bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3950: Dedifferentiation unveils origin of Ewing sarcoma
Authors: Kapoor Utkarsh , Hafemeister Christoph , Shaw Lisa , Muelbacher Karin , Moldaschl Julia , Egger Dominik , Toegel Stefan , Kasper Cornelia , Farlik Matthias , Halbritter Florian , Kovar Heinrich 
Published: March 2024

Abstract
Ewing sarcoma (ES) is an aggressive pediatric bone tumor in adolescents primarily driven by the expression of the fusion oncogene EWS::FLI1. Although the etiology of ES remains controversial, human mesenchymal stem cells (hMSCs) are considered to be the likely cell of origin. This is not only due to their ability to tolerate ectopic EWS::FLI1 expression, but also because the transcriptome of EWS::FLI1 expressing hMSCs is highly similar to that of primary Ewing tumors. However, to date a cellular differentiation-based model of ES does not exist. With the intent to understand ES histogenesis, this study aims to establish the first comprehensive single-cell differentiation atlas (both transcriptome and epigenome) of juvenile bone marrow-derived hMSCs with and without EWS::FLI1 expression. We sought to study the consequences of inducing the EWS::FLI1 oncogene expression at various time points of hMSC differentiation into adipo-, chondro-, osteo- and neuro-genic lineages. Our workflow utilizes physiology-mimicking conditions including serum-free differentiation, hypoxia, and growth/differentiation as spheroids. We pooled bone marrow-derived hMSCs isolated from eleven healthy juvenile donors, engineered them to conditionally express EWS::FLI1, and carried out multi-lineage differentiation for 10 days where EWS::FLI1 was induced daily for 24h or 72h. This temporally resolved atlas of 105 samples representing normal and perturbed differentiation allowed us to map ES patient tumor data to multiple lineages and time-points across stages of lineage commitment. Single-cell RNA-seq analysis of ~271,000 transcriptomes revealed an apparent and dynamic dedifferentiation in the presence of EWS::FLI1 across all four lineages. Preliminary analysis of genes detected in the EWS::FLI1 high cluster uncovers a specific lineage preference and time window that shares the transcriptomic signature with tumor cells, indicating the potential cell/stage of tumor-origin. Our results provide new insight into the enigmatic cell of origin of Ewing sarcoma, laying the foundation for the development of much-needed pre-clinical models for tailoring therapies. This study is supported by a generous grant (#20) of the Alex’s Lemonade Stand Foundation (ALSF) Crazy8 Program.
Citation Format: Utkarsh Kapoor, Christoph Hafemeister, Lisa Shaw, Karin Muelbacher, Julia Moldaschl, Dominik Egger, Stefan Toegel, Cornelia Kasper, Matthias Farlik, Florian Halbritter, Heinrich Kovar. Dedifferentiation unveils origin of Ewing sarcoma [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 3950.
Abstract 4086: ABN202 (anti-Trop-2-interferon-beta mutein): A potent antibody-cytokine fusion protein for the treatment of Trop-2 positive solid tumors
Authors: Park Hee Geon , Lee Hyun Kyung , Seo Myeung Ryun , Kim Daa Eun , Bang Sang Beom , Lee Ji Yang , Hong Sung Youl , Song Kyoung , Lee Chan Gyu , Jeong Hae Min , Lee Sae Hyung , Kim Na Young , Choi Jun Young , Shin Young Kee 
Published: March 2024

Abstract
Trop-2, trophoblast cell-surface antigen 2, is a type 1 transmembrane glycoprotein overexpressed in many solid cancers, including breast, lung, pancreatic, bile duct and bladder cancer. Overexpression of Trop-2 in cancer patients is associated with disease progression and poor prognosis. The antibody-drug conjugate (ADC) targeting Trop-2, Sacituzumab-govitecan (Trodelvy®), is approved for patients with triple-negative breast cancer (TNBC) and bladder cancer. However, Trop-2 targeting ADCs exhibit a high frequency of grade 3/4 adverse events and a short duration of response. Therefore, there is an unmet medical need for new treatment strategies beyond ADCs. In a previous study, we designed ABN202 (αTrop-2) to comprise a Trop-2 targeting antibody (Sacituzumab) and IFN-β mutein (ABN102) for the Trop2-positive tumor-specific delivery of ABN102. We confirmed anti-cancer activities of ABN202 against Trop-2 positive bladder cancer. In this study, we evaluated in vitro and in vivo anti-cancer efficacy of ABN202 (αTrop-2) in Trop-2 positive TNBC, bile duct cancer and bladder cancer cell lines. To identify response biomarkers for ABN202 (αTrop-2), we analyzed cell lines exhibiting both response and non-response to ABN202 (αTrop-2). In conclusion, ABN202 (αTrop-2) demonstrated potent anti-cancer efficacy compared to Trodelvy®. Our results support ABN202 (αTrop-2) as a promising drug candidate against Trop2-positive solid tumors.
Citation Format: Hee Geon Park, Hyun Kyung Lee, Myeung Ryun Seo, Daa Eun Kim, Sang Beom Bang, Ji Yang Lee, Sung Youl Hong, Kyoung Song, Chan Gyu Lee, Hae Min Jeong, Sae Hyung Lee, Na Young Kim, Jun Young Choi, Young Kee Shin. ABN202 (anti-Trop-2-interferon-beta mutein): A potent antibody-cytokine fusion protein for the treatment of Trop-2 positive solid tumors [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 4086.
Abstract 417: Chromosomal instability leads to durable tumor suppression upon macrophage-checkpoint disruption, with induction of anti-tumor IgG
Authors: Discher Dennis E. 
Published: March 2024

Abstract
Solid tumors generally exhibit chromosome copy number variation caused by chromosomal instability (CIN) in mitosis, and the resulting aneuploidy associates with poor prognosis in various cancer types and poor Tcell checkpoint blockade response in melanoma. In such contexts, however, macrophages and the SIRPa-CD47 checkpoint are understudied. Here, CIN is induced pharmacologically in poorly immunogenic B16F10 mouse melanoma cells, generating micronuclei plus diverse aneuploidy and skewing macrophages towards an anti-cancer phenotype based on markers and short-term tumor studies. Mice bearing CIN-afflicted tumors with wild-type CD47 levels survive only slightly longer compared to chromosomally stable controls, but long-term survival can be maximized when anti-tumor IgG opsonization is combined with adoptive transfer of macrophages with SIRPa blockade or with CD47 knockout of the B16F10. Multi-epitope, de novo anti-cancer IgG in survivors promote phagocytosis of CD47 knockout B16F10 cells by macrophages and suppress tumoroids in vitro and growth of tumors in vivo. An unexpected benefit of pairing CIN with maximal macrophage anti-cancer activity is thus an anti-cancer vaccination-like response that can lead to durable cures and potentiate cell-mediated acquired immunity.
Citation Format: Dennis E. Discher. Chromosomal instability leads to durable tumor suppression upon macrophage-checkpoint disruption, with induction of anti-tumor IgG [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 417.
Abstract 4192: In-depth evaluation of chemotherapy-induced mucositis in intestinal organoids using holotomography
Authors: Lee Mahn Jae , Lee Jaehyeok , Park Weisun , Kim Geon , Kim Hye-Jin , Park YongKeun 
Published: March 2024

Abstract
Intestinal mucositis is a prevalent adverse event associated with antineoplastic therapies, such as chemotherapy, which still lacks a targeted and effective treatment regimen. The difficulty in preclinical prediction and prevention of drug-induced intestinal mucositis is attributed to the intricate underlying mechanisms of its onset and the broad spectrum of patient-specific responses to chemotherapeutic agents. Advancements in regenerative medicine have enabled the generation of intestinal organoids from adult stem cells, serving as a personalized model to emulate disease pathology and simulate individual drug responses. Various imaging techniques are employed to evaluate the responses of the organoids to pharmacological agents, but the inherent complexity of their three-dimensional (3D) architecture poses significant challenges in organoid imaging. These challenges are exacerbated by the standard preparation processes for imaging, including fixation and staining, which do not allow for the observation of dynamic, real-time effects of drugs on living organoids. In this study, we focused on meticulously examining the histopathological alterations in small intestinal organoids subjected to chemotherapeutic agents that induce mucositis, specifically 5-fluorouracil and irinotecan. Employing holotomography, a label-free real-time 3D imaging technology, we were able to visualize the destructive processes affecting the intestinal organoids, including the breakdown of the epithelial lining, the exfoliation of dead cells, and the alteration of the villus/crypt structure. Furthermore, we propose a novel methodology for quantifying the viability of intestinal organoids. This quantification is essential for assessing the extent of damage caused by the chemotherapeutic agents and for determining the maximum drug concentrations that can be deemed safe for use, thereby minimizing the risk of inducing mucositis while maintaining therapeutic efficacy. These results provide new insights into the toxic mechanisms of chemotherapeutic drugs and highlight the importance of using organoid models in drug safety evaluation throughout the development phase.
Citation Format: Mahn Jae Lee, Jaehyeok Lee, Weisun Park, Geon Kim, Hye-Jin Kim, YongKeun Park. In-depth evaluation of chemotherapy-induced mucositis in intestinal organoids using holotomography [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 4192.
Abstract 4284: Macrophage reprogramming and immune suppression through extracellular vesicles loaded eIF4A1in ovarian cancer
Authors: Mittal Sonam , Kadamberi Ishaque Pulikkal , Kumar Sudhir , George Jasmine , Singh Mona , Geethadevi Anjali , Chaluvally-Raghavan Pradeep , Pradeep Sunila 
Published: March 2024

Abstract
Background- In ovarian carcinoma (OvCa), macrophages are reprogrammed toward pro-tumorigenic phenotypes, including releasing anti-inflammatory cytokines and expressing immunosuppressive molecules. However, how these macrophages acquire their phenotype remains largely unexplored. To understand the mechanism driving pro-tumorigenic phenotype in macrophages, we studied the role of tumor cell-derived extracellular vesicles (EVs) in the cross-talk with macrophages in OvCa. We found that EVs from ovarian cancer cells contain eukaryotic translation initiation factor 4A1 (eIF4A1). eIF4A1 containing EVs from ovarian cells enhanced macrophage translational activity and PD-L1 expression. However, the detailed mechanism that explains how eIF4A1-packaged EVs induce immunosuppressive phenotype in macrophages is necessary to develop novel immunotherapy strategies for advanced OvCa treatment.
Methods- We performed SUnSET assay (surface sensing of translation) to determine whether eIF4E-EVs affect global translation in macrophages. SILAC (Stable isotope labeling by amino acids) based mass spectrometry was used to identify the downstream targets of eIF4A1 in macrophages. We isolated murine peritoneal macrophages from naïve C57BL/6 female mice and co-cultured the macrophages with EVs derived from ovarian cancer cell lines. The expression of PD-L1, CD206, interleukin-6 (IL-6), and other inflammatory cytokines on EVs treated macrophages was evaluated using flow cytometry and a cytokine array kit. Further, we created a Rab27aKO ovarian cancer in vivo model to study the effect of eIF4A1 packaged EVs on the immune suppressive ability of macrophages and tumor progression.
Results- Our study shows that tumor cells employ EVs to deliver eIF4A1 to the tumor microenvironment, facilitating the release of cytokines such as IL-6 and the expression of PD-L1 on macrophages and supporting tumor growth. In addition, our data shows that eIF4A1-EVs enhance protein synthesis in macrophages. Our data show that in the Rab27aKO ovarian cancer in vivo mouse model, intravenous injection of eIF4A1-packaged EVs increased the tumor burden, metastasis, and ascites accumulation as compared to PBS control. eIF4A1-EVs treatment increased the infiltration of tumor-associated macrophages (TAM) in ascites. We also found increased expression of PD-L1 and CD206 on TAM isolated from ascites
Citation Format: Sonam Mittal, Ishaque Pulikkal Kadamberi, Sudhir Kumar, Jasmine George, Mona Singh, Anjali Geethadevi, Pradeep Chaluvally-Raghavan, Sunila Pradeep. Macrophage reprogramming and immune suppression through extracellular vesicles loaded eIF4A1in ovarian 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 4284.
Abstract 4287: Serological quantification of fibroblast activation protein (FAP) cleaved type III collagen: A biomarker for FAP activity
Authors: Pedersen Rasmus Sund , Karsdal Morten , Willumsen Nicholas 
Published: March 2024

Abstract
Introduction: Fibroblast activation protein (FAP) has unique proteolytic activity with very low expression in healthy tissues, while being upregulated in diseased tissues including many types of cancer for example non-small cell lung cancer (NSCLC). The disease specific expression and unique proteolytic activity have made FAP an interesting protein to be utilized for drug targeting purposes. Therefore, it is important to identify the patients with FAP activity. The aim of the study was to develop a tool to non-invasively quantify FAP activity and investigate its potential as a biomarker for patients with NSCLC.
Methods: We developed an ELISA (named C3F), with monoclonal antibodies raised against a FAP generated fragment of type III collagen that was identified by MS, to quantify FAP-mediated cleavage of type III collagen in serum to reflect proteolytic activity of FAP. We confirmed that the biomarker reflects proteolytic activity of FAP by incubating type III collagen with or without FAP and measured C3F. In addition, we confirmed elevated FAP expression in NSCLC (adenocarcinoma and squamous cell carcinoma) compared to healthy tissue and correlation between FAP and COL3A1 expression using data from The Cancer Genome Atlas (TCGA). The comparisons between FAP expression in healthy and cancer tissue was done using one-way ANOVA and correlation between FAP and COL3A1 was done using Spearman correlation. Lastly, C3F was measured in serum samples from patients with NSCLC (n = 109) and healthy controls (n = 42) and the two groups was compared using Mann Whitney test and area under receiver operating characteristic curves (AUROCs).
Results: A C3F signal only appeared after type III collagen incubation with FAP, supporting that C3F reflects FAP proteolytic activity. C3F was significantly elevated in serum from patients with NSCLC compared to healthy controls (p &lt; 0.0001, AUROC = 0.78). In support, FAP expression (TCGA) was significantly elevated in NSCLC tissue compared to normal lung tissue (p &lt; 0.0001) and FAP expression correlated with expression of COL3A1 (persons r = 0.83).
Conclusion: The FAP-cleavage mediated type III collagen fragment C3F reflects FAP activity and can be quantified non-invasively in serum. In this study we show C3F as promising diagnostic biomarker in NSCLC, however as the biomarker reflects FAP activity the optimal use is more is potentially as a predicter of treatment response from FAP-based drug delivery systems.
Citation Format: Rasmus Sund Pedersen, Morten Karsdal, Nicholas Willumsen. Serological quantification of fibroblast activation protein (FAP) cleaved type III collagen: A biomarker for FAP activity [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 4287.
Abstract 4303: Enrichment of nonadherent prostate cancer stem cell populations using simulated microgravity bioreactor
Authors: Khazaw Kezhan , Unlu Sebnem , Dwead Abdulrahman M. , Cinar Bekir 
Published: March 2024

Abstract
Prostate cancer is the most prevalent and the leading cause of cancer-related death among men, particularly African Americans. The cellular and molecular mechanisms contributing to this deadly disease remain largely unknown. As such, there are no effective strategies to treat metastatic cancer and improve patient outcomes. Anchorage-independent growth of circulating prostate tumor cell clusters is essential for developing cancer metastasis. However, there is no model system to study the molecular and functional characteristics of prostate tumor cell clusters reminiscent of the bloodstream in a laboratory setting. In addressing this need, we have established nonadherent LNCaP cell clusters, LN-G2 and LN-G3, under androgen-depleted growth conditions in a simulated microgravity bioreactor called Slow Turning Lateral Vessel (STLV). Our quantitative PCR analysis repeatedly demonstrated that LN-G2 and LN-G3 cell populations expressed high levels of the well-characterized CD44 and CXCR4 cancer stem cell maker, respectively, compared to the LNCaP parental. In addition, our functional analysis indicates that, unlike the LNCaP cell, LN-G2 and LN-G3 cells showed superior clonogenic and growth behaviors in response to androgen depletion and enzalutamide-treatment under adherent monolayer and nonadherent conditions. These observations suggest that cancer stem cell-like cell clusters that survived under microgravitational stress confer distinctive molecular and functional properties associated with superior survival and contribute to castration-resistant prostate cancer. Furthermore, the STLV bioreactor could help enrich cancer stem cell populations and enhance our understanding of the underlying mechanisms of lethal cancer, which may lead to novel therapeutics to improve patient outcomes.
Citation Format: Kezhan Khazaw, Sebnem Unlu, Abdulrahman M. Dwead, Bekir Cinar. Enrichment of nonadherent prostate cancer stem cell populations using simulated microgravity bioreactor [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 4303.
Abstract 4338: A pan-cancer single-cell analysis of intratumoral copy number diversity and evolution
Authors: Ye Hanghui , McDonald Thomas , Sei Emi , Minussi Darlan Conterno , Hu Min , Tang Chenling , Wang Junke , Wang Kaile , Casasent Anna , Chen Hui , Michor Franziska , Navin Nicholas 
Published: March 2024

Abstract
Aneuploidy is a hallmark of human cancers and studies have shown that cancer patients harbor many differences in their copy number aberrations (CNAs) reflecting interpatient heterogeneity (IPH). While IPH has been studied extensively, the intratumoral heterogeneity (ITH) of CNAs within a tumor remains understudied. Here, we conducted a pan-cancer analysis of 94 human tumor samples at single cell genomic resolution, representing seven major cancer types: bladder, breast, colon, glioblastoma, kidney, lung, and ovary. In total, 62,646 aneuploid cells were analyzed by single cell copy number profiling and bulk exome sequencing was performed. In most cancer types, increased subclonal diversity was associated with higher CNA burden, whole genome doubling (WGD) events, and TP53 mutations. In all tumors, our data show that cancer cells share a clonal set of truncal CNAs or mutations, suggesting these tumors evolved from a single ancestral cell. In 18/94 cases we identified subclonal WGD events, which resulted in a higher number of copy number losses after tetraploidization. Macro-spatial sampling showed that increased clonal diversity also correlated with increased spatial geographical diversity. We found that many cancers evolved CNAs in short punctuated bursts of evolution, and that this was not restricted to a specific cancer type. Collectively, these data show that copy number ITH is universally associated with molecular features across these human cancer types.
Citation Format: Hanghui Ye, Thomas McDonald, Emi Sei, Darlan Conterno Minussi, Min Hu, Chenling Tang, Junke Wang, Kaile Wang, Anna Casasent, Hui Chen, Franziska Michor, Nicholas Navin. A pan-cancer single-cell analysis of intratumoral copy number diversity and evolution [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 4338.
Abstract 4448: Effects of adagrasib on cholesterol, lipid and glucose gene expression regulation in tumor xenograft models and patient samples
Authors: Shelton Fabiola , Hoffman Natalie , Trinh David , Helu Xousaen M. , Calinisan Andrew , Hebbert Allan , Yan Larry , Briere David M. , Hover Laura , Fernandez-Benet Julio , Anderes Kenna , Christensen James G. , Hallin Jill , Olson Peter 
Published: March 2024

Abstract
Introduction: Clinically active KRASG12C inhibitors have represented a key research breakthrough and led to novel treatment options for lung, colorectal and other cancer patients harboring this mutation. While treatment with KRASG12C inhibitors are clinically active in the majority of patients, the depth and duration of response is variable and most patients ultimately progress. This variation in therapeutic response highlights the need for a better understanding of drug mechanism of action and the identification of rational combination strategies. Oncogenic KRAS mutations hyperactivate the MAPK pathway, create an immunosuppressive tumor microenvironment, and promote glycolysis even in the presence of oxygen commonly known as the Warburg effect. This altered metabolic state is marked by increased glucose uptake and lactate production, providing necessary substrates for rapid tumor growth.
Results: Pharmacological inhibition of KRASG12C with a potent and selective KRASG12C inhibitor, adagrasib, revealed marked alterations of metabolic gene expression programs in tumor samples collected from mouse xenograft studies and repeat biopsies provided by patients enrolled on adagrasib clinical trials. Upregulation of genes involved in reverse cholesterol transport including ApoE, NR1H3 (LXRa) and ABCA1 was observed across both preclinical tumor xenografts and patient samples following adagrasib treatment. Additionally, decreased expression of Glut1 and low-density lipoprotein receptor (LDLR) genes were also observed in both tumor models and patients suggesting that adagrasib treatment results in an extensive shift in uptake and utilization of cholesterol, lipid, and glucose. The impact of adagrasib treatment on circulating metabolic parameters in tumor xenograft-bearing mice were investigated in follow up studies.
Conclusions: Taken together, these data suggest adagrasib modulates cholesterol efflux, glucose and lipid pathways and alters tumor and systemic metabolic regulation. Additional research may yield a targetable collateral vulnerability and rational combinatorial strategy.
Citation Format: Fabiola Shelton, Natalie Hoffman, David Trinh, Xousaen M. Helu, Andrew Calinisan, Allan Hebbert, Larry Yan, David M. Briere, Laura Hover, Julio Fernandez-Benet, Kenna Anderes, James G. Christensen, Jill Hallin, Peter Olson. Effects of adagrasib on cholesterol, lipid and glucose gene expression regulation in tumor xenograft models and patient samples [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 4448.