bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1533: Long non-coding RNA control of cancer cell growth
Authors: Su Tong , Kong Bobby , Huang Calvin , Zhu Jonathan , McHugh Colleen 
Published: June 2022

Abstract
Long non-coding RNAs (lncRNAs) are involved in controlling regulatory networks critical for gene expression, cellular growth, and development. Altered expression of lncRNAs are associated with tumor progression in multiple types of human cancers, but the mechanisms by which lncRNAs may control growth and proliferation in cancer cells remain unknown in most cases. Development of interventions targeting non-coding RNA regulation of cell growth would open new avenues for cancer treatment. To identify growth regulatory pathways controlled by non-coding RNAs, we used proteomics and genomics tools to study the effect of changes in lncRNA expression levels in human cancer cell lines. First, we identified five growth regulator lncRNAs based on data mining of CRISPR/Cas9 screens and high throughput sequencing studies from patient tumor and normal cells. These lncRNAs have been associated with progression and metastasis in breast, lung and colon cancers. We hypothesized that growth regulator lncRNAs play a role in cancer development by recruiting effector proteins to regulate gene expression. Next, we evaluated the cellular growth phenotype for each lncRNA in overexpression and knockdown strains using multiple established cancer cell lines. We analyzed cellular transcriptome changes after lncRNA perturbation using high-throughput RNA sequencing. Finally, RNA-protein interactions for each growth regulator lncRNA were identified using an RNA hybridization capture method paired with mass spectrometry that enables purification of direct and specific endogenous RNA-binding proteins. Using this combination of transcriptomics and proteomics data, we discovered that perturbation of growth regulator lncRNAs results in dysregulation of growth signaling pathways and increased expression of p53. We are currently identifying the sequence and structure determinants of RNA-protein complex formation to uncover the mechanisms of action of lncRNAs in controlling cancer cell growth.
Citation Format: Tong Su, Bobby Kong, Calvin Huang, Jonathan Zhu, Colleen McHugh. Long non-coding RNA control of cancer cell growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1533.
Abstract 1541: LncRNA MALAT1 as a potential therapeutic target in triple negative breast cancer
Authors: Adewunmi Oluwatoyosi , Rosen Jeffrey 
Published: June 2022

Abstract
In the United States 1 in 8 women will be diagnosed with breast cancer within their lifetime, accounting for nearly 30% of cancer diagnoses annually. Although improvements have been made in early diagnoses and treatment, the heterogeneity of breast cancer often makes treatment of the disease a challenge. Triple negative breast cancer (TNBC) ranks as the 5th leading cause of cancer related death in women, while also being more prevalent in younger African American and Hispanic premenopausal women. The invasive nature of TNBC increases the risk of metastasis and recurrence, and patients will often acquire resistance to existing treatment options, emphasizing the need for new breast cancer therapies. A novel therapeutic approach is the inhibition of the highly abundant long noncoding RNA (lncRNA), metastasis-associated lung adenocarcinoma transcript (MALAT1) using an antisense oligonucleotide (ASO). MALAT1 has been shown to be upregulated in several breast cancer subtypes, increasing the migratory and invasive properties of tumor cells. Using a MALAT1 ASO in our preclinical syngeneic p53 null TNBC tumor mouse models, we were able to significantly knockdown MALAT1 RNA expression and observed a delay in primary tumor growth as well as an improvement in tumor response when used in combination with the chemotherapy drugs carboplatin or docetaxel. Additionally, immunophenotyping of tumor infiltrating lymphocytes show that MALAT1 inhibition alters the tumor microenvironment with a significant decrease in immunosuppressive CD206+ Arginase+ macrophages and myeloid derived suppressor cells (MDSC) as well as an increase in cytotoxic CD8+ T cells. The immuno-stimulatory effects of MALAT1 inhibition highlight the benefit of a MALAT1 ASO therapeutic and its potential to be used in combination with current chemotherapies and/or developing immunotherapies.
Citation Format: Oluwatoyosi Adewunmi, Jeffrey Rosen. LncRNA MALAT1 as a potential therapeutic target in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1541.
Abstract 1545: The cytostatic effect of miR-3189-3p in triple negative breast cancer cells involves inhibition of mitochondrial-mediated apoptosis
Authors: Vittori Cecilia , Yousefi Hassan , Reiss Krzysztof , Peruzzi Francesca 
Published: June 2022

Abstract
Our laboratory has previously characterized a microRNA, miR-3189-3p, with potent anti-cancer activity against glioblastoma and triple negative breast cancer (TNBC), two of the most aggressive types of tumors. Intriguingly, while miR-3189-3p inhibits proliferation, migration, and invasion of glioblastoma and TNBC cells, it does not induce apoptosis. The BCL2 family of proteins controls mitochondrial-mediated cell death through binding affinity and abundance of pro- and anti-apoptotic factors. Here, we investigated the mechanisms of the cytostatic effect of miR-3189-3p on MDA-MB-231 cells and found that the BCL2-family members and pro-apoptotic factors BAK1, BMF, and HRK, which are predicted gene target of this miRNA, are indeed downregulated by the miRNA mimic. In addition, we found that expression of miR-3189-3p improved the metabolic fitness of TNBC cells through increasing both mitochondrial respiration and glycolysis. Ongoing experiments are aimed at understanding how changes in the metabolic profile and cytostatic activity of miR-3189-3p could be used for therapeutic intervention against this aggressive tumor.
Citation Format: Cecilia Vittori, Hassan Yousefi, Krzysztof Reiss, Francesca Peruzzi. The cytostatic effect of miR-3189-3p in triple negative breast cancer cells involves inhibition of mitochondrial-mediated apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1545.
Abstract 155: An endosomal type Igamma PIP 5-kinase controls endosome maturation, lysosome function, and autophagy by modulating Rab7a
Authors: Sun Ming , Luong Gary , Plastikwala Faiz , Sun Yue 
Published: June 2022

Abstract
Endosomes are major protein-sorting stations in cells. Defects in endosomal sorting are implicated in various human pathologies, such as cancer and neurodegenerative disorders. The small GTPase Ras-related protein Rab-7a (Rab7a) serves as a key organizer of the endosomal-lysosomal system. However, molecular mechanisms controlling Rab7a activation levels and subcellular translocation are still poorly defined. Here, we demonstrate that type Igamma phosphatidylinositol phosphate 5-kinase i5 (PIPKIgammai5), an endosome-localized enzyme that produces phosphatidylinositol 4,5-bisphosphate (PI4,5P2), directly interacts with Rab7a and plays critical roles in the control of endosomal-lysosomal system. The loss of PIPKIgammai5 blocks Rab7a recruitment to early endosomes, which prevents the maturation of early to late endosomes. In this way, PIPKIgammai5 is required for Epidermal Growth Factor Receptor (EGFR) sorting from endosomes to lysosomes, which controls the down-regulation of EGFR signaling. Furthermore, PIPKIgammai5 loss disturbs retromer complex connection with Rab7a, which blocks the retrograde sorting of Cation-independent Mannose 6-Phosphate Receptor (CI-MPR) from late endosomes. This leads to the decreased sorting of hydrolases to lysosomes. Thus, loss of PIPKIgammai5 causes lysosome dysfunction and reduces the autophagic degradation. By modulating retromer-Rab7a connection, PIPKIgammai5 is also required for the recruitment of the GTPase-activating protein (GAP) TBC1 domain family member 5 (TBC1D5) to late endosomes, which controls the conversion of Rab7a from the active state to the inactive state. Altogether, PIPKIgammai5 is critical for the modulation of Rab7a activity, localization, and function in the endosomal-lysosomal system.
Citation Format: Ming Sun, Gary Luong, Faiz Plastikwala, Yue Sun. An endosomal type Igamma PIP 5-kinase controls endosome maturation, lysosome function, and autophagy by modulating Rab7a [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 155.
Abstract 1558: Drug repurposing strategies for pancreatic cancer management
Authors: Gaikwad Shreyas R. , Srivastava Sanjay K. 
Published: June 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the currently the third leading cause of cancer related deaths and is projected to be the second leading cause by 2030. The difficulty in diagnosis and aggressiveness of the disease makes it a difficult-to-treat cancer. Currently, treatment of PDAC mainly involves use of standard chemotherapeutic combinations. Although effective, the current options do not always provide a benefit and patients develop resistance over time. Additionally, the adverse effect profile of standard regimen is a concern. Thus, novel agents which offer better clinical and survival response are urgently required. Drug repurposing is an effective strategy to overcome the limitations in current treatment options. Through drug repurposing, we identified the anti-cancer effects of a compound MBO in human PDAC cell lines AsPC-1, MiaPaCa-2, BXPC3, Panc-1 and SUIT-2. Further, we observed the ability of MBO to suppress colony formation in PDAC cell lines AsPC-1, MiaPaCa-2 and BXPC3. Additionally, MBO induced cell death by apoptosis in PDAC cell lines which was confirmed by Annexin V/FITC analysis using flow cytometry. MBO significantly suppressed tumor growth in a subcutaneous model of PDAC. Studies are currently ongoing to explore the mechanism of action as well as effect of MBO in orthotopic PDAC models.
Citation Format: Shreyas R. Gaikwad, Sanjay K. Srivastava. Drug repurposing strategies for pancreatic cancer management [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1558.
Abstract 1566: Influence of age on fibroblast derived extracellular vesicles and their role in melanoma progression
Authors: Hueser Laura , Chhabra Yash , Gololobova Olesia , Fane Mitchell , Witwer Kenneth , Weeraratna Ashani 
Published: June 2022

Abstract
Age is an important prognostic factor in cutaneous melanoma, which commonly arises in the elderly. Melanoma progression is the concerted outcome of cellular and molecular changes that occur not just within the tumor cells but also within the milieu of the stromal cells (fibroblasts, immune cells, adipocytes), collectively referred to as the tumor microenvironment (TME). Moreover, TME-secreted growth factors, cytokines, and extracellular matrix (ECM) are vital to tumor progression and therapy resistance. Aging causes remodeling of the TME that becomes conducive to melanoma progression. In addition, extracellular vesicles (EVs) have been shown to transport lipids, mRNAs and functional proteins between different cells in vitro and across tissues in vivo. EVs have also been shown to play an important role in tumor progression in different cancer types, and aging can change their composition as well as their cargo. We performed proteomics on EVs released by young and aged dermal fibroblasts, the predominant stromal cell population of melanoma TME, to investigate how aging of the cells changes the EVs released by them. Moreover, we performed functional assays to investigate what influence this will have on the tumor progression. Our study shows that EVs secreted by dermal fibroblasts change in their composition as well as their cargo adding another dimension to age-associated increase in melanoma progression, and therapy resistance.
Citation Format: Laura Hueser, Yash Chhabra, Olesia Gololobova, Mitchell Fane, Kenneth Witwer, Ashani Weeraratna. Influence of age on fibroblast derived extracellular vesicles and their role in melanoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1566.
Abstract 1583: The interaction of stromal components and tumor cells dictates the tumor progression and clinical outcomes in stomach cancer
Authors: Lee Seungho , Kim Taemin , Cheong Jaeho , Kim Hyongbum , Lee Sunghwan 
Published: June 2022

Abstract
A subset of gastric cancers (GC) show activated epithelial-to-mesenchymal transformation (EMT), but it is of debate as to the origins of the EMT signals (i.e., from tumor cells or microenvironments) and how they are associated with clinical outcomes. In this study, we observed that mesenchymal GCs comprising 30-40% of datasets showed elevated level of infiltrating stromal cells and worse clinical outcomes. The analysis of xenograft sequencing revealed that the transcriptional signals representing EMT mainly come from stromal cells instead of tumor cells. In addition, no evidence of tumor-originating, EMT-driven stromal cells was found in single cell RNA sequencing data. Interestingly, expression of EMT signature genes in primary tumor was highly correlated with that of mouse genes. Microenvironment profiling identified a specific T cell subtypes associated with mesenchymal GCs such as T cell gamma-delta. Finally, deconvolution-based tumor, immune and stromal cells in mesenchymal GCs showed the YAP1 activation, representing the consequences of interactions of stromal component and cancer as well as defining the intrinsic and extrinsic hallmarks of mesenchymal GCs.
Citation Format: Seungho Lee, Taemin Kim, Jaeho Cheong, Hyongbum Kim, Sunghwan Lee. The interaction of stromal components and tumor cells dictates the tumor progression and clinical outcomes in stomach cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1583.
Abstract 1592: Pulsatile Myc expression as a source of Myc heterogeneity in cancer cells
Authors: Liu Chad , Gascoigne Karen 
Published: June 2022

Abstract
Myc is the most commonly amplified oncogene, and is known to play critical roles in cancer establishment and maintenance. Myc expression heterogeneity has also been linked to cancer drug resistance; however, the source of this heterogeneity remains poorly characterized. Even in isogenic cancer cell lines, we found that Myc is one of the most heterogeneously expressed transcription factors at the single-cell level. This heterogeneity is independent of cell cycle progression, local cell density, and p53/p21 signaling. To elucidate the source and duration of Myc heterogeneity, we endogenously tagged Myc with a fluorescent protein and used long-term live-cell imaging techniques to monitor Myc expression over time at single-cell resolution. Surprisingly, we found that Myc expression is pulsatile, explaining why Myc expression appears heterogeneous at a given point in time. Furthermore, we found that Myc dynamics are heterogeneous, and the dynamics are not always heritable. Additionally, Myc pulse amplitude is correlated with the duration of G1 and the overall cell cycle, suggesting that the pulses may be a mechanism for escaping many chemotherapy agents. Finally, we show that Myc pulses are primarily transcription-driven and controlled by at least one negative feedback loop. Our findings demonstrate for the first time that Myc expression is pulsatile, and provide insights into Myc regulation in cancer.
Citation Format: Chad Liu, Karen Gascoigne. Pulsatile Myc expression as a source of Myc heterogeneity in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1592.
Abstract 1597: Characterization of genomic diversity in high grade serous ovarian and triple negative breast cancer at single cell resolution
Authors: Williams Marc J. , Funnell Tyler , O'Flanagan Ciara H. , McPherson Andrew , Aparicio Samuel , Shah Sohrab P. 
Published: June 2022

Abstract
Copy number alterations and structural variants are associated with disease progression, therapeutic response, and metastasis in human cancers, yet the extent and mechanisms driving continued genomic instability remain poorly understood. We generated more than 20,000 single-cell whole genomes from 25 high-grade serous ovarian and triple-negative breast cancers across a range of mutational subtypes. Through the development of new computational methods, we resolved alterations into cancer haplotypes, providing fine-grained resolution of genomic events in single-cells and exposing extensive cell-to-cell genomic variation. We identified 3 key processes that contribute to this diversity. Firstly, we observed that parallel copy number events - whereby different cancer cells harbor chromosomal aberrations with identical total copy number but different combinations of maternal and paternal alleles - were present in &gt; 80% of the tumors. This is consistent with extensive convergent evolution in these tumors. Secondly, we identified considerable cell-to-cell variability in the amplitude of high-level amplifications, often impacting oncogenes. Single-cell transcriptomes and immunohistochemistry from the same samples showed that this genomic diversity led to phenotypic differences between cells. Finally, we observed copy number break-point variability consistent with progressive genomic diversification, which we termed serriform structural variation (SSV). Both SSV’s and variable high-level amplifications were enriched in foldback inversion (FBI) bearing tumors relative to homologous recombination deficient tumors, highlighting that FBI tumors have greater levels of structural instability. Our study sheds new light on the evolution of genomically unstable tumors with implications for cancer evolution, therapeutic targeting, and patient stratification.
Citation Format: Marc J. Williams, Tyler Funnell, Ciara H. O'Flanagan, Andrew McPherson, Samuel Aparicio, Sohrab P. Shah. Characterization of genomic diversity in high grade serous ovarian and triple negative breast cancer at single cell resolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1597.
Abstract 1602: Lineage plasticity enables low ER luminal tumors to evolve and gain basal-like traits
Authors: Mohamed Gadisti Aisha Nurulhijjah Binti , Ognjenovic Nevena B. , Mahmood Sundis , Lee Sarah Min Kyung , Christensen Brock C. , Muller Kristen E. , Pattabiraman Diwakar R. 
Published: June 2022

Abstract
Stratifying breast cancer into specific molecular or histological subtypes aids in therapeutic decision-making and predicting outcomes, however, these subtypes may not be as distinct as previously thought. Patients with luminal-like, Estrogen Receptor (ER)-expressing tumors have better prognosis than patients with more aggressive, triple-negative or basal-like tumors. There is, however, a subset of luminal-like tumors that express lower levels of ER, which exhibit more basal-like features. Previous studies have suggested that triple negative, basal-like tumors may arise from a luminal cell-of-origin, but there are no definitive studies that identify the cell-of-origin of these low ER tumors.
Analysis of 2208 invasive breast carcinomas from 2012-2020 revealed that 2% of tumors have low ER expression (less than 10% ER positive cells), which are mostly high-grade carcinomas and exhibit basal-like features. TCGA analysis revealed that tumors with lower ER expression (lowest quartile of ER expression) expressed higher basal signature genes as compared to tumors with higher levels of ER expression. This variation within the ER+ subtype and the emergence of basal-like characteristics within low ER tumors suggest that some luminal tumors may evolve into a more basal-like or triple-negative subtype.
The luminal mouse mammary tumor, MMTV-PyMT, was used to model low ER human tumors and, similar to the patient tumor samples, basal-like tumor cells were also found within these tumors. Lineage tracing using tissue-specific and inducible Cre recombinase-based labelling was performed to elucidate the lineage-of-origin of these basal-like cells, revealing that these basal-like cells were derived from normal luminal epithelial cells, not basal cells.
Our study uncovers the existence of luminal-basal plasticity within tumors of a low ER subtype that enables these cells to transition into a more basal-like state. Understanding the factors that enable this plasticity to occur may reveal opportunities to curb the evolution of more aggressive traits, potentially improving the way breast cancer is currently managed and treated.
Citation Format: Gadisti Aisha Nurulhijjah Binti Mohamed, Nevena B. Ognjenovic, Sundis Mahmood, Sarah Min Kyung Lee, Brock C. Christensen, Kristen E. Muller, Diwakar R. Pattabiraman. Lineage plasticity enables low ER luminal tumors to evolve and gain basal-like traits [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1602.