bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 439: From foe to friend: In vivo reprogramming of tumor-associated macrophages to an anti-cancer phenotype by modulating N-myristoyltransferase activity
Authors: Kallemeijn Wouter W. , Spear Sarah , Walton Josephine , Bussi Claudio , Soudy Christelle , Flynn Helen R. , Skehel Mark , Carling David , Solari Roberto , McNeish Iain A. , Tate Edward W. 
Published: April 2023

Abstract
Tumor-associated macrophages (TAMs) play a central role in cancer by driving tumor growth, metastasis, therapy failure and cancer recurrence. Macrophage plasticity and diversity allows classification along a M1-M2 polarization axis, where TAMs have a M2-like polarization, associated with a pro-tumoral phenotype, whereas M1 macrophages exhibit anti-tumor functions. Reprogramming TAMs to a M1-like anti-cancer phenotype is an increasingly coveted therapeutic strategy in oncology. Here, we report TAMs can be favorably reprogrammed by modulating N-myristoyltransferase (NMT) activity using on-target, drug-like inhibitors (NMTi). We identified &gt;100 N-myristoylated proteins differentially expressed by macrophages along the M1-M2 polarization axis. In TAM-like M2 macrophages, 42 N-myristoylated proteins exhibited higher NMTi sensitivity as compared to other polarizations, and these NMT substrates significantly enriched in anti-inflammatory, immunity- and metabolism-related pathways. Unique to TAM-like M2 macrophages, NMT modulation by NMTi induces significant transcriptomic and proteomic changes, effectively switching the polarization towards a M1-like anti-cancer phenotype that is characterized by a M1-like spindle morphology, a M1-like glycolytic state, and induction of a pro-inflammatory secretome exhibiting potent anti-tumoral activity towards ovarian cancer spheroids in vitro. In vivo proof-of-principle was established in the syngeneic, macrophage-driven ID8 mouse model for human ovarian cancer, where NMTi treatment significantly reprogrammed murine M2-like TAMs into a M1-like anti-cancer phenotype, concomitantly reducing tumor burden without observable side-effects, and significantly extending median survival by 16 days. We are currently further investigating the intricacies that N-myristoylation plays in macrophage polarization, as well as further establishing the scope of NMTi-driven in vivo reprogramming of TAMs beyond ovarian cancer.
Citation Format: Wouter W. Kallemeijn, Sarah Spear, Josephine Walton, Claudio Bussi, Christelle Soudy, Helen R. Flynn, Mark Skehel, David Carling, Roberto Solari, Iain A. McNeish, Edward W. Tate. From foe to friend: In vivo reprogramming of tumor-associated macrophages to an anti-cancer phenotype by modulating N-myristoyltransferase 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 439.
Abstract 4486: Proof of principle for pharmacogenomic-guided precision oncology for pediatric malignancy
Authors: Lee Gi Ju , Choi Seung-Won , Choi Seung Ah , Cho Hee-Jin , Gartrell Robyn , Lee Ji Won , Kim Joo Whan , Her Nam-Gu , Rabadan Raul , Sung Ki Woong , Nam Do-Hyun , Kim Seung-Ki 
Published: April 2023

Abstract
Childhood cancers are rare and clinically diverse. They are typically associated with few driver mutational events than adult cancers, constituting potential targets for patient-specific precision therapy approaches. Here, we evaluated the feasibility of using a patient-derived tumor cell (PDC) based drug screening system and integrated multi-omics data to achieve precision oncology for pediatric patients. We established a PDC library derived from a few passage-cultured tumor cells from surgically resected tumor specimens and conducted chemical screening, which composed of various target agents of major oncogenic pathways (e.g. receptor tyrosine kinase inhibitor, proteasome inhibitor and histone deacetylase etc.). Next Generation Sequencing was performed to characterize the genomic and transcriptomic traits of tumors. Overall, success of establishing PDCs of pediatric cancers was high (80.4%) and comparable to adult cancers. The amount of obtained tissue was an important factor for the success of PDC establishment; the estimated optimal weight for PDC establishment was small (1.14g) and it is noteworthy that a small amount of tumor sample is sufficient to identify the potential hit(s) of parental tumors. The platform provided therapeutic options to pediatric tumors regardless of actionable targets. Our PDC approach identified several potential gene-drug associations, including anti-PI3K/Akt agents for neuroblastomas and anti-SHH agents for sarcomas with EWSR1 fusion. Given that a considerable proportion of pediatric tumors still lack actionable targets with matched treatment options, PDC-based drug screening profiles can be an optimal therapeutic strategy for these cases. Collectively, our analysis confirmed the feasibility of PDC-based in vitro drug screening systems to guide the therapeutic strategy for pediatric patients. This approach will accelerate the preclinical research for pediatric tumors to understand their pathophysiology and investigate the potential therapeutic strategies to fulfill the future precision oncology.
Citation Format: Gi Ju Lee, Seung-Won Choi, Seung Ah Choi, Hee-Jin Cho, Robyn Gartrell, Ji Won Lee, Joo Whan Kim, Nam-Gu Her, Raul Rabadan, Ki Woong Sung, Do-Hyun Nam, Seung-Ki Kim. Proof of principle for pharmacogenomic-guided precision oncology for pediatric malignancy. [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 4486.
Abstract 4495: A mechanistic study of the TFE3-splicing machinery gene fusions reveals a new druggable target for translocation renal cell carcinoma
Authors: Damayanti Nur , Orsi Sabrina , Cordova Ricardo , Rupert Christopher , Shen Li , Linehan William Marston , Staschke Kirk , Hollenhorst Peter , Heppner David , Pili Roberto 
Published: April 2023

Abstract
TFE3 is a member of basic helix-loop-helix leucine zipper MiT transcription factor family and its chimeric proteins are associated with translocation renal cell carcinoma (tRCC). Despite the variety of genes fusions, most of TFE3 fusions partner genes are linked to spliceosome machinery. Dissecting the function of TFE3 fused to spliceosome machinery factors (TFE3-SF) could direct the development of effective therapies for this lethal disease, which is refractory to standard treatments for kidney cancer. Here, by using a combination of in silico structure prediction, molecular cloning, next generation transcriptomics, FRET technology, mutagenesis, proteomics, and high-throughput high-content screening (HTHCS) we interrogated a series of oncogenic mechanisms of TFE3-SF-containing fusions, including spontaneous nuclear translocation, nuclear paraspeckle occupancy, enhanced in vitro proliferation and in vivo growth, transcriptome remodeling, alternative splicing reprogramming, and novel dimer partner recruitment. Molecular inhibition of TFE3-SF dimerization reverses its oncogenic activity and represents a potential new target for therapeutic intervention. By using HTHCS combined with FRET technology we screened FDA approved drugs library (LOPAC) and small molecule library (Microsource) and identified hits compounds which inhibit TFE3-SF dimerization. Hits compounds were validated in 2D and 3D models utilizing patient derived xenolines expressing TFE3-SF. Ouabain and terfenadine demonstrated decreased cell proliferation, reduced spheroid growth and in vivo tumor growth. Overall, our results unmask synthetic vulnerabilities of TFE3-SF dimerization for novel therapeutic strategies in patients with this aggressive type of kidney cancer.
Citation Format: Nur Damayanti, Sabrina Orsi, Ricardo Cordova, Christopher Rupert, Li Shen, William Marston Linehan, Kirk Staschke, Peter Hollenhorst, David Heppner, Roberto Pili. A mechanistic study of the TFE3-splicing machinery gene fusions reveals a new druggable target for translocation renal cell carcinoma. [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 4495.
Abstract 4553: How do shiitake and reishi mushrooms work on lung cancer?: A high throughput screening of 3D cell culture
Authors: Yang Mihi , Jang Hee-Kyung , Kang Huiwon 
Published: April 2023

Abstract
Shiitake (Lentinula edodes) and reishi mushrooms (Ganoderma sichuanense) have been noticed for desirable chemoprevention, such as improving immunity, overcoming anticancer drug resistance, etc. Particularly, beta-glucans have been mostly mentioned as the active component of the mushrooms. However, the right preparation and effective usage of the mushrooms for cancers are unclear, yet. Thus, we screened various extractions of the two mushrooms and combinations of the extracts, using a high throughput screening of 3D cell culture system on 384-pillar plates with various cancer cells and Cell Titer-Glo 3D cell viability assay kit (Promega). We also quantified the beta-glucans in all extractions with the Megazyme Mushroom and Yeast Beta-Glucan kit (K-YBGL) by excluding the alpha-glucans content from the total-glucans. As results, most of the extracts showed cytotoxicity on the lung cancer cells, A549 cells, rather than on the other cells, such as HepG2 (N=9 for each treatment). The extracts of reishi mushroom in 60% of methanol (dose range, 0.21-2.3 mg/ml) showed the strongest cytotoxicity on the lung cells, IC50=0.90 +/- 0.01 mg/ml, among the extracts of different methanol contents (10-60%) or different temperatures (50-90 °C) of hot water. However, the 60 % of methanol reishi extracts included relatively low levels of beta-glucans, compared to other extracts (18.57 +/- 0.31 vs. 22.42 +/- 5.56 % w/w). In addition, the levels of beta-glucans in all of reishi mushroom extracts were lower than those in all of the shiitake extracts (17.70 +/- 1.89 % vs. 27.05 +/- 4.21 % w/w: p&lt;0.01). Moreover, there was no association between the levels of beta-glucans and IC50 in A549 cells. Interestingly, the combination (1:1) of the above 60% of methanol extracts of reishi mushroom and the 30% methanol extracts of shiitake (dose range, 0.30-3.26 mg/ml) showed synergic effects, i.e., 2-7 fold stronger effects (average of IC50=0.40 mg/ml) than every single treatment (average of IC50=0.90-2.63 mg/ml). Taken together, the reishi mushroom may have other strong chemopreventive materials rather than beta-glucans, while the shiitake may have a potentiation effect, when combined with the reishi mushroom. In conclusion, our 3D cell culture system showed high throughput performance to find the right preparation and effective usage of the two mushrooms and provided useful information for the next clinical studies for lung cancer.
Citation Format: Mihi Yang, Hee-Kyung Jang, Huiwon Kang. How do shiitake and reishi mushrooms work on lung cancer?: A high throughput screening of 3D cell culture. [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 4553.
Abstract 4673: Therapeutic potential of polatuzumab vedotin for the treatment of diffuse large B-cell lymphoma
Authors: Qi Hui , Wang Fuyang , Han Bingrui , Wang Xiaomin , Qiang Xiangnan , Zhang Zhixiang , Gu Qiangyang 
Published: April 2023

Abstract
Background Diffuse large B-cell lymphoma (DLBCL) is typically treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Although most patients can be cured with R-CHOP, up to one-third of them relapses with a dismal outcome in most cases. Numerous approaches have been attempted to improve the treatment outcomes with R-CHOP. Polatuzumab vedotin is an antibody-drug conjugate targeting CD79b, which is ubiquitously expressed on over 90% of B-cell NHL malignancies, including DLBCL. To determine the potential of polatuzumab vedotin as a therapeutic agent, we evaluate its potency across a series of DLBCL patient derived xenograft (PDX) models.
Method We established and characterized a series of DLBCL lymphoma PDX models. Eight DLBCL PDX models were selected for polatuzumab vedotin efficacy study, of which three are GCB DLBCL. Gene expression analysis of these lymphoma PDX models was performed using an Illumina NovaSeq 6000 system following Illumina-provided protocols for 2 × 150 paired-end sequencing. The expression status of CD79b on these DLBCL PDX models was also evaluated by IHC.
Conclusion Our data showed that a single dose of polatuzumab vedotin at just 2 mg/kg could reached a comparable effect with R-CHOP and no significant body weight loss was observed. Our result showed that there is no apparent correlation between polatuzumab vedotin responses (TGI) and the CD79b expression (IHC Score). Although polatuzumab vedotin demonstrated encouraging activity in the treatment of DLBCL, some of the PDX models are also resistant to polatuzumab vedotin treatment. To further investigate the molecular parameters of the relative sensitivity of polatuzumab vedotin. Gene expression profiling of those PDX models and their sensitivity to polatuzumab vedotin were conducted, we found that the expression level of BCL-XL was correlated with reduced sensitivity to polatuzumab vedotin.
Citation Format: Hui Qi, Fuyang Wang, Bingrui Han, Xiaomin Wang, Xiangnan Qiang, Zhixiang Zhang, Qiangyang Gu. Therapeutic potential of polatuzumab vedotin for the treatment of diffuse large B-cell lymphoma. [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 4673.
Abstract 4814: Compensatory interplay of p97 segregase and HSP70 chaperone protect cancer cells from heat-induced proteotoxicity
Authors: Skrott Zdenek , Chroma Katarina , Muller Petr , Panacek Ales , Bartek Jiri , Mistrik Martin 
Published: April 2023

Abstract
Due to malignant transformation, cancer cells are characterized by elevated levels of genotoxic, replication or proteotoxic stresses, which makes them vulnerable to various external conditions, including increased temperature. Thus, hyperthermia represents a very effective therapeutic modality usually combined with standard chemotherapy or radiation. Moreover, the elevated temperature is often used in experimental studies related to protein aggregation, cellular heat shock response and other proteostasis mechanisms relevant to cancer progression and treatment. Recently, we developed a single-cell method to inflict defined, subcellular thermal damage, adopting the plasmon resonance principle. Dose-defined heat causes protein damage in subcellular compartments, rapid heat-shock chaperone recruitment, and ensuing engagement of the ubiquitin-proteasome system, providing unprecedented insights into spatiotemporal response to protein damage relevant to cancer. Using this versatile method, we discovered so-far unsuspected compensatory interplay of p97 translocase, the ubiquitin-proteasome system and heat shock protein chaperones in the processing of heat-damaged proteins. As both, p97 and heat shock proteins, represent potential cancer-relevant drug targets, these results can contribute to the development and better implementation of related therapies in cancer treatment.
Citation Format: Zdenek Skrott, Katarina Chroma, Petr Muller, Ales Panacek, Jiri Bartek, Martin Mistrik. Compensatory interplay of p97 segregase and HSP70 chaperone protect cancer cells from heat-induced proteotoxicity. [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 4814.
Abstract 4815: TMEM9 decreases ER stress-induced misfolded proteins via lysosomal protein degradation
Authors: Wi Dong-Han , Jung Su-Rin , Lee Seong-Ju , Jeon Ye-seul , Jung Youn-Sang , Park Jae-Il 
Published: April 2023

Abstract
The endoplasmic reticulum (ER) contributes to various protein modifications such as protein folding. Also, the ER-associated degradation (ERAD) complex removes defective proteins, which prevents the accumulation of misfolded proteins to avoid abnormality of physiological activity. Several physiological and pathological stimuli, such as hypoxia and nutrient starvation lead to unfolded protein responses (UPRs). Given that hyper-proliferation causes hypoxia and glucose shortening, cancer cells might induce UPRs resulting in misfolded protein accumulation and aggregation. Although the ERAD complex removes defective proteins, the capacity of the proteasomal degradation pathway is not enough to completely clear defective proteins in hyper-proliferative cancer cells. Thus, it is likely that cancer cells require additional misfolded protein degradation systems. Transmembrane protein 9 (TMEM9) has been identified as a vesicular acidification amplifier, which is upregulated in cancer cells for Wnt/β-catenin signaling activation via lysosomal protein degradation. In this study, TMEM9 downregulated ER stress-induced misfolded proteins that decrease cancer cell proliferation and viability. ERAD inhibitor declined cancer cell proliferation, reverted by TMEM9. Intriguingly, TMEM9 decreased ERAD-induced apoptosis instead of promoted autophagic cell death under glucose shorten conditions. Here we suggest that lysosomal protein degradation is an additional protein degradation system for the removal of defective proteins and contributes to stable cancer cell proliferation via the clearing of garbage proteins.
Citation Format: Dong-Han Wi, Su-Rin Jung, Seong-Ju Lee, Ye-seul Jeon, Youn-Sang Jung, Jae-Il Park. TMEM9 decreases ER stress-induced misfolded proteins via lysosomal protein degradation. [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 4815.
Abstract 4820: The disassembly of amyloid-bodies
Authors: Kirk Chloe , Bokros Michael , Grunfeld Alex , Lee Stephen 
Published: April 2023

Abstract
The ability of cells to adapt to a wide variety of stress conditions plays a critical role in various physiological and pathological settings, including development, cancer and neurological disorders. We recently reported the discovery of stress-induced low complexity noncoding RNA derived from stimuli-specific loci of the ribosomal intergenic spacer (rIGSRNA); an enigmatic region of the human genome historically dismissed as “junk” DNA. We showed that low complexity rIGSRNA activate a physiological amyloidogenic program that converts the nucleolus into Amyloid-bodies: a molecular prison of immobilized proteins in an amyloid-like state. This conserved post-translational regulatory pathway enables cells to rapidly and reversibly store an array of endogenous proteins in Amyloid-bodies and enter a dormant-like phenotype in response to severe environmental insults. While many membrane-less compartments have been described as liquid-like (e.g., stress granules, P-bodies, germ cell granules), our discovery of Amyloid-bodies provided evidence of an amyloidogenic process that can physiologically transition biological matter to a solid-like state. The ability of mammalian cells to efficiently dissemble Amyloid-bodies raises a fundamental question: Are mammalian cell disaggregases involved in Amyloid-body disassembly? Here, we show that Amyloid-bodies undergo a solid-to-liquid-phase transition to release sequestered proteins and restore nucleolar functions. An RNAi screened identified key Heat Shock Proteins (Hsps) that remodel Amyloid-bodies back to the liquid nucleoli on stress termination. The composition of mammalian disaggregases differs considerably from non-metazoans and those involved in disassembly of pathological amyloids in vitro. Activation of mammalian disaggregases and Amyloid-body disassembly is dependent on ATP concentration. Conceptually, this work identifies metazoan disaggregases challenging the widely accepted paradigm that the amyloid state is irreversible in mammalian cells. The data also provides alternative insights into pathogenic amyloids by examining their disassembly in cellular systems.
Citation Format: Chloe Kirk, Michael Bokros, Alex Grunfeld, Stephen Lee. The disassembly of amyloid-bodies. [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 4820.
Abstract 4847: Investigating the transcriptional regulation by estrogen-related receptor alpha (ERRα) under different metabolic conditions
Authors: Hua Brittney A. , Chen Chien-yu , Li Yang , He Lina , Stiles Bangyan , Slarve Ielyzaveta 
Published: April 2023

Abstract
Estrogen-related receptors (ERRs) are orphan nuclear receptors identified based on their high sequence similarity to estrogen receptors (ERs), but ERRs do not have a known endogenous ligand. ERRs play a primary role in regulating the transcription of genes involved in mitochondrial and lipid metabolism and are abundantly expressed across tissues. Because of ERR’s role in metabolism, it is suggested that they may also play a role in tumor metabolism, where dysfunction in lipid metabolism promotes tumor cell growth. The ERR subfamily is comprised of three isoforms: ERRα, ERRβ, and ERRγ. Studies targeting the ERR isoforms found that the absence of ERRα presents obesity and insulin resistance with an increase in bone mass, deletion of ERRβ causes placental abnormalities and embryonic lethality, and deletion of ERRγ leads to mitochondrial dysfunction. Together, these studies strongly suggest that ERRs, particularly ERR α and γ, function primarily as metabolic regulators, with ERRα being the predominant isoform expressed in the liver. In addition, the mechanisms leading to lipid accumulation vary under different feeding conditions. Previous studies from our lab showed that PTEN and PI3K/AKT signaling regulates ERRa expression and its function. Furthermore, we demonstrated that inhibiting ERRα blocks liver steatosis and steatohepatitis developed in a mouse model where loss of tumor suppressor PTEN drives both steatosis and cancer development. In addition, we found that ERR-PA, a small molecule inhibitor for ERR, attenuated cancer cell growth and proliferation in both mouse hepatocytes and human cancer cell lines. Here, we report transcriptome network regulated by ERRα under different metabolic conditions and further explored its regulation by the PI3K/AKT pathway. A better understanding of the role ERRα plays in physiology will allow further development of ERR-PA as a potential therapy for liver steatohepatitis, which progresses to end stage cirrhosis and ultimately liver cancer.
Citation Format: Brittney A. Hua, Chien-yu Chen, Yang Li, Lina He, Bangyan Stiles, Ielyzaveta Slarve. Investigating the transcriptional regulation by estrogen-related receptor alpha (ERRα) under different metabolic conditions. [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 4847.