bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB224: Neoplastic immune mimicry potentiates breast cancer progression
Authors: Berens Eric B. , Khou Sokchea , Huang Elaine , Hoffman Amber , Johnson Briana , Werb Zena , Heiser Laura M. , Coussens Lisa M. 
Published: April 2024

Abstract
Dedifferentiation programs are commonly enacted during breast cancer progression where they enable novel cellular phenotypes. Increased cellular plasticity within the neoplastic compartment of tumors correlates with disease aggressiveness, often manifesting as greater resistance to cytotoxic therapies or increased ability to metastasize to distant organs. Here we report that subpopulations of ostensibly stem-like neoplastic breast epithelial cells express canonical leukocyte cell surface receptor proteins, and have named this unique cellular program ‘immune mimicry’ (IM). We have documented neoplastic cells engaging in IM by examination of histopathological breast tumor specimens and their derived cell lines, public human breast tumor single-cell RNA-seq datasets, and in murine transgenic and cell line-derived mammary cancer models. Immune-mimicked neoplastic cells harbor hallmarks of dedifferentiation and appear enriched for developing aggressive and high-grade tumors. Experimental studies with breast cancer cell lines revealed that neoplastic cells expressing leukocyte surface features are elicited by growth-arresting conditions, such as conventional cytotoxic chemotherapeutic treatments and during metastatic dissemination in mice. In addition, using proof-of-concept studies, we leveraged the canonical leukocyte activation marker CD69, to demonstrate how its expression by neoplastic epithelial cells confers a proliferative advantage under low-density conditions. We conclude that neoplastic breast epithelial cells expressing leukocyte surface receptors may signify a particularly malignant and tumor-initiating cell state. Moving forward, neoplastic IM will be evaluated for prognostic utility in breast cancer to determine whether this unique cell state stratifies patients with increased risks for tumor recurrence and metastasis.
The authors acknowledge NIH/NCI (K00 CA212132, T32 CA254888, P30 CA069533), the Collins Medical Trust, the Susan G Komen Foundation, and the National Foundation for Cancer Research for funding.
Citation Format: Eric B. Berens, Sokchea Khou, Elaine Huang, Amber Hoffman, Briana Johnson, Zena Werb, Laura M. Heiser, Lisa M. Coussens. Neoplastic immune mimicry potentiates breast cancer progression [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 LB224.
Abstract LB245: Single cell guided identification of logic-gated cell surface combinations for selective and safe CAR therapy design
Authors: Madan Sanna , Chang Tiangen , Wang Binbin , Dhruba Saugato Rahman , Schäffer Alejandro A. , Ruppin Eytan 
Published: April 2024

Abstract
The advancement of chimeric antigen receptor (CAR) T-cell therapy has been groundbreaking in the treatment of hematological malignancies. However, its application in solid tumors is constrained by antigen variability and unintended off-tumor, on-target toxicities. Addressing these issues, we introduce a genetic algorithm to analyze single-cell transcriptomics data from patient tumors. This method pinpoints sets of surface antigens exclusive to cancer cells, utilizing the logical operators "AND," "OR," and "NOT." Our technique scales to gene combinations of any size and exhibits robust performance across diverse parameter settings. When applied to five breast cancer datasets, this algorithm successfully uncovered triplet antigen combinations superior to current clinical single antigen targets in distinguishing between cancerous and healthy cells. This strategy offers a promising pathway toward the design of more selective and safe CAR therapies.
Citation Format: Sanna Madan, Tiangen Chang, Binbin Wang, Saugato Rahman Dhruba, Alejandro A. Schäffer, Eytan Ruppin. Single cell guided identification of logic-gated cell surface combinations for selective and safe CAR therapy design [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 LB245.
Abstract LB260: Overexpression of ABCC1 and ABCG2 confers resistance to talazoparib, a poly polymerase inhibitor
Authors: Fang Shuo , Fang Xiaona 
Published: April 2024

Abstract
Aims: The overexpression of ABC transporters on cancer cell membranes is one of the most common causes of multidrug resistance (MDR). This study investigates the impact of ABCC1 and ABCG2 on the resistance to talazoparib (BMN-673), a potent poly (ADP-ribose) polymerase (PARP) inhibitor, in ovarian cancer treatment.
Methods: The cell viability test was used to indicate the effect of talazoparib in different cell lines. Computational molecular docking analysis was conducted to simulate the interaction between talazoparib and ABCC1 or ABCG2. The mechanism of talazoparib resistance was investigated by constructing talazoparib-resistant subline A2780/T4 from A2780 through drug selection with gradually increasing talazoparib concentration.
Results: Talazoparib cytotoxicity decreased in drug-selected or gene-transfected cell lines overexpressing ABCC1 or ABCG2 but can be restored by ABCC1 or ABCG2 inhibitors. Talazoparib competitively inhibited substrate drug efflux activity of ABCC1 or ABCG2. Upregulated ABCC1 and ABCG2 protein expression on the plasma membrane of A2780/T4 cells enhances resistance to other substrate drugs, which could be overcome by the knockout of either gene. In vivo experiments confirmed the retention of drug-resistant characteristics in tumor xenograft mouse models.
Conclusions: The therapeutic efficacy of talazoparib in cancer may be compromised by its susceptibility to MDR, which is attributed to its interactions with the ABCC1 or ABCG2 transporters. The overexpression of these transporters can potentially diminish the therapeutic impact of talazoparib in cancer treatment.
Citation Format: Shuo Fang, Xiaona Fang. Overexpression of ABCC1 and ABCG2 confers resistance to talazoparib, a poly polymerase inhibitor [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 LB260.
Abstract LB261: Establishment and characterization of a paclitaxel-resistant human triple-negative breast cancer cell line
Authors: Yih Ling-Huei , Kuo Hsiao-Hui , Fang Chieh-Ting 
Published: April 2024

Abstract
Triple-negative breast cancer (TNBC) is a lethal female cancer, of which paclitaxel resistance is a major factor limiting treatment outcomes, and continued unmet needs for more effective therapeutic strategies are arduous. The aim of this study is to establish a paclitaxel-resistant TNBC cell line and to characterize the underlying mechanism for potential strategies to overcome the resistance. The human TNBC cell line MDA-MB-231 was exposed to stepwise escalating paclitaxel concentration from 0.5 to 50 nM and a resistant cell line T50R was selected. The IC50 of paclitaxel was 2 and &gt;100 nM in MDA-MB-231 and T50R cells respectively. However, T50R cells required 50 nM Taxol for proliferation. When cultured in the absence of paclitaxel, T50R cells arrested at mitotic stage with high levels of spindle abnormalities. Since induction of microtubule (MT) stabilization plays critical roles in paclitaxel’s potency, we thus measure cell MT polymerization and kinetochore-MT stability. The results showed that, compared to parental MDA-MB-231 cells, the interphase MTs were less polymerized and the kinetochore-MTs were less stable in T50R cells, indicating that the MT dynamic instability was significantly increased in T50R cells. Thus, the increased dynamic unstable MTs in T50R cells might contribute to drug requirement for cell growth and counteract with paclitaxel effects, and consequently lead to drug-resistant phenotype. Identification and interference of endogenous regulators involved in the increased MT instability in T50R cells might provide leads to overcome paclitaxel resistance.
Citation Format: Ling-Huei Yih, Hsiao-Hui Kuo, Chieh-Ting Fang. Establishment and characterization of a paclitaxel-resistant human triple-negative breast cancer cell line [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 LB261.
Abstract LB279: The combination therapy with B7-H3 antibody drug conjugates for effective radiation treatment
Authors: Son Gawon , Ju Eunjin , Park Jin , Shin Seolhwa , Ko Eunjeong , Kwon Miri , Lee Hyewon , Seo Beomseok , Lee Sangkwang , Park Seoksoon , Jeong Seongyun , Song Siyeol , Choi Eunkyung 
Published: April 2024

Abstract
Purpose: Antibody-drug conjugate (ADC) is a promising treatment modality because it enables effective tumor-specific delivery of anticancer drugs by targeting cancer antigens with antibodies. By using ADC, each treatment can be used at an optimal dose, thereby minimizing side effects, and maximizing treatment effects. The ADC used in this experiment targets B7-H3, and the B7-H3 protein is highly expressed in various cancer types. Recent studies have shown that B7-H3 is increased by radiation in various cancer cells. This study aims to demonstrate the efficacy of the B7-H3 ADC and confirm its combined effect with radiotherapy.
Method: In vitro, colony forming assay, CCK-8 assay, FACs and western blotting were performed in JIMT-1 and HCT116 cell lines. In vivo, JIMT-1, HCT116 and Colon PDX models were developed to monitor tumor growth and survival rate. Biodistribution was performed through the IVIS (In Vivo Imaging System) spectrum.
Result: The B7-H3 ADC used in the experiment was developed by combining DUBA as a toxin with anti-B7-H3 antibody In in vitro experiments, the combined treatment of radiation and B7-H3 ADC reduced cell viability via apoptosis more effectively than treatment alone. In the in vivo mouse models, we observed that the combined treatment of radiation and B7-H3 ADC was more effective in inhibiting tumor growth than the single treatment groups. The survival rate of the mice was also improved when the radiation was combined with B7-H3 ADC treatment compared to the other treatment groups alone. In the biodistribution results, the accumulation of B7-H3 ADC-Cy7 was further enhanced when irradiated.
Conclusion: The results show that B7-H3 ADC can be used as a promising therapeutic agent and the combined treatment with radiation can obtain an improved anticancer effect than the single treatment, suggesting another cancer treatment method.
Citation Format: Gawon Son, Eunjin Ju, Jin Park, Seolhwa Shin, Eunjeong Ko, Miri Kwon, Hyewon Lee, Beomseok Seo, Sangkwang Lee, Seoksoon Park, Seongyun Jeong, Siyeol Song, Eunkyung Choi. The combination therapy with B7-H3 antibody drug conjugates for effective radiation treatment [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 LB279.
Abstract LB289: Single-cell CRISPR screens at scale to understand T cell biology
Authors: Untermoser Nicole , Irnstorfer Johanna , Vasilyev Anatoly , Vinko Nikola , Pawar Sumit , Loregger Anke , Krejci Adam , Schmidt Henrik , Bürckstümmer Tilmann 
Published: April 2024

Abstract
CRISPR screens have become the primary discovery engine in modern biology and are widely used to uncover novel targets in immuno-oncology. However, these genetic screens are usually coupled to rather simplistic read-outs such as cell fitness. In contrast, CROP-Seq (or “CRISPR Droplet” Sequencing) screens combine CRISPR perturbation with single-cell transcriptomics, enabling high-content phenotyping at single-cell resolution. Briefly, cells are perturbed with a pooled sgRNA library and transcriptomic profiles of each cell are recorded using conventional single-cell RNA sequencing platforms. Currently, the scale of these screens is limited to the perturbation of a couple of hundred genes, possibly up to 1.000 genes, because of increased costs for single-cell library preparation and next generation sequencing (NGS). At Myllia, we have built a platform allowing high-content CROP-Seq screens in both CRISPR-ready cancer cell lines as well as primary immune cells, e.g., human T cells. Using CRISPR KO, CRISPR interference or CRISPR activation workflows, we can help accelerate the identification of target genes and regulatory networks involved in immuno-oncology. Primary T cells are of great interest in the immunotherapy community as they are key players in autoimmune and inflammatory disease. Engineered T-lymphocytes such as CAR-T cells are currently developed as novel cellular medicines, yet many T cell-intrinsic features involved in CAR-T potency remain elusive. To enable the discovery of novel targets, we have performed multiple customized CROP-Seq CRISPR KO screens in primary human T cells investigating T cell stemness and effector phenotypes as well as CD4+ T helper cell differentiation towards Th1, Th2, or Th17 subsets. Here, we present screens for regulators of functional T cell plasticity and Th2 commitment in which we aimed to identify genes determining critical T cell fate decisions, potentially linking gene (dys)function to either autoimmune/inflammatory disease or functional persistence of cytotoxic T cells for cancer immunotherapy. Overall, the advanced CROP-Seq platform combining large-scale perturbations and targeted sequencing (TA) read-outs will catalyse a paradigm shift for CROP-Seq enabling high-throughput functional genomic screens that support the validation of drug targets in autoimmunity, inflammation and immuno-oncology.
Citation Format: Nicole Untermoser, Johanna Irnstorfer, Anatoly Vasilyev, Nikola Vinko, Sumit Pawar, Anke Loregger, Adam Krejci, Henrik Schmidt, Tilmann Bürckstümmer. Single-cell CRISPR screens at scale to understand T cell biology [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 LB289.
Abstract LB295: Unsaturated fatty acid synthesis is associated with poor prognosis and is differentially regulated by MYCN and tumor suppressor microRNAs in neuroblastoma
Authors: Sheeter Dennis A. , Garza Secilia , Park Hui Gyu , Benhamou Lorraine-Rana , Badi Nikki R. , Espinosa Erika C. , Kothapalli Kumar , Brenna J. Thomas , Powers John T. 
Published: April 2024

Abstract
Dysregulated metabolism is a hallmark of cancer. While the role of glucose metabolism in cancer has been extensively studied, relatively little has been done to understand the role of poly-unsaturated fatty acids in cancer biology. To gain insight into their contribution to cancer progression we determined the expression patterns and outcome associations of both saturated and unsaturated fatty acid synthesis (UFAS) genes in pediatric neuroblastoma (NB), and fatty acid levels in NB cell lines derived from high-risk tumors. MYCN amplification and disruption of tumor suppressor miRNAs (TSmiR) function are central drivers of poor outcomes in NB. MYC, MYCN, and TSmiRs regulate glucose metabolism; however, their role in UFAS remains poorly understood. Using complementary analysis of publicly available genomic datasets and cultured NB cell measurements we examined the potential regulation of UFAS genes through MYCN and MYC activity and posttranscriptional regulation by TSmiRs. Here we show that de novo and UFAS pathway genes FASN, ELOVL6, SCD, FADS2, and FADS1 are upregulated in high-risk NB and are associated with poor prognosis. RNA-Seq analysis of eight human NB cell lines revealed parallel UFAS gene expression patterns. Consistent with this, we found that NB-related TSmiRs were predicted to extensively target these genes. Additionally, we observed that both MYC and MYCN upregulated UFAS pathway genes while suppressing TSmiR host gene expression, thereby creating a possible UFAS regulatory network between MYCN and TSmiRs in NB. Furthermore, using mass spectrometry analysis we found NB cells to be high in de novo synthesized omega 9 (ω9) unsaturated fatty acids and low in both ω6 and ω3. This finding provides a plausible means for NB to limit cell-autonomous immune stimulation and reactive oxygen species (ROS)-driven apoptosis from ω6 and ω3 unsaturated fatty acid derivatives, respectively. We propose a model in which the UFAS pathway, through novel regulation by MYCN and TSmiRs, plays a key role in neuroblastoma pathology with implications for other MYC-driven cancers.
Citation Format: Dennis A. Sheeter, Secilia Garza, Hui Gyu Park, Lorraine-Rana Benhamou, Nikki R. Badi, Erika C. Espinosa, Kumar Kothapalli, J. Thomas Brenna, John T. Powers. Unsaturated fatty acid synthesis is associated with poor prognosis and is differentially regulated by MYCN and tumor suppressor microRNAs in neuroblastoma [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 LB295.
Abstract LB297: Toll-like receptor 8 in tumor associated macrophages regulates miR-192-5p expression and drug resistance in neuroblastoma
Authors: Toldo Nicolo , Rodriguez Verena Martinez , Fabbri Muller 
Published: April 2024

Abstract
MicroRNAs (miRs) are small non-coding RNAs (ncRNAs) with gene expression regulatory functions. MiRs are frequently dys-regulated in human cancers and orchestrate the biology of the disease, and its resistance to chemotherapy. Increasing evidence supports a role of the tumor microenvironment (TME) in promoting cancer growth and resistance to treatments. Tumor Associated Macrophages (TAMs) are a predominant cellular component of the TME of several types of cancers, including neuroblastoma (NB), the most frequent pediatric extra-cranial solid tumor. NB cells secrete miRs within small extracellular vesicles called exosomes, and these miR are shuttled to surrounding TAMs. Our lab was the first to show that cancer-derived exosomal miRs bind to Toll-like receptor 8 (TLR8) in TAMs, triggering an NF-κB-dependent production of TAM-derived miRs, that are then shuttled back to NB cells. Following up on that discovery, we identified a signature of miRs that are up/down-regulated in NB cells when co-cultured with TAMs expressing TLR8 or in which the TLR8 had been deleted with CRISPR/Cas9 engineering. We identified miR-192-5p as significantly down-regulated in NB cells when co-cultured with wild-type TAMs, however miR-192-5p expression was significantly increased in NB cells when co-cultured with TLR8-knock out TAMs, supporting a TLR8-mediated modulation of miR-192-5p in the NB TME. Additionally, we found that over-expression of miR-192-5p in NB cells increased sensitivity of NB cells to temozolomide and cisplatin, two commonly used drugs in the treatment of this malignancy. Overall, these findings support the use of TLR8 inhibitors to up-regulate miR-192-5p and increase sensitivity of NB cells to chemotherapy.
Citation Format: Nicolo Toldo, Verena Martinez Rodriguez, Muller Fabbri. Toll-like receptor 8 in tumor associated macrophages regulates miR-192-5p expression and drug resistance in neuroblastoma [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 LB297.
Abstract LB303: Suppression of stress granule formation is a novel vulnerability imposed by mutant p53
Authors: Thoenen Elizabeth , Ranjan Atul , Parrales Alejandro , Nishikawa Shigeto , Dixon Dan , Oka Sugako , Iwakuma Tomoo 
Published: April 2024

Abstract
Mutation of the tumor suppressor p53 is the most common cancer specific event. Most of these mutations are missense mutations in the DNA-binding domain of p53, causing loss of wild-type p53 (wtp53) transcriptional activity. Missense mutant p53 (mutp53) also enhances cancer malignancy in a manner independent of wtp53. Hence, mutp53 is an ideal therapeutic target due to its uniqueness and high expression levels in cancers; however, directly targeting mutp53 protein itself has been challenging. To better understand the mechanism of oncogenic function of mutp53, we performed in silico TCGA database analysis and found that patients with missense mutp53-carrying hepatocellular carcinoma (HCC), but not other types of cancer, had unexpectedly better overall survival than patients with p53-null HCC. Since sorafenib (SOR) has historically been used as a single agent chemotherapy for HCC, unlike other cancer types, we hypothesized that SOR treatment may have yet unappreciated advantages for treating mutp53-expressing tumors. Indeed, knockdown of mutp53 rendered HCC cells and xenografts more resistant to SOR. Consistent with a report showing that SOR induces ER stress-mediated pro-survival stress granule (SG) formation, mutp53-expressing HCC cells, treated with SOR or other ER stress inducers, formed significantly fewer SGs with increased apoptosis, as compared with mutp53-knockdown cells. This result was partly due to mutp53’s ability to interact with an eIF2α kinase PERK and a key SG core protein, G3BP1. Moreover, the oligomerization domain of mutp53 was required for the interaction of mutp53 with G3BP1 and subsequent suppression of ER-stress-mediated SG formation and survival. These results suggest that inhibition of SG formation is a novel vulnerability imposed by mutp53, leading to sensitization of cancer cells to ER stress. Our results also emphasize the use of ER stress inducers to treat mutp53-expressing tumors and mutp53 as a biomarker of SOR sensitivity.
Citation Format: Elizabeth Thoenen, Atul Ranjan, Alejandro Parrales, Shigeto Nishikawa, Dan Dixon, Sugako Oka, Tomoo Iwakuma. Suppression of stress granule formation is a novel vulnerability imposed by mutant p53 [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 LB303.