bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2959: Signatures of therapy-induced senescence in glioblastoma-derived extracellular vesicles
Authors: DeLuca Valerie , Digumarti Priya , Garcia-Mansfield Krystine , Pirrotte Patrick , Berens Michael E. 
Published: March 2024

Abstract
The recalcitrant nature of glioblastoma (GBM) may be due, in part, to the promotion of therapy-induced senescence (TIS) by standard of care treatments. TIS is a prolonged growth arrest associated with epigenetic, metabolic, and biochemical alterations, as well as a robust secretory phenotype. Despite an initial period of tumor stasis due to the loss of cell proliferation, TIS is associated with the development of stemness, increased drug resistance, and immune suppression. Our preliminary data demonstrate the prominent induction of TIS in GBM tumor cells and astrocytes following standard of care therapies for GBM in vitro. However, studies of TIS in GBM patients have been limited due to i) the impracticality of receiving multiple GBM biopsies post-treatment but prior to recurrence and ii) the lack of robust detection methods for TIS even with appropriate biopsy. These challenges argue the need for novel methods to survey TIS in patients. Extracellular vesicles (EVs) are small membrane-bound particles that readily cross the blood brain barrier, and convey information about originating cell identity and cell state through their cargo content. We hypothesize that TIS in host and tumor cells drives the elaboration of senescence-associated EVs (senEVs) with quantifiable senescence protein cargo signatures, and consequently, that EVs can serve as a liquid biopsy for senescence in patients. In a preliminary experiment, two patient derived xenografts grown as short-term in vitro cultures were exposed to 6GY irradiation, with supernatant collected prior to radiation (D0), at peak senescence (D7), and at late senescence (D10). EVs were isolated and subjected to unbiased mass spectrometry. Following unsupervised clustering, EVs were grouped by treatment rather than by cell line. Approximately 6000 proteins were identified across the entire data set, with 105 proteins unique to D7 samples, 162 proteins unique to D10 samples, and 688 proteins exclusive to D7 and D10 samples. Further, proteins from two established senescence gene sets were identified as unique to the D7 and/or D10 conditions. Current work to more robustly identify enrichment of senescence gene sets in EV cargo post-irradiation is underway. We have also established shRNA knockdown cell lines with abrogated TIS to equip validation studies of the TIS-EV cargo relationship. We anticipate that these studies will aid in the development of EVs as a novel reporter of senescence in the clinic.
Citation Format: Valerie DeLuca, Priya Digumarti, Krystine Garcia-Mansfield, Patrick Pirrotte, Michael E. Berens. Signatures of therapy-induced senescence in glioblastoma-derived extracellular vesicles [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 2959.
Abstract 2998: Regulation of epidermal growth factor receptor signaling by BRCA1-microRNA 146a network
Authors: Kumaraswamy Easwari , Shimak Raeann M. Koren , Gunewardena Sumedha , Wendt Karen L. , Alexander Dani , Hembruff Stacey L. , Jensen Roy A. 
Published: March 2024

Abstract
Inherited defects in the breast cancer susceptibility gene, BRCA1 are associated with an increased risk for hereditary breast, ovarian, and other cancers. BRCA1-associated basal like breast cancers (BLBCs) are high-grade ductal carcinomas that do not express ER, PR or HER2, but frequently overexpress epidermal growth factor receptor (EGFR/ErbB1/HER1). The EGFR-driven signaling network plays a pivotal role in BLBC pathogenesis. EGFR overexpression is associated with tumor progression and metastasis, resistance to radiation and chemotherapy, and poor prognosis. Growth factor receptors are regulated by multiple miRNAs, each having many targets, coordinately controlling the complex pathways of downstream signaling. We have previously reported a post-transcriptional mechanism by which BRCA1 regulates EGFR expression through the induction of miR-146a and provided a rationale for the development of miR-146a based therapeutic strategies. In addition, we have shown that BRCA1 also exerts regulatory control over dozens of important miRNAs that appear to play a critical role in breast neoplasia. From TCGA analysis, we show that low expression of these miRNAs is associated with distinctively poor overall survival of TNBC patients. Using miR-146a loss or gain of function experiments in vitro, we show that BRCA1 and miR-146a regulate EGFR signaling, stemness, epithelial-to-mesenchymal transition (EMT), extracellular matrix (ECM) remodeling and chemoresistance. Using in vivo mouse models, we demonstrate that miR-146a overexpression delays tumor formation leading to better overall survival. BLBC unlike the other subtypes, lacks targeted therapy approaches making cytotoxic chemotherapy essentially the only option for treatment. Though EGFR inhibitors have been used to treat other cancers, clinical trials for breast cancer have so far been unsuccessful due to poor response rates. Since one miRNA can target multiple genes and regulate multiple signaling pathways, our study provides evidence to suggest that restoring miR-146a could suppress EGFR-RAS-MEK signaling and the other compensatory pathways, providing a targeted therapeutic option for BRCA1 associated BLBC.
Citation Format: Easwari Kumaraswamy, Raeann M. Koren Shimak, Sumedha Gunewardena, Karen L. Wendt, Dani Alexander, Stacey L. Hembruff, Roy A. Jensen. Regulation of epidermal growth factor receptor signaling by BRCA1-microRNA 146a network [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 2998.
Abstract 2999: Evaluation of microRNA expression in metastatic and non-metastatic salivary gland mucoepidermoid carcinoma
Authors: Trevizani Maria E. , Oliveira Katia K. , Marchi Fabio A. , Bizinelli Daniela , Mariano Fernanda V. , Nagano Cibele P. , Costa Felipe A. , Pinto Clovis A. , Kowalski Luiz P. , Lourenço Silvia V. , Coutinho-Camillo Cláudia M. 
Published: March 2024

Abstract
Salivary gland tumors are a heterogeneous group of lesions, being mucoepidermoid carcinoma (MEC) the malignant neoplasm with the highest incidence, occurring mainly in the parotid gland. Characterization of its histological grade (high, intermediate, and low) is important for determining patient prognosis. Metastasis is more common high-grade tumors and can occur at regional lymph nodes or distant sites. Although the mechanisms underlying the metastatic process are largely unknown, large-scale microRNA expression profiling studies of human cancers have demonstrated that dysregulation of miRNA is frequently associated with many cancer types. The aim of this study is to validate the use of microRNA expression for the discrimination of the metastatic potential of MEC samples. Using Real Time RT-PCR (qPCR) we have analyzed the expression of 384 miRNAs and controls in 4 non-metastatic MECs, 3 MECs with lymph node metastasis, 3 MECs with distant metastasis, and 2 non-neoplastic human salivary gland samples. Comparing the expression among these groups we identified 45 differentially expressed miRNAs that may be related with the metastatic potential of these tumors. To validate the microRNA expression associated with the metastatic potential, we selected 7 out of the 45 differentially expressed microRNAs and 7 MEC samples from the different groups of samples. Considering the 7 microRNAs evaluated, we validated that the expression of miR-191 was increased in non-neoplastic samples when compared to MECs with lymph node metastasis and the expression of miR-494 was increased in non-neoplastic samples when compared to MECs with distant metastasis, suggesting that loss of these microRNAs might be involved in the development of metastasis in mucoepidermoid carcinoma. The determination of a miRNA expression profile could provide a better understanding of the molecular basis of MEC and facilitate the determination of diagnosis and prognosis of patients.
Citation Format: Maria E. Trevizani, Katia K. Oliveira, Fabio A. Marchi, Daniela Bizinelli, Fernanda V. Mariano, Cibele P. Nagano, Felipe A. Costa, Clovis A. Pinto, Luiz P. Kowalski, Silvia V. Lourenço, Cláudia M. Coutinho-Camillo. Evaluation of microRNA expression in metastatic and non-metastatic salivary gland mucoepidermoid 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 2999.
Abstract 3007: AZGP1 inhibits angiogenesis in prostate cancer
Authors: Wen Ru , Wen G Edward , Qiu Zhengyuan , Peterson Eric E , Marques Fernando Jose Garcia , Bermudez Abel , Pollack Jonathan R , Zhao Hongjuan , Pitteri Sharon , Brooks James 
Published: March 2024

Abstract
AZGP1 is involved in various biological processes, including lipid metabolism, regulation of cell proliferation, migration and invasion, and immune response. The loss of AZGP1 is associated with worse clinical outcomes, and AZGP1 has been indicated as a potential biomarker for prostate cancer. However, the underlying mechanisms of AZGP1 function in prostate cancer are unknown. This study reports AZGP1's pivotal involvement in angiogenesis within the prostate cancer tumor environment. Neither knockout nor overexpression of AZGP1 affects in vitro prostate cancer cell proliferation, migration, or invasion. Morphologically, AZGP1-deficient mouse prostates appear normal, but exhibit increased fibroblast growth in periglandular stroma after 6 months. The overexpression of AZGP1 does not impact the growth of PC3 and DU145 tumors; instead, these tumors significantly reduced microvessel density, suggesting AZGP1 exhibits anti-angiogenic properties. Proteomic profiling shows distinct profile of angiogenesis-related proteins between PC3-AZGP1-OV and PC3 control cells, featuring proteins like PDCD6 and MMP9. This study provides insights into the anti-angiogenic attributes of AZGP1 in prostate cancer, underscoring its potential as a therapeutic target for prostate cancer.
Citation Format: Ru Wen, G Edward Wen, Zhengyuan Qiu, Eric E Peterson, Fernando Jose Garcia Marques, Abel Bermudez, Jonathan R Pollack, Hongjuan Zhao, Sharon Pitteri, James Brooks. AZGP1 inhibits angiogenesis in prostate cancer [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 3007.
Abstract 3023: Master corepressor inactivation through oncogene suppressor RAI2 mediated polymerization
Authors: Goradia Nishit , Werner Stefan , Mullapudi Edukondalu , von Amsberg Gunhild , Pantel Klaus , Wilmanns Matthias 
Published: March 2024

Abstract
Imbalanced transcription of a large number of genes can be caused at various levels, ranging from alterations in individual transcription factors to dysfunctional corepressor and coactivator complexes [1]. C-terminal binding proteins (CtBPs) are ubiquitous master transcriptional coregulators associated with the Polycomb Repressive Complex 2 (PRC2), with essential functions in the development and oncogenesis of various tumor entities, including breast cancer and prostate cancer (PC) [2,3]. As CtBPs bind to short linear PxDLS-like sequence motifs (SLiMs), the presence of such motifs in tandem on the putative metastasis suppressor RAI2 [4] suggested a previously undiscovered dual interaction with CtBPs. Here, we show that RAI2 induces CtBP polymerization through well-ordered filaments of stacked tetrameric CtBP layers, as illustrated by a high-resolution single particle cryo electron microscopy structure. These filaments are mirrored by RAI2-mediated CtBP nuclear foci and relief of CtBP corepressor function in RAI2-expressing cancer cells. Analyses of a diverse PC patient cohort revealed a substantial decrease in RAI2 in the aggressive subtypes, suggesting a pivotal role of RAI2 in the transition to androgen receptor signaling-independent progression. Taken together, our data demonstrate a previously unknown mechanism of multivalent short linear sequence motif-induced polymerization. As RAI2-like SLiM motifs are found in a wide range of organisms, including pathogenic viruses, our findings serve as a paradigm for diverse functional effects through multivalent interaction-mediated polymerization by disordered proteins in healthy and diseased conditions. The specific properties of these repeated interactions open up new therapeutic opportunities.
References
[1] Lee, T.I. & Young, R.A. Transcriptional regulation and its misregulation in disease. Cell 152, 1237-51 (2013).
[2] Di, L.J. et al. Genome-wide profiles of CtBP link metabolism with genome stability and epithelial reprogramming in breast cancer. Nat Commun 4, 1449 (2013).
[3] Wang, R. et al. Role of transcriptional corepressor CtBP1 in prostate cancer progression. Neoplasia 14, 905-14 (2012).
[4] Werner, S. et al. Suppression of early hematogenous dissemination of human breast cancer cells to bone marrow by retinoic Acid-induced 2. Cancer Discov 5, 506-19 (2015).
Citation Format: Nishit Goradia, Stefan Werner, Edukondalu Mullapudi, Gunhild von Amsberg, Klaus Pantel, Matthias Wilmanns. Master corepressor inactivation through oncogene suppressor RAI2 mediated polymerization [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 3023.
Abstract 3027: p53 aggregation promotes transformation from non-malignant lesions to high-grade serous ovarian carcinomas
Authors: Sartini Sara , Omholt Lexi , Moatamed Neda A. , Soragni Alice 
Published: March 2024

Abstract
High-Grade Serous Ovarian Cancer (HGSOC) is the most common and aggressive gynecological malignancy. It is typically diagnosed in late stages due to lack of diagnostic tests and current therapies available are not efficacious when the tumor is advanced. HGSOC is characterized by ubiquitous loss of functional p53 tumor suppressor protein function, largely due to point mutations that arise very early in carcinogenesis. P53 mutations are detected in pre-neoplastic cells of the fallopian tube mucosa, called p53 signature, and in early precursor lesions called serous tubal intraepithelial carcinoma (STIC). Some mutations promote the misfolding and aggregation of p53, transforming the protein into a cancer-promoting oncogene. Here, we hypothesize that the transition from folded, soluble to aggregated mutant p53 underlies the transformation from a pre-neoplastic lesion (p53 signature, STILs), to STICs and eventually HGSOC. We first set to determine the proportion of cells carrying soluble vs misfolded mutant p53 in fallopian tube tissues collected from n=10 patients undergoing salpingo-oophorectomy. We performed conformation-sensitive staining and quantification of folded and unfolded p53 cases and demonstrated that p53 misfolding, a mandatory precursor to aggregation, is present in STICs and HGSOCs, but notably absent from p53 signatures and surrounding healthy tissue. To better characterize the role of aggregated p53 in the progression of HGSOC, we took advantage of primary human fallopian tube secretory epithelial cells (FTSEC) that mimic early and more advanced stages of carcinogenesis. We utilize the FTSEC cells line FT282, immortalized by introducing hTERT and the aggregation-prone mutant TP53R175H that is found in p53 signature lesions and STILs, as well as the FT282-CCNE1, derived from FT282 cell line with overexpression of CCNE1, representing a more malignant phenotype.We used these models to investigate p53 aggregation, characterize the mutant p53 interactome and test the efficacy of ReACp53, a p53 aggregation-targeting peptide we developed. Our results demonstrated that p53 aggregation is more severe in the FT282-CCNE1 line, with a higher susceptibility to ReACp53 compared to the FT282 cells. Overall, our results demonstrated that aggregation of mutant p53 is a structural defect that can distinguish between pre-malignant and malignant HGSOC lesions and can potentially be targeted, offering a potential window for early intervention in halting ovarian cancer progression.
Citation Format: Sara Sartini, Lexi Omholt, Neda A. Moatamed, Alice Soragni. p53 aggregation promotes transformation from non-malignant lesions to high-grade serous ovarian carcinomas [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 3027.
Abstract 3031: Overcoming drug resistance in cancer: A paradigm shift with FoxM1 targeting
Authors: Pettersson Martin , Bae Su Jung , Cho Kyu-kwang , Yun Hye-yeoung , Park Hee-Sung 
Published: March 2024

Abstract
In cancer treatment, overcoming drug resistance remains a formidable challenge. The oncogenic transcription factor FoxM1 is widely recognized for its crucial role in promoting drug resistance to various chemotherapeutic and target therapies. Its involvement is attributed to pivotal pathways, encompassing cell cycle progression, angiogenesis, and metastasis. Despite its prominent role in tumor drug resistance, achieving modulation of FoxM1 using small molecule therapeutics has proven elusive. 5-fluorouracil (5-FU), a commonly used chemotherapeutic agent, is known to induce a significant upregulation of FoxM1. In this study, we demonstrate that our novel compound A3 leads to a robust dose-dependent reduction of FoxM1 driven by 5-FU in HT-29 colorectal cancer cells. Notably, exposure of 5-FU-treated HT-29 cells to A3 was shown to promote apoptosis via pro-apoptotic factors, including PUMA. The mechanism of action was further elucidated through a comprehensive analysis of cell signaling molecules. This study presents an innovative approach using small molecule modulators to control FoxM1 levels, providing profound insights for potential therapeutic interventions in cancer treatment.
Citation Format: Martin Pettersson, Su Jung Bae, Kyu-kwang Cho, Hye-yeoung Yun, Hee-Sung Park. Overcoming drug resistance in cancer: A paradigm shift with FoxM1 targeting [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 3031.
Abstract 3074: Regulating lactate levels in triple negative breast cancer presents a promising avenue for therapeutic intervention
Authors: Prasad Chandra Prakash , Umar Sheikh Mohammad , Dev J. R. Arundhathi , Kashyap Akanksha , Rathee Meetu 
Published: March 2024

Abstract
Introduction: Among all subtypes of breast cancer, triple-negative breast cancer (TNBC) is associated with the most unfavorable prognosis, emphasizing the critical need to pinpoint therapeutic targets tailored to TNBCs. Lactate, produced as a by-product of aerobic glycolysis, acts as an oncometabolite and plays a substantial role in promoting tumor aggressiveness, particularly in TNBCs. In our ongoing laboratory investigations, we are actively exploring strategies to mitigate the influence of lactate on TNBCs.
Methods: The experiments utilized two triple-negative breast cancer (TNBC) cell lines, i.e., MDA-MB231 and MDA-MB468. The inhibitors employed in this study are FOXY5, XAV939, PFK15, and Quercetin. Protein expression was examined using Western blotting and Immunofluorescence assays. Trans-well and wound healing assays were employed to assess cell migration and invasion. Colony formation assays (CFU) were utilized to investigate stem cell potential and proliferation. In vivo experiments were conducted using 4T1-orthotopic Balb/c mice.
Results: Using triple-negative breast cancer (TNBC) cells, we have demonstrated the pivotal role of the WNT/β-catenin signaling pathway in promoting the generation of extracellular lactate, thus driving the progression and metastasis of TNBCs. Additionally, we have shown that inhibiting lactate production in TNBC cells, and consequently impeding cell migration and invasion, can be achieved by using recombinant WNT5A or its mimicking hexa-peptide FOXY5. Similarly, employing a β-catenin inhibitor such as XAV939 can yield comparable outcomes in relation to TNBC cells. In an alternative approach, we conducted inhibition experiments targeting PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase), a key regulator of aerobic glycolysis in cancer cells. Our findings indicate that a combined approach involving siPFKL and iPFKFB3 is more promising in suppressing lactate production in TNBCs when compared to the effects of individual iPFKFB3 treatment.
Conclusions: Our present investigations suggest that employing inhibitors targeting the WNT/β-catenin signaling pathway, PFKP, and PFKEB3 could be a promising therapeutic strategy to effectively reduce lactate levels in TNBCs.
Citation Format: Chandra Prakash Prasad, Sheikh Mohammad Umar, Arundhathi Dev J. R., Akanksha Kashyap, Meetu Rathee. Regulating lactate levels in triple negative breast cancer presents a promising avenue for therapeutic intervention [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 3074.