell theory of cancer, indicating that the dysregulation of KRAS isoforms impacts colon cell differentiation in colon crypts and could lead to CRC. Interestingly, we also found that the 3’ splice site(3’SS) of exon 4A is highly conserved. RBM39, a 3’SS recognition homolog, and SRSF1 have also been shown to play a role in KRAS splicing. We hypothesize that RBM39 regulates KRAS splicing by binding the 3’SS, and SRSF1 may play a role either by binding the pre-mRNA directly or through its interaction with RBM39. Therefore, we propose a new model for alternative splicing of KRAS. The abundance of KRAS splice variants may determine the fate of colon cell differentiation and drive CRC tumorigenesis.
Citation Format: Harika Reddy Pulipelli, Dr. Klemens J. Hertel. The Ratio of Alternatively Spliced KRAS Isoforms Plays a Role in The Tumorigenesis of Colorectal Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr B020.
Abstract B025: Redox reprogramming by SOD1 knockdown: A novel liposomal siRNA strategy to overcome platinum resistance in ovarian cancer
Authors: Szenasi Attila , Rocha Sonia , Wang Mu 
Published: November 2024

Abstract
Platinum resistance remains a significant obstacle in the treatment of advanced-stage ovarian cancer, frequently leading to therapeutic failure. Our previous research identified Superoxide Dismutase 1 (SOD1) as a key antioxidant target for re-sensitizing platinum-resistant ovarian cancer cells to platinum-based therapies through both enzymatic inhibition and RNA interference (RNAi) utilizing a graphene-based siRNA delivery platform. Building on these findings, we have now developed a liposomal formulation of chemically modified siRNA targeting SOD1, which demonstrates potent knockdown efficiency and significantly enhances the sensitivity of resistant ovarian cancer cells to cisplatin in vivo. While SOD1 inhibition or knockdown via RNAi effectively re-sensitizes resistant cells to cisplatin, the underlying redox-sensitive signaling pathways remain largely unexplored in ovarian cancer. Our current study reveals that SOD1 knockdown acts as a redox switch, triggering cellular reprogramming in drug-resistant cells through post-translational cysteine modifications. This reprogramming leads to the rewiring of critical cancer hallmarks, culminating in the restoration of a cisplatin-sensitive phenotype. These findings suggest that a liposomal, chemically modified SOD1 siRNA formulation could serve as a promising therapeutic approach for reversing platinum resistance in ovarian cancer by exploiting redox-mediated reprogramming of cancer hallmarks. This study not only underscores the therapeutic potential of targeting SOD1 but also highlights the broader implications of redox signaling in the etiology of platinum resistance, providing a novel avenue for therapeutic intervention.
Citation Format: Attila Szenasi, Sonia Rocha, Mu Wang. Redox reprogramming by SOD1 knockdown: A novel liposomal siRNA strategy to overcome platinum resistance in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr B025.
Abstract I002: Alternative polyadenylation as a therapeutic target in cancer
Authors: Banjo Toshihiro , Kaito Satoshi , Gabel Austin M , Abdel-Wahab Omar , Bradley Robert K 
Published: November 2024

Abstract
Alternative polyadenylation (APA) is markedly dysregulated across cancer types. Although this phenomenon is well established and associated with altered patient prognosis, the functional importance of most dysregulated polyadenylation to cancer phenotypes remains unknown, as does the potential therapeutic impact of dysregulated APA. Recent work by our lab and others to address this gap has systematically identified specific APA events that alter key tumor phenotypes, including malignant cell growth and tumor recognition by cytotoxic T cells. Motivated by these studies, we sought to identify small molecules that modulate APA for therapeutic intent. We created a sensitive reporter of APA and used this reporter to conduct a molecular phenotypic reporter screen for APA-altering compounds. This screen revealed a diversity of compounds that altered APA transcriptome-wide. Phenotypic characterization of the strongest hit emerging from this screen revealed that it strongly induced cell differentiation and death of myeloid leukemia cells, with negligible toxicity for normal hematopoietic stem cells. Overall, these results highlight the untapped but promising therapeutic potential of targeting APA in cancer.
Citation Format: Toshihiro Banjo, Satoshi Kaito, Austin M Gabel, Omar Abdel-Wahab, Robert K Bradley. Alternative polyadenylation as a therapeutic target in cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr I002.