bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3660: Bone mechanics influence cancer stem cell formation in osteosarcoma
Authors: Shoaib Zunaira , Tiffany Aleczandria S. , Harley Brendan , Irudayaraj Joseph , Fan Timothy M. 
Published: April 2023

Abstract
Osteosarcoma (OS) is the most common primary tumor of bone and is characterized by rapid bone remodeling accompanied by structural and mechanical heterogeneity across the tumor. Chemoresistance and recurrence of OS can be attributed to a subpopulation of OS cells known as cancer stem-like cells (OS-CSCs). It can be hypothesized that tumor niches possessing distinct structural and mechanical properties could be harboring different OS cell populations, and certain niches might be more conducive for OS-CSCs formation and maintenance.
To evaluate the presence of OS-CSCs, mineralized collagen scaffolds mimicking heterogenous bone niches with distinct structural and mechanical properties were fabricated by changing collagen content and pore alignment and were cultured with the highly metastatic human OS cell line 143B. Scaffolds with 47% collagen by weight but different pore alignment were chosen for further analysis because they possessed different stiffness and topographical properties. Cytoskeletal changes, epigenetic changes, chemoresistance and chemoresistance-related pathways, and the levels of stemness genes were assessed in the 3D scaffold cultures.
A consistent trend of OS-CSC phenotype was observed in the cell population grown in the softer bone niches (12 kPa) with aligned pores as compared to stiffer niche (31 kPa) with non-aligned pores. The cell population growing in softer, aligned scaffolds had a significantly higher expression of stemness genes (OCT4, NANOG, SOX2, ALDH1A1) and drug efflux gene ABCB1 and increased chemoresistance to doxorubicin and cisplatin. Epigenetic changes associated with cisplatin resistance in OS such as a decrease in methyl transferase EZH2 accompanied by the upregulation of LIF/Notch and PRKCA pathways was observed in cells grown in softer, aligned niches. Fluorescent imaging of actin organization showed rounder cells in the aligned niche indicative of the CSC phenotype, and stretched, elongated cells in the non-aligned niche indicative of a differentiated phenotype.
Our study showed that the mechanical and structural properties of bone niches influence the formation of distinct OS cell populations. A softer niche with an aligned structure is more conducive for maintaining OS-CSCs.
Citation Format: Zunaira Shoaib, Aleczandria S. Tiffany, Brendan Harley, Joseph Irudayaraj, Timothy M. Fan. Bone mechanics influence cancer stem cell formation in osteosarcoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3660.
Abstract 3681: c-MAF-driven metabolic reprogramming mediates H3K27 hyperacetylation to regulate super enhancer-associated genes
Authors: Chong Phyllis SY , Lim Sze Lynn Julia , Zhou Jianbiao , Leow Aaron Chung Yong , Chng Wee Joo 
Published: April 2023

Abstract
Overexpression of transcription factor c-MAF is found in about 50% of multiple myeloma cases, and associated with the prognostically unfavorable t(14;16) translocation subtype. Genetic alterations can modify the epigenome through metabolite availability that act as substrates in histone modifications, but how this translates into specificities in gene regulation is unclear. Here, we report a novel involvement of c-MAF in metabolically-driven histone acetylation, including the superenhancer mark H3K27ac, through altering acetyl-CoA metabolism. To sustain high levels of acetylation, c-MAF acquired the metabolic flexibility to utilize glutamine in addition to glucose, feeding into the tricarboxylic acid (TCA) cycle as acetyl-CoA sources. Loss-of-function studies indicated that c-MAF is important for citrate-derived acetyl-CoA and H3K27ac levels through metabolic enzymes citrate synthase (CS) and ATP-citrate lyase (ACLY). Furthermore, blocking citrate export from mitochondrial via CRISPR/Cas9 targeting of SLC25A1 reproduced the reductions in H3K27ac. Silencing of c-MAF also displayed defective mitochondrial oxidative phosphorylation attributed to reduced metabolic flux through TCA cycle and downregulation of electron transport chain complex I/II expression, without affecting mitochondrial DNA content. To identify c-MAF-regulated superenhancer genes, we overlapped our previously published H3K27ac ChIP-seq dataset on t(14;16) MM cell lines with c-MAF RNA-seq data. We found signal enrichment of H3K27ac at ZC3H3 locus responsible for its transcriptional upregulation, and knockdown of ZC3H3 inhibited cell growth specifically in the t(14;16) subtype. Altogether, we demonstrated a non-canonical c-MAF role in epigenetics that is connected to its altered metabolic state, and suggest metabolic disruptions as a new therapeutic direction in t(14;16) myeloma.
Citation Format: Phyllis SY Chong, Sze Lynn Julia Lim, Jianbiao Zhou, Aaron Chung Yong Leow, Wee Joo Chng. c-MAF-driven metabolic reprogramming mediates H3K27 hyperacetylation to regulate super enhancer-associated genes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3681.
Abstract 3688: Exploring metabolic vulnerabilities of metastatic prostate cancer to bone
Authors: Mossa Federica , Robesti Daniele , Vellano Christopher , Titus Mark , Marszalek Joe , Frigo Daniel , Logothetis Christopher , Gujral Taranjit , Dondossola Eleonora 
Published: April 2023

Abstract
Currently, limited knowledge is available on subtype-specific metabolic features and their implications for treatment. Here, we investigated the metabolic determinants of the two major subtypes of castration-resistant prostate cancer (androgen receptor-expressing prostate cancer, ARPC; and aggressive variant prostate cancer, AVPC). Transcriptomic analyses revealed enrichment of gene sets involved in oxidative phosphorylation in ARPC tumor samples compared to AVPC. Unbiased screening of metabolic signaling pathways in PDX models by proteomic analyses further supported an enrichment of oxidative phosphorylation in ARPC compared to AVPC, and a skewing toward glycolysis by AVPC. Metabolic in vitro analyses showed that C4-2B cells depended on aerobic respiration, while PC3 cells relied more heavily on glycolysis, as further confirmed by pharmacological interference using IACS-010759, a clinical grade inhibitor of oxidative phosphorylation tested in patients. In vivo studies confirmed a significant reduction by IACS-010759 in C4-2B tumors implanted subcutaneously or in bone, and no effect in subcutaneous PC3 tumors. Unexpectedly, PC3 tumors in bone responded to IACS-010759, indicating a microenvironment-induced metabolic reprogramming. These results suggest that castration-resistant ARPC and AVPC exhibit different metabolic dependencies with aerobic respiration being a major driver of ARPC, while AVPC depends on glycolysis, but can undergo metabolic reprogramming in bone. Such metabolic vulnerabilities may be exploited to either introduce further lines of treatments or in combination with the existing therapies. These findings also underscore the important role that the tumor microenvironment can play in reprogramming prostate cancer metabolism and thus, influence the efficacy of metabolically targeted therapies.
Citation Format: Federica Mossa, Daniele Robesti, Christopher Vellano, Mark Titus, Joe Marszalek, Daniel Frigo, Christopher Logothetis, Taranjit Gujral, Eleonora Dondossola. Exploring metabolic vulnerabilities of metastatic prostate cancer to bone. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3688.
Abstract 370: Potential of inflammation pro-resolving lipid mediators in controlling cancer cachexia
Authors: Attaya Ahmed , Haak Victoria , Kelly Abigail , Yang Haixia , Rothenberger Eva , Freedman Steven D. , Serhan Charles N. , Panigrahy Dipak 
Published: April 2023

Abstract
Most people with advanced cancer exhibit cachexia, a syndrome of progressive weight loss that leads to the death of 20% of patients. The mechanisms underlying cachexia remain poorly understood and, as a result, no treatment has proven effective to date. Cachexia is characterized by systemic hyperinflammation, massive apoptotic cell death (“debris”), and skeletal muscle wasting. Here, we hypothesize that disrupted resolution of inflammation contributes to cancer cachexia, and pro-resolving lipid mediators, specifically novel specialized pro-resolving mediators (SPMs), could control cachexia. SPMs enhance resolution of inflammation by stimulating debris clearance, promoting tissue regeneration, and regulating major immune cell types. In testing our hypothesis, we profiled lipid mediators in a variety of metastatic cachexia models via metabololipidomics and investigated the changes of leukocytes, e.g., T lymphocyte, natural killer (NK), and macrophage cells, in various skeletal muscles (e.g., tibialis anterior and gastrocnemius). Dysregulation of SPMs was identified in different tissues in 5 cachexia models. The SPMs resolvin (RvD)2 and maresin (MaR)1 were reduced in the liver and spleen of colon cancer (CT26)-induced cachectic mice on day 35 post-tumor cell injection and RvD1, RvD2, lipoxin (LXA)4, and MaR1 were dysregulated in Lewis lung carcinoma (LLC)-induced cachectic mice on day 20. Chemotherapy was also found to dysregulate SPMs and induce cachexia in lymphoma (EL4) and ovarian cancer (ID8) mouse models. Ten days post-LLC tumor resection, the RvD1 receptor (ALX/FPR2) KO and RvE1 receptor (ChemR23/ERV) KO mice exhibited a 20-23% loss in body weight compared to WT mice. This shows that neutralizing the pro-resolving activity of RvD1 and RvE1 induces cancer cachexia. Moreover, RvD2 and PCTR (protectin conjugates in tissue regeneration)-2 prevented LLC- and B16F10 melanoma-induced cachexia at 15 ng/day. RvD4, RvD5, MCTR1, or MCTR2 inhibited inflammation-stimulated cytokine storm by counter-regulating the production of CCL3, CCL4, CXCL2, TNF-α, CCL2, G-CSF, and PAI-1. These results indicate that disrupted resolution of inflammation leads to the progression of cancer cachexia, and dysregulated SPMs are potential early markers for cachexia. This study provides a basis for the clinical translation of SPM-directed treatments as a new direction to potentially control cancer cachexia in humans.
Citation Format: Ahmed Attaya, Victoria Haak, Abigail Kelly, Haixia Yang, Eva Rothenberger, Steven D. Freedman, Charles N. Serhan, Dipak Panigrahy. Potential of inflammation pro-resolving lipid mediators in controlling cancer cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 370.
Abstract 3708: Platelet-derived microparticles modulate breast cancer malignant processes
Authors: Veilleux Vanessa , Pichaud Nicolas , Boudreau Luc H. , Robichaud Gilles A. 
Published: April 2023

Abstract
Breast cancer is one of the leading causes of morbidity and mortality among women, where metastasis accounts for the majority of deaths associated with this disease. Thus, the potential to effectively target tumor malignancy offers hope to mitigate disease progression and improve patient outcomes. It is well established that platelets promote multiple processes of metastasis cascade. Recently, platelets have received new attention for their impact in cancer through the production of platelet-derived microparticles (PMPs). Interestingly, PMPs allow intercellular exchange and trafficking of bioactive material through the internalization of these vesicles into recipient cells. As a result, the delivery of the intravesicular cargo can modulate signaling and activation processes of recipient cells. We recently identified a new subpopulation of these vesicles (termed mitoMPs) containing functional mitochondria. Given the predominant role of mitochondria in cancer malignancy, we believe that mitoMPs provide an important source of foreign mitochondria to support recipient breast cancer cells in malignancy and disease progression. We therefore set out to study the impact of mitoMPs on breast cancer metabolic and phenotypic processes involved in metastasis. Technically, PMPs were generated and purified from human blood platelets and co-incubated with various breast cell models (MB231, MCF7 and MCF10A). The physiological significance of mitoMPs in breast cancer disease was then assessed using various cellular and molecular assays. We demonstrate that the level of PMP internalization is highly dependent upon the type of breast cancer recipient cells. Furthermore, we show that the cargo of mitoMPs (notably mitochondria) is biologically active where recipient breast cancer cells acquired mitochondria-dependent functions, such as increased oxygen consumption rates and intracellular ATP production. Finally, we observe that mitoMPs promote malignant features such as cancer cell migration and invasion. Overall, we demonstrate that PMPs can modulate cancer cell activation and behaviour. These findings provide a better understanding of the extracellular tumor environment and the contribution of mitoMPs in supporting breast cancer cells through the metastatic landscape. The knowledge gained will further provide new avenues for therapeutic strategies in breast cancer patients.
Citation Format: Vanessa Veilleux, Nicolas Pichaud, Luc H. Boudreau, Gilles A. Robichaud. Platelet-derived microparticles modulate breast cancer malignant processes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3708.
Abstract 3715: Pharmacological targeting of circadian clock genes reveals regulatory mechanisms of E-box regulated genes in cancer
Authors: Pan Yuanzhong , Lenz Heinz-Josef , Torres Evanthia Roussos , Kay Steve A. 
Published: April 2023

Abstract
Transcription factors (TFs) are key regulators of homeostasis and cancer. Recent advances in pharmacological targeting of TFs makes them valuable targets in various diseases, but systems-level understanding of the function and regulation of TFs from different families in cancers remains lacking. Our lab and collaborators have been developing new small molecules to modulate the functions of key regulators of the circadian clock BMAL1 and CLOCK, which are bHLH family TFs that activate gene expression by binding to a DNA motif called E-box, with a consensus sequence of CANNTG. E-boxes are ubiquitous in the genome and broadly regulate essential physiological processes of the cell, but their molecular biology in cancer is largely unknown. In the current work we tested the ability of small molecules to regulate the expression of BMAL1 and CLOCK target genes. Across different cell lines of various cancer types, we found that stabilization of one of the negative regulators of CLOCK, CRY2, by our novel compound called SHP1705, is the most consistent to suppress canonical BMAL1 target genes. GO and GSEA analysis of RNA-seq data shows that SHP1705 also significantly changed most core regulators of circadian rhythms as well as other E-box-binding proteins. However, SHP1705 has IC50 values above 10µM in most tested cells, creating a challenge for efficacy in a clinical setting. Because BMAL1 requires the proteasome to sustain the turnover of a transcription burst, we hypothesized proteasome inhibitors (PI) MG132 and carfilzomib may synergize with SHP1705. Consequently, we found strong synergy with both PIs. Analysis of TF-target genes in combination-treated cells reveals significant changes in expression profiles, suggesting that these genes are regulated by E-box, and other related/alternative promoter elements: CCAAT-box, CG-rich motifs, and ATGGC. Co-enrichment of these elements revealed the components of E-box containing promoters and showed potential properties of E-box-regulated gene expression. Co-existence of these motifs in the same proximal promoter also potentially allows RNAPII multiple choices of alternative promoters and could promote expression of variants in cancer cells. Our results support the necessity of inhibiting the whole promoter and provide an example of how to approach designer pharmacological strategies to achieve this purpose.
Citation Format: Yuanzhong Pan, Heinz-Josef Lenz, Evanthia Roussos Torres, Steve A. Kay. Pharmacological targeting of circadian clock genes reveals regulatory mechanisms of E-box regulated genes in cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3715.
Abstract 3719: Targeting the eIF6 and 60S ribosomal subunit interaction interface in cancers
Authors: Harish Kavya Meena , Biswas Aparna , Roshan Poonam , Origanti Sofia 
Published: April 2023

Abstract
Translational control is integral to cancer initiation and progression. A subset of translation initiation factors are deregulated in cancers to facilitate their rampant growth and proliferation. Eukaryotic translation initiation factor 6 (eIF6) is one such factor that is over expressed in many cancers including lung, colon, ovarian and breast cancers, and deregulation of eIF6 is correlated with a poor cancer prognosis. Association of eIF6 with 60S is critical for 60S assembly. However, eIF6 must be released from 60S prior to translation to permit inter subunit interactions between 60S and 40S and to facilitate the formation of translationally proficient 80S complex. Release of eIF6 is deregulated in the ribosomopathy- Shwachman Diamond Syndrome that is predisposed to leukemias. Also, loss of eIF6 markedly delays tumorigenesis without affecting normal growth, which presents eIF6 as a viable therapeutic target. A potential therapeutic strategy is to target the eIF6 and 60S ribosomal interaction interface. Through extensive biophysical analyses, we had identified residues that are critical for the interaction between eIF6 and 60S ribosomal subunit. We show that targeting these key residues in the eIF6-60S interaction interface markedly delays colonic cancer growth and inhibits protein synthesis. Interestingly, targeting eIF6 leads to an upregulation of p53 independent of the DNA damage response, suggesting that ribosomal stress contributes to the stabilization of p53. Future studies will determine the mRNA targets that are translationally deregulated by inactivation of eIF6. We will also determine the effect of targeting eIF6 function in inhibiting tumor growth and progression in vivo.
Citation Format: Kavya Meena Harish, Aparna Biswas, Poonam Roshan, Sofia Origanti. Targeting the eIF6 and 60S ribosomal subunit interaction interface in cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3719.
Abstract 3720: Cysteine palmitoylation of astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) regulates its biological and immunological activity
Authors: Del Carmen Camarena Maria , Komaniecki Garrison , Manna Debashri , Mendoza Rachel , Subler Mark A. , Windle Jolene J. , Dozmorov Mikhail G. , Lin Hening , Sarkar Devanand 
Published: April 2023

Abstract
Non-alcoholic steatohepatitis (NASH) is a major risk factor for hepatocellular carcinoma (HCC). Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) augments steatosis, inflammation, and tumorigenesis, thereby promoting the whole spectrum of this disease process. Targeting AEG-1 is a potential interventional strategy for NASH and HCC. Thus, proper understanding of the regulation of this molecule is essential. We found that AEG-1 is palmitoylated at residue Cysteine75 (Cys75). Mutation of Cys75 to Serine (Ser) completely abolished AEG-1 palmitoylation.Systematic knockdown studies identified zinc finger DHHC-type palmitoyltransferase 6 (ZDHHC6) as the palmitoyltransferase catalyzing the process. To obtain insight into how palmitoylation regulates AEG-1 function, we generated a knock-in mouse by CRISPR/Cas9 in which Cys75 of AEG-1 was mutated to Ser (AEG-1-C75S). No developmental or anatomical abnormality was observed between AEG-1-wild type (AEG-1-WT) and AEG-1-C75S littermates. However, global gene expression analysis by RNA-sequencing unraveled that signaling pathways and upstream regulators, which contribute to cell proliferation, motility, inflammation,angiogenesis, and lipid accumulation, are activated in AEG-1-C75S hepatocytes compared toAEG-1-WT. Feeding these mice with high fat/high sugar diet for 20 weeks showed accumulation of T-regulatory cells and exhausted CD8 T-cells in the livers of AEG-1-C75S mice vs AEG-1-WT, and only in females, suggesting that inhibition of AEG-1 palmitoylation creates an immunosuppressive milieu favoring tumorigenesis. Collectively, these findings suggest that AEG-1-C75S functions as dominant positive, and palmitoylation restricts oncogenic and NASH-promoting functions of AEG-1. Studies are ongoing to unravel the mechanism by which palmitoylation restricts AEG-1 function, and to understand the sex-specific immune-modulatory role of AEG-1 palmitoylation in hepatocarcinogenesis.
Citation Format: Maria Del Carmen Camarena, Garrison Komaniecki, Debashri Manna, Rachel Mendoza, Mark A. Subler, Jolene J. Windle, Mikhail G. Dozmorov, Hening Lin, Devanand Sarkar. Cysteine palmitoylation of astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) regulates its biological and immunological activity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3720.
Abstract 3727: Development of a new All-In-One inducible lentiviral shRNA/gRNA Vector
Authors: Wu Lipeng , Su Hua , Fellows Justin , Fu Mao , Heller Julian , Park Brian , Yin Dezhong 
Published: April 2023

Abstract
Tet-On is a powerful inducible system and a classical tool to regulate gene expression in mammalian cells. It has also been applied to regulate Pol III-driven transcription, such as shRNA or gRNA driven by a U6 or H1 promoter. However, all of the current versions of Tet-On shRNA vectors are based on H1-2O2 or U6-2O2 promoters, which are only compatible with first-generation tetracycline repressor TetR. In addition, these promoters have the problem of driving downstream transcription without the binding of the Tet regulatory protein. Here, we developed a new system that is built upon tetracycline activator protein, Tet-On 3G, combined with a new structure of Tet responsive promoter H1-4O4, which tightly regulates the downstream transcription of gRNA or shRNA. The responsiveness of our system to Doxycycline regulation is dramatically improved compared with the current versions. The new Tet-On system is further optimized into a compact structure to be compatible with the lentivirus package (All-In-One Lenti-Tet-On system), which still keeps the leaky expression at an undetectable level. Combined with all these features, the new generation of the Tet-On system offers broad applications in gene knocking down and genomic editing.
Citation Format: Lipeng Wu, Hua Su, Justin Fellows, Mao Fu, Julian Heller, Brian Park, Dezhong Yin. Development of a new All-In-One inducible lentiviral shRNA/gRNA Vector. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3727.