bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB308: Transcriptional profiling uncovers a unified program underlying the human metastatic and adjacent microenvironments
Authors: Aber Etan R. , Contreras Cristina F. , Sikder Mohd Omar , Li Kathy P. , Forbes Greta E. , Gopalan Vishaka , Hannenhalli Sridhar , Kaplan Rosandra N. 
Published: April 2024

Abstract
Metastasis is the primary cause of death in patients with solid tumors, yet the treatment-refractory metastatic microenvironment is poorly characterized. To gain a comprehensive understanding of microenvironmental regulation of human metastasis, we performed single-cell RNA sequencing covering endothelial, stromal, myeloid, lymphoid, and malignant cells from 28 lung and liver samples of the metastatic microenvironment and metastasis-free adjacent microenvironment from patients with metastatic adrenocortical carcinoma compared to healthy donors for a total of 275,903 cells. We discovered that the adjacent microenvironment in patients with metastatic cancer is significantly different from healthy tissue without cancer: The adjacent microenvironment has many immunosuppressive and pro-tumorigenic features similar to primary tumor and metastatic tissue. As adjacent tissues are potential sites for subsequent metastasis, the shared changes between the adjacent and metastatic microenvironments suggest that these elements of the treatment-refractory metastatic microenvironment may dictate metastasis. Importantly, these pathologic features of the adjacent and metastatic microenvironments associate with poor outcomes for patients and may be targetable. Lastly, we identify a mechanism by which tumor cells may be remotely driving and coordinating these changes in both the metastatic and adjacent microenvironments. Taken together, our study identifies shared and microenvironment-specific changes underlying a global program of metastasis.
Citation Format: Etan R. Aber, Cristina F. Contreras, Mohd Omar Sikder, Kathy P. Li, Greta E. Forbes, Vishaka Gopalan, Sridhar Hannenhalli, Rosandra N. Kaplan. Transcriptional profiling uncovers a unified program underlying the human metastatic and adjacent microenvironments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB308.
Abstract LB314: Organ-specific roles of CD83+ macrophages in breast cancer
Authors: Singh Swarnima , Bado Igor 
Published: April 2024

Abstract
The purpose of this study is to understand how heterogeneity in organ-specific immune infiltrates can lead to Triple Negative Breast Cancer (TNBC) progression and immunotherapies resistance in metastasis. Both innate and adaptive immune responses are essential for breast cancer progression. Using single-cell multiplexing technology on human and murine models of primary and metastatic breast cancers, we investigated the pattern of immune cell infiltration in bone and lung metastases in a temporal manner. The parallel profiling of metastasis sites revealed a strong involvement of the innate immunity in restraining tumor progression with an acute increase in Mrc1+ Cd83+ tumor-associated macrophages at the early stage of lung colonization. Interestingly, the increase was modest in bone metastasis and remained consistent overtime despite bone metastasis progression. In contrast, we saw an increase in the number of Ly6G+ Lrg1+ granulocytes. Profiling of paired TNBC patient samples from the primary and metastatic sites have shown an immunologically quiescent tumor microenvironment in metastasis as compared to the primary tumors. Hence, to further explore the role of Mrc1+ Cd83+ macrophages on therapeutic resistance, we profiled the orthotopic claudin-low TNBC models, T11 and T12, following their exposure to chemotherapy. While responsive tumors displayed a decreased infiltration of Mrc1+ Cd83+ macrophages, the opposite phenotype was observed in non-responders, suggesting their involvement in tumor progression. Overall, our results suggest differential responses in untreated lung/bone metastases and primary tumors indicating divergent roles for Cd83+ TAMs in restraining or promoting tumor progression, while also indicating some crosstalk between neutrophils and stromal cells that aid in bone metastatic progression. These site-specific differences in immune cell phenotype indicate that there is a great need to thoroughly characterize the tumor immune compartment in both the primary and the metastatic setting to improve treatment responses. Considering the inhibitory effect of macrophages on T cells in these models, this study highlights a tissue-specific reprogramming of immune cells in breast cancer metastasis.
Citation Format: Swarnima Singh, Igor Bado. Organ-specific roles of CD83+ macrophages in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB314.
Abstract LB321: Identification of a novel mode of action and scaffold for modulation of cancer-associated fibroblast through Chip-seq analysis
Authors: Yeo So-Young , Farh Mohamed , Sohn InSuk , Kim Seok-Hyung , Lee Keun-Woo 
Published: April 2024

Abstract
Cancer microenvironment (CME) possess a crucial function in tumor mass, in which it control tumor growth, progression, metastasis, and even chemotherapy resistance. The CME is a complex and dynamic system that is an integral part of the entire tumor. Among the components of CME, in particular, CAFs promote cancer progression and directly stimulate cancer cell proliferation. Thus, targeting CAF would be a promising approach for the treatment of cancer. Looking at models of the evolution of CAFs during tumor progression, CAFs have heterogeneous and dynamic properties. Tumor progression may be associated with a decrease in the tumor inhibitory CAF/tumor supporting CAF ratio, with tumor inhibitory CAF occurring at the highest levels in early tumor stages in response to tumor emergence and gradually switching to tumor support CAFs towards tumor progression/metastatic process. In other words, in order to suppress solid tumors accompanied by desmoplastic stroma, it is necessary to regulate CAFs, a key component. We performed ChiP-seq using an antibody against H3k27ac with CAFs that have a strong ability to promote cancer and NFs that do not. As result, we identified a novel mode of action and scaffold (ARC2-002 and ARC2-003) for modulating CAF via suppressing CAF proliferation, contraction, and collagen deposition. Finally, through 3D co-culture, we confirmed that the two novel scaffolds had excellent anticancer effects when administered alone as well as in combination with an existing anticancer drug. The compounds identified in this study may represent a new therapeutic agent targeting fibroblasts with abnormal activation, and their efficacy may be increased when combined with existing anticancer drugs.
Citation Format: So-Young Yeo, Mohamed Farh, InSuk Sohn, Seok-Hyung Kim, Keun-Woo Lee. Identification of a novel mode of action and scaffold for modulation of cancer-associated fibroblast through Chip-seq analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB321.
Abstract LB332: Spatial transcriptomic and proteomic analysis of the treatment resistant slow cycling micro environment in GBM
Authors: Chakraborty Avirup , Feier Diana , Silver Aryeh , Yang Changlin , Anica Miruna , Pittu Avinash , Sobanjo Olusegun , Hodge Ethan , Engelbart Mia , Von Roemeling Christina , Rahman Maryam , Sarkisian Matthew , Huang Jianping , Harrison Jeffrey , Mitchell Duane , Deleyrolle Loic 
Published: April 2024

Abstract
Within the Glioblastoma (GBM) microenvironment, there are micro-niches originating from independent lineages of cancer stem cells with distinct metabolic requirements that are characterized by Fast cycling cells (FCCs) and Slow cycling cells (SCC). The FCCs employ aerobic glycolysis for energy, while the treatment-resistant SCCs primarily rely on lipid metabolism. Our study allows for the molecular and spatial decoding of the heterogeneity within the GBM microenvironment, with a specific focus on decoding the dichotomy of the immune infiltrates and studying the interactions between the SCCs and the immune compartment in human GBM patients. Our research reveals a new paradigm of interaction within the tumor microenvironment (TME) of glioblastoma (GBM) patients, in which SCCs are instrumental in altering the tumor milieu to favor immune suppression. These SCCs actively recruit and harness sub-population of immune cells of myeloid origin that promote tumor growth and simultaneously provide metabolic aid to these treatment-resistant cells. Our research maps out the intricate metabolic dialogues within GBM and evaluates the potential therapeutic effect of disrupting this interaction to open up new treatment avenues. The findings based on our spatial transcriptomic and proteomic study on brain biopsies from human patients provide a deeper understanding of the critical links among the tumor's local environment, cellular metabolism, anti-tumor immunity, and potential treatment vulnerabilities. In summary, our investigation offers novel insights into how metabolic exchanges contribute to the evolution of GBM leading to the development of drug and immune resistant GBM. Our data is suggestive that therapies aimed at these metabolic interactions, especially those between SCCs and metabolically supporting immunosuppressive myeloid originating immune cells, hold potential as effective therapeutic strategy for GBM.
Citation Format: Avirup Chakraborty, Diana Feier, Aryeh Silver, Changlin Yang, Miruna Anica, Avinash Pittu, Olusegun Sobanjo, Ethan Hodge, Mia Engelbart, Christina Von Roemeling, Maryam Rahman, Matthew Sarkisian, Jianping Huang, Jeffrey Harrison, Duane Mitchell, Loic Deleyrolle. Spatial transcriptomic and proteomic analysis of the treatment resistant slow cycling micro environment in GBM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB332.
Abstract LB365: Generation of a novel severely immunodeficient Sprague Dawley rat model for xenograft studies
Authors: Nie Yanhui , Zhang Meiqi , Zhong Wanling , Feng Jia , Huwatibieke Bahetiyaer , Yu Zhaoxue 
Published: April 2024

Abstract
The recombinant-activating gene 2 (Rag2) plays a critical role in the recombination of the immunoglobulin and T cell receptor genes during the maturation of T and B cells. Loss of Rag2 protein leads to a lack of functional T and B cells, which eliminates the adaptive immune response. However, Rag2 deficiency alone may not guarantee the success of xenograft implantation, due to NK cells and other innate cells remaining. Il2rg is a key component of several cytokine receptors involved in differentiation and/or function of numerous adaptive and innate immune cells, including NK cells, mast cells, basophils, and dendritic cells. To generate a more severely immunodeficient rat model, both the Rag2 and Il2rg genes were knocked out in Sprague Dawley (SD) rats; this model was termed B-SDG rats. The immune profile and organ weights of thymus and spleen were investigated in B-SDG rats in comparison with Rag2-/- and wild-type SD rats. The spleen weights of both Rag2-/- and B-SDG rats were similar, but significantly reduced compared to wild-type SD rats. Notably, the thymus weights of B-SDG male rats were significantly smaller than those of Rag2-/- males. The immune cell profiles in thymus, spleen and blood were next evaluated by flow cytometry. A complete lack of B and T cells was observed in both Rag2-/- and B-SDG rats. B-SDG rats lacked CD161+ NK cells in the spleen and blood, which were maintained in Rag2-/- rats. Dendritic cells, monocytes, macrophages, and neutrophils were detected in all strains. In vivo xenograft implantation with human lung, bladder, breast, pancreas, acute monocytic and myelomonocytic leukemia tumor cell lines was next evaluated in B-SDG rats, which demonstrated successful engraftment. Furthermore, several efficacy studies were performed in B-SDG rats, including cisplatin chemotherapy on human breast invasive ductal carcinoma cell (HCC1954) and human large cell lung cancer cell (NCI-H460) xenografts, and a HER2-targeting ADC therapy was tested in B-SDG rats harboring human non-small cell lung cancer tumors (NCI-H1975). Taken together, these data confirm that B-SDG rats provide a powerful immunodeficient model for preclinical in vivo evaluation of novel drug candidates.
Citation Format: Yanhui Nie, Meiqi Zhang, Wanling Zhong, Jia Feng, Bahetiyaer Huwatibieke, Zhaoxue Yu. Generation of a novel severely immunodeficient Sprague Dawley rat model for xenograft studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB365.
Abstract LB376: Tirzepatide inhibits tumor growth in mice with diet-induced obesity
Authors: Pollak Michael N. , Zeng Jibin , Huang Linxuan , Wang Ye , Rahbani Janane , Kazak Lawrence 
Published: April 2024

Abstract
Tirzepatide, a drug used in management of type II diabetes, is an activator of both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptors. Tirzepatide treatment leads to weight loss in murine models of obesity, and clinical trials have shown the drug can achieve ∼ 20% weight loss in obese patients. Obesity has been shown to increase risk and/or to worsen prognosis of certain common cancers, including colon cancer, but the effect of tirzepatide on neoplasia has not been examined in detail. We studied the effects of this drug on mouse weight and energy balance and on the murine MC38 colon cancer model, which was previously shown to exhibit accelerated growth in hosts with diet-induced obesity. Tirzepatide led to substantial reductions in food intake, to reduced adipose tissue mass, and to significant decreases in circulating levels of insulin and leptin. Tirzepatide did not cause tumor regression, but reduced tumor growth rates by ∼ 50%. Tirzepatide had no effect on MC38 cancer cell proliferation in vitro, and the effect of tirzepatide on tumor growth in vivo could be phenocopied in placebo treated mice simply by restricting food intake to the amount consumed mice receiving the drug. This provides evidence that the drug acts indirectly to inhibit tumor growth. Our findings raise the possibility that use of tirzepatide or similar agents may benefit patients with obesity-related cancers.
Citation Format: Michael N. Pollak, Jibin Zeng, Linxuan Huang, Ye Wang, Janane Rahbani, Lawrence Kazak. Tirzepatide inhibits tumor growth in mice with diet-induced obesity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB376.
Abstract LB379: HLA-DQB1*05:02: An independent genetic marker for oral cavity squamous cell carcinoma susceptibility
Authors: Huang Shiang-Fu , Chien Huei-Tzu , Young Chi-Kuan , Lee Yun-Shien , Liao Chun-Ta , Cho Kai-Lun , Chen Ching-Han 
Published: April 2024

Abstract
Environmental exposure to carcinogens causes mucosal damage in the upper aerodigestive tract, which can lead to cancers. The genetic basis of head and neck cancer is controversial. To identify susceptibility genes in head and neck cancers, we enrolled patients with early-onset disease in Taiwan. This case-control study included 54 young male patients with oral squamous cell carcinoma (OSCC) who were treated between March 1996 and December 2016, as well as 2,400 healthy controls. A single-nucleotide polymorphism (SNP) array was used to determine genetic loci that increase susceptibility to OSCC. Sequencing-based typing (TBG Biotechnology Corp., Taipei, Taiwan) was used to determine the HLA-DQB1 genotype in another cohort of 147 OSCC patients. We analyzed the allele frequencies of 664,994 autosomal SNPs in the 54 OSCC cases. In a genome-wide association analysis, four SNPs within loci on chromosomes 6, 7, 9, and 12 were significantly different between OSCC patients and controls (corrected P &lt; 1.0 × 10−6). HLA-DQB1 was closest to rs28451423 on chromosome 6. HLA-DQB1*05:02 in OSCC (18.5%) was significantly different from normal population (7.0%) (P = 0.009). The influence of disease onset was independently significant after adjusting cigarette smoking, alcohol drinking and areca-quid chewing (P = 0.015, OR: 3.922, 95% confidence interval: 1.311 - 11.734). Furthermore, HLA-DQB1*05:02 was associated with early-onset OSCC (P = 0.004). HLA-DQB1*05:02 is associated with OSCC independent of environmental exposures. HLA-DQB1*05:02 is also related with early onset of OSCC. It provides evidence of a genetic basis for OSCC.
Citation Format: Shiang-Fu Huang, Huei-Tzu Chien, Chi-Kuan Young, Yun-Shien Lee, Chun-Ta Liao, Kai-Lun Cho, Ching-Han Chen. HLA-DQB1*05:02: An independent genetic marker for oral cavity squamous cell carcinoma susceptibility [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB379.
Abstract LB396: The power of NetraAI: Precision medicine in oncology through sub-insight learning from small data sets
Authors: Qorri Bessi , Tsay Mike J. , Leonchyk Paul , Alphs Larry , Pani Luca , Geraci Joseph 
Published: April 2024

Abstract
The capabilities of artificial intelligence (AI) and machine learning (ML) are pivotal for refining patient stratification and subtype discrimination in clinical trials. Conventional ML methods often rely on large data sets for meaningful discoveries. NetraAI is a novel ML approach designed and trained to work with smaller data sets. The challenge with smaller data sets is that they do not reflect the totality of the disease that they represent. NetraAI employs a novel approach termed “Sub-Insight Learning”, utilizing validated mathematical methods to analyze even small patient data sets. This allows the system to decompose the data sets into high and low confidence patient subpopulations, enhancing predictive model accuracy and reducing overfitting. Further, the system explains what variables are driving the etiology defining the subpopulations of patients. Using two non-small cell lung cancer (NSCLC) data sets (GSE18842 and GSE10245) consisting of only 104 samples from adenocarcinoma (ADC) and squamous cell carcinoma (SCC), NetraAI distinguished the two subtypes through unique genetic signatures. Notably, nine of the ten variables identified correlate with known NSCLC markers, with PIGX emerging as a novel target. Leveraging protein-protein interaction networks (PPI) revealed connections between PIGX and BACE1. BACE1 has been implicated as a driver of NSCLC brain metastasis. These findings shed light on the biology of membrane proteins and their post-translational modifications, a factor implicated in various diseases, prompting further exploration. NetraAI demonstrates a significant breakthrough in precision medicine for oncology, capable of generating meaningful insights from small data sets. The discovery of novel biomarkers and their implications in cancer and other diseases underline the potential of this AI-driven approach in advancing current research paradigms and patient-specific treatments.
Citation Format: Bessi Qorri, Mike J. Tsay, Paul Leonchyk, Larry Alphs, Luca Pani, Joseph Geraci. The power of NetraAI: Precision medicine in oncology through sub-insight learning from small data sets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB396.
Abstract LB404: ATR inhibitors synergize with DHFR inhibitors in rhabdomyosarcoma cells by disrupting DNA damage checkpoint
Authors: Jo Ukhyun , Annor George K , Shern Jack F. 
Published: April 2024

Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents. RMS tumors are classified into four subtypes: embryonal, alveolar, spindle cell/sclerosing, and pleomorphic. Treatment options for RMS include a combination of surgery, chemotherapy, and radiation therapy and regimens for patients with relapsed and metastatic RMS remain limited. However, a recent study has reported that pharmacological inhibitors targeting ataxia telangiectasia and Rad3-related protein (ATR) are currently undergoing phase I/II trials and may be utilized for the treatment of alveolar RMS. Interestingly, we identified that the gene signature of replication stress positively correlated with dihydrofolate reductase (DHFR) expression in the cancer cell line database (CellMinerCDB, discover.nci.nih.gov/cellminercdb; Pearson correlation (r)=0.66). DHFR is an important therapeutic target for cancer and autoimmune diseases, and its inhibitors are routinely used and clinically approved. DHFR inhibitors are known to exhibit their anticancer effects by inhibiting nucleotide synthesis and DNA replication. In this study, we aimed to explore a potential synergistic interaction using a combination treatment of ATR inhibitors (elimusertib and ceralasertib) and DHFR inhibitors (pralatrexate, methotrexate, and raltitrexated) in multiple RMS cell lines. We used a drug matrix reduction format and found that combined treatment of ATR inhibitors and DHFR inhibitors induced a synergistically decreased RMS cell viability, showing higher synergy in fusion-positive RMS cells than in fusion-negative RMS cells. Mechanistically, ATR inhibitors abrogated DNA damage response checkpoint CHK1 activation caused by DHFR inhibitor, leading to increased γH2AX and decreased DNA replication activity. Accordingly, the accumulation of DNA damage in combination with ATR inhibitor and DHFR inhibitor triggered higher cell cycle arrest and apoptotic cell death than single agent treatment of DHFR inhibitor. Our findings warrant further research into identifying genomic regions where the DNA damage is enriched in combination treatment by using END-sequencing and synthesis-associated with repair sequencing (SAR-seq). In conclusion, this study provides promising rationale for the combination treatment of ATR and DHFR inhibitors to treat RMS patients, including those with advanced, relapsed, and metastatic states.
Citation Format: Ukhyun Jo, George K Annor, Jack F. Shern. ATR inhibitors synergize with DHFR inhibitors in rhabdomyosarcoma cells by disrupting DNA damage checkpoint [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB404.