bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3610: Utilizing fructose metabolism to fuel anti-tumor immunity
Authors: Schild Tanya , Chirayil Rachel , Haughton Lyric , Wallisch Patrick , Berishaj Marjan , Scheinberg David A. , Keshari Kayvan R. 
Published: March 2024

Abstract
Consumption of fructose in the form of high fructose corn syrup is elevated in the western diet, but it is not fully understood how fructose metabolism influences anti-tumor immunity. Fructose is canonically metabolized in the intestine and the liver and can shunt into glycolysis. In certain tumor types, fructose metabolism becomes deregulated, allowing tumor cells to metabolize fructose to power their biosynthetic processes. Similarly, reprogramming immune cells to be able to efficiently metabolize fructose may help us power immunotherapy to work in difficult to treat cancers, especially in individuals who have high fructose in their blood or in the tumor microenvironment (TME). Imparting effector T cells with the ability to use fructose for fuel can overcome one of the major metabolic limitations of the TME: limited nutrient supply. As T cells become activated, they alter their metabolism to support growth and proliferation. Activated CD8+ T cells upregulate their glycolysis which results in increased biosynthetic processes, such as synthesis of macromolecules and effector cytokines. However, tumor cells also consume substantial amounts of glucose, resulting in a glucose-depleted microenvironment, which could be one of the major barriers to immunotherapy working in solid tumors. Therefore, we engineered T cells to overexpress a fructose transporter, GLUT5, which is normally not expressed in the immune compartment at high levels. We hypothesized that increased fructose uptake by CD8+ T cells will ameliorate exhaustion caused by the glucose-low tumor microenvironment. Indeed, we determined that GLUT5 T cells are more efficient in killing in low glucose supplemented with fructose. We also observed that GLUT5 expression restores T cell glycolytic capacity under fructose to that of unexhausted T cells under glucose replete conditions. Similarly, GLUT5-expressing T cells proliferate faster in vitro and exhibit an improved ability to control B16 tumor growth in vivo. Additionally, combining GLUT5 cell infusion with checkpoint inhibition resulted in durable tumor control and prolonged mouse survival. Further, engineered CD19-targeted CAR T cells with expression of GLUT5 were more metabolically active and cytotoxic in low glucose conditions, mimicking the TME. In conclusion, GLUT5 expression in effector CD8+ and CAR T cells may allow immunotherapy to function in solid tumors under low glucose conditions.
Citation Format: Tanya Schild, Rachel Chirayil, Lyric Haughton, Patrick Wallisch, Marjan Berishaj, David A. Scheinberg, Kayvan R. Keshari. Utilizing fructose metabolism to fuel anti-tumor immunity [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 3610.
Abstract 3681: Transcribed ultraconserved regions are associated with survival in multiple tumor types
Authors: Rodrigues Ana Carolina , Adamoski Douglas , Gradia Daniela F. , de Oliveira Jaqueline Carvalho 
Published: March 2024

Abstract
Ultraconserved regions (UCRs), encompassing 481 genomic segments identical across humans, mice, and rats, and conserved in other species, are distributed across all human chromosomes except 21 and Y. Over 90% of these regions, termed transcribed ultraconserved regions (T-UCRs) are expressed in at least one human tissue. Although extensively studied in the context of cancer since their discovery, the prognostic significance of T-UCRs in a pan-cancer context has not been explored. For this, TCGA data extracted from the TANRIC platform was utilized, differential expression and survival analysis was performed on different tumor types. Our analysis revealed that approximately 300 UCRs were expressed in the majority of the 20 tumor tissues. Additionally, it was noted that all examined tumor tissues expressed a higher number of UCRs compared to their non-tumor counterparts. Through t-distributed stochastic neighbor embedding (t-SNE) analysis, UCR expression patterns could distinguish primary tumor origins and types. Regarding the prognostic value, we identified 100 (20,8%) T-UCRs associated with disease-specific survival (DSS) and 102 (21.2%) T-UCRs associated with progression-free interval (PFI). Those T-UCRs are particularly important in the survival outcomes of kidney renal clear cell carcinoma (KIRC) and low-grade gliomas (LGC). In addition, we verified that uc.44, uc.48, uc.135, uc.144, uc.153, uc.217, uc.255, uc.256, uc.344, uc.357, uc.390, uc.427 and uc.436 were associated with survival of more than one tumor. Particularly, uc.135 high expression was associated with poor prognosis in Kidney Renal Papillary Cell Carcinoma (KIRP) and LGC, and good prognosis in KIRC. Uc.135 are mapped on MECOM gene, coding an oncoprotein acting as transcriptional regulator and involved in apoptosis, proliferation, and cell differentiation. Our findings suggest that analysis of T-UCRs expression have the potential to be used as predictive biomarkers and can help in studying the mechanisms and specific roles of the highlighted T-UCRs in cancer.
Citation Format: Ana Carolina Rodrigues, Douglas Adamoski, Daniela F. Gradia, Jaqueline Carvalho de Oliveira. Transcribed ultraconserved regions are associated with survival in multiple tumor types [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 3681.
Abstract 3704: Whole genome and targeted proteome analysis of single cancer cells
Authors: Alyasin Atieh , Weidele Kathrin , Botteron Catherine , Klein Christoph A. , Czyż Zbigniew T. 
Published: March 2024

Abstract
The simultaneous genome and proteome analysis of very rare single cells would enable addressing important biological and diagnostic questions particularly in cancer. Here, we introduce a novel genome and proteome (G&P) analytic workflow, a method allowing comprehensive analysis of single-cell DNA and targeted profiling of protein expression in single cells. As a proof of concept, we demonstrate the capability of the method by quantifying copy number of the ERBB2 gene alongside with protein expression levels of HER2 and phospho-HER2 in single cells. The G&P workflow utilizes antibodies conjugated with DNA oligonucleotides designed to enable their amplification alongside the single-cell genome facilitating parallel genome and proteome profiling by either quantitative PCR (qPCR) or sequencing. We utilized antibodies targeting cytokeratin 8/18/19, HER2 and phospho-HER (Tyr1248). Performance of each DNA-conjugated antibody was assessed by immunofluorescence staining in a variety of breast cancer cell lines (MDA-MB231, MDA-MB453, BT474 and MCF7) and sample types. Stained cells were isolated by manual micromanipulation and subjected to whole genome amplification (WGA). Protein expression levels, derived from quantification of the amplified DNA tags, were measured by qPCR. Shallow whole genome sequencing was employed to facilitate genome-wide profiling of copy number variations (CNVs), including the ERBB2 locus. We successfully developed and tested a G&P workflow allowing parallel genome-wide CNV profiling and quantification of three target proteins. G&P measurement yielded concordant results to immunofluorescence quantification for all tested markers. Furthermore, the workflow allowed direct correlation of copy numbers of the ERBB2 gene with HER2 expression in single cancer cells. Notably, the method enabled measurements of cellular and molecular responses at the single-cell level to lapatinib treatment, i.e. monitoring of the HER2 pathway activation level. Our novel multiplex G&P technique is capable of generating multiparametric measurements linking DNA copy numbers and expression levels of selected genes of interest. The method is optimized for analysis of single cells from rare cell populations and is readily translatable to study circulating tumor cells (CTCs) and disseminated cancer cells (DCCs), enabling for the first time pathway analysis via phosphoprotein analyses of these cells.
Citation Format: Atieh Alyasin, Kathrin Weidele, Catherine Botteron, Christoph A. Klein, Zbigniew T. Czyż. Whole genome and targeted proteome analysis of single cancer cells [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 3704.
Abstract 3717: Sudocetaxel Zendusortide (TH1902) triggers the cGAS/STING pathway and potentiates anti-PD-L1 immune-mediated tumor cell killing
Authors: Demeule Michel , Currie Jean-Christophe , Charfi Cyndia , Zgheib Alain , Cousineau Isabelle , Lullier Veronique , Beliveau Richard , Marsolais Christian , Annabi Borhane 
Published: March 2024

Abstract
The potential impact of the immune tumor microenvironment (iTME) was assessed with respect to the anticancer efficacy of sudocetaxel zendusortide (TH1902), a peptide-drug conjugate internalized through a sortilin (SORT1)-mediated endocytic pathway. In the triple-negative breast cancer (TNBC)-derived MDA-MB-231 immunocompromised xenograft tumor model, TH1902 induced complete tumor regression for more than 40 days after the last treatment. Surprisingly, immunohistochemistry analysis revealed higher staining of CD45 leukocytes and of STING, a master regulator in the cancer-immunity cycle, in comparison to docetaxel. Additionally, in a murine B16-F10 melanoma syngeneic tumor model, weekly administration of TH1902 as a single agent also demonstrated superior tumor growth inhibition than did docetaxel. Although B16-F10 is considered a non-immunogenic “cold” tumor model, we observed a net increase in CD45 leukocyte infiltration within TH1902-treated tumors, especially for tumor-infiltrating lymphocytes and tumor-associated macrophages. Moreover, in TH1902-treated tumors, increased staining of perforin, granzyme B, and caspase-3 was suggestive of elevated cytotoxic T and natural killer cell activities. Combined TH1902/anti-PD-L1 treatment led to increased tumor growth inhibition and median animal survival. Accordingly, TH1902 inhibited cell proliferation and triggered apoptosis and senescence in B16-F10 cells in vitro, while inducing several downstream effectors of the cGAS/STING pathway and the cell surface expression of MHC-I and PD-L1. This is the first evidence that TH1902 exerts its antitumor activity, in part, through modulation of the iTME and that the combination of TH1902 with checkpoint inhibitors (anti-PD-L1) could lead to improved clinical outcomes.
Citation Format: Michel Demeule, Jean-Christophe Currie, Cyndia Charfi, Alain Zgheib, Isabelle Cousineau, Veronique Lullier, Richard Beliveau, Christian Marsolais, Borhane Annabi. Sudocetaxel Zendusortide (TH1902) triggers the cGAS/STING pathway and potentiates anti-PD-L1 immune-mediated tumor cell killing [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 3717.
Abstract 372: Cell polarity proteins as novel regulators of macropinocytosis in pancreatic cancer
Authors: Barjau Guillem Lambies , Lee Szu-Wei , Commisso Cosimo 
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest cancers. This is likely because it is detected at a very late stage and the therapeutic approaches that have been used for its treatment have proven to be quite ineffective. Therefore, new therapeutic strategies are needed for a better prognosis in patients suffering of pancreatic cancer. PDAC cells often rewire their metabolism to survive and progress. This metabolic rewiring permits the acquisition of nutrients by the cells when these are exposed to a poor nutrient microenvironment. One of the most used processes in nutrient stress conditions is the “cell-drinking” pathway macropinocytosis, an endocytic pathway that cancer cells exploit to support cancer metabolism in such unfavorable conditions. Macropinocytosis inhibition has shown to suppress PDAC growth in mice and thus, it has become a promising therapeutic target for PDAC treatment. Here, we describe that atypical Protein Kinase C (aPKC) isoforms Protein Kinase C zeta (PKCζ) and Protein Kinase C iota (PKCι) regulate PDAC macropinocytosis in the context of glutamine stress. Genetic depletion and pharmacological inhibition of aPKC impair macropinocytosis promotion in PDAC cells exposed to a glutamine-deprived environment and in cells treated with DON, a glutamine analog that blocks glutamine metabolism. In epithelial cells, aPKCs are known to regulate the establishment of cell polarity in association with the scaffold proteins Par3 and Par6, constituting the cell polarity complex, which controls the function of different targets such as Par1 kinases. Loss of Par3, Par6 and Par-1a affects glutamine stress associated macropinocytosis in a similar extent than aPKC depletion, presenting a novel role of the cell polarity protein network in the modulation of macropinocytic uptake.
Citation Format: Guillem Lambies Barjau, Szu-Wei Lee, Cosimo Commisso. Cell polarity proteins as novel regulators of macropinocytosis in pancreatic 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 372.
Abstract 3791: A prognostic signature based on inherited genetic polymorphisms for patients with uveal melanoma
Authors: Verrier Thibault , Ven Anaïs Le , Houy Alexandre , Garcia Agathe , Gaelle Pierron , Cassoux Nathalie , Rodrigues Manuel , Noirel Josselin , Stern Marc-Henri 
Published: March 2024

Abstract
Introduction: Uveal melanoma (UM) is the most frequent eye malignancy in adults. Two UM subtypes exist, defined by Gene Expression Profiling or by genomic status: GEP class 1/disomy 3 [D3] and GEP class 2/monosomy 3 [M3] defining low-risk or high-risk of developing metastasis, respectively. However, these prognostic signatures require tumor samples, which may be difficult to obtain. We previously identified by a genome-wide association study (GWAS) frequent single nucleotide polymorphisms (SNP) in IRF4 and HERC2 associated with risk for D3 or M3 UM, respectively (1). Here, we aim to design a prognostic signature for the D3 and M3 UM subtypes based on these constitutive polymorphisms, available from blood samples.
Experimental Procedures: We used the GWAS cohort of 1476 UM patients genotyped on GSA or Omni5. Risk SNPs coupled with clinical variables were used on a cohort of 497 UM patients (191 D3, 306 M3) in a statistical machine learning process to define a predictive signature of UM subtype. A cohort of 852 UM patients was used for validation.
Results: We retained two SNPs, rs12203592 (in IRF4) and rs12913832 (in HERC2), tumor diameter and thickness, age at diagnosis and gender. We validated the predictive model in the validation cohort. The predicted high-risk group showed a decrease in time to relapse (TR) (HR: 3.72 [2.57 - 5.41], logrank p-value = 1.35E-15), overall survival (OS) (HR: 3.85 [2.58 - 5.73], logrank p-value = 1.24E-14) and progression-free-survival (PFS) (HR: 3.61 [2.32 - 5.61], logrank p-value = 6.55E-11), compared with the predicted low-risk group.
Conclusion: Common germline polymorphisms contribute to the prediction of metastatic risk in patients with localized uveal melanoma. This information could be especially useful when access to the tumor is problematic.
1. Mobuchon et al, J Natl Cancer Inst, 114, 2, (2022)
Citation Format: Thibault Verrier, Anaïs Le Ven, Alexandre Houy, Agathe Garcia, Pierron Gaelle, Nathalie Cassoux, Manuel Rodrigues, Josselin Noirel, Marc-Henri Stern. A prognostic signature based on inherited genetic polymorphisms for patients with uveal melanoma [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 3791.
Abstract 3798: Advancements in multiplexed spatial phenotyping
Authors: Montoya Leticia , Clarke Scott , Harvey Austin , Serafin Jen , Voeun Mae 
Published: March 2024

Abstract
Spatial omics is an expanding research area focused on integrating spatial knowledge of tissue with transcriptomics (RNA) and proteomics (protein). Understanding the complexity of the biological structure(s) is an important biological process in cancer immunotherapy research which requires accurate target classification. Translational profiling of 4+ targets on a single sample at one time can be difficult in many ways, such as, panel design, staining protocols, and data analysis. Furthermore, to design a reliable multi-target biomarker panel, there are many parts to overcome, such as protein abundance and localization, fluorophore compatibility, varying tissue types, and data characterization, to name a few. To address the needs of high target multiplex ability, labeling methods have advanced in cyclic detection enabling iterative labeling and detection using automated fluidics, however these approaches suffer from low simultaneous target throughput. Thermo Fisher Scientific can now provide a streamline process for tissue labelling; a process that enables sufficient labelling of high multiplexed panels completed within a couple of hours. We show successful detection of a wide range of various protein markers across numerous tissue organs used in various biological research applications with our uniform technique of labelling.
Citation Format: Leticia Montoya, Scott Clarke, Austin Harvey, Jen Serafin, Mae Voeun. Advancements in multiplexed spatial phenotyping [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 3798.
Abstract 3842: Neuroendocrine differentiation and treatment of human SCLC: NRF2 has a role
Authors: Hamad Samera , Joshi Hansa , Li Yahui , Toma Helen , Bendjilali Nasrine , Jefferys Stuart , Corcoran David , Elbezanti Weam , Major Ben , Bernard Weissman , Spitz Francis 
Published: March 2024

Abstract
SCLC is a lethal form of lung cancer and highly metastatic disease with limited therapeutic options. Four main neuro and non-neuroendocrine SCLC molecular subtypes have been identified which further complicate the efforts of finding targeted therapies. NRF2 is a transcription factor that is known to protect cells from oxidative damage by regulating more than 500 cytoprotective genes. NRF2 is frequently mutated in non-small cell lung cancer (NSCLC), however, whether alterations occur in small cell lung cancer (SCLC) is not clear due to limited sequencing data. Recently, our group has discovered a previously unrecognized role of NRF2 signaling pathway in the development of SCLC using a novel genetically engineered mouse model (GEMM). In this study, we have investigated the role of NRF2 in the progression and regression of human SCLC. Human SCLC cell lines were generated with NRF2E79Q/+ mutation (one of the most common mutations found in human tumors) to allow the constitutive activation of NRF2 in these cells. Results from hSCLC cell lines showed that NRF2 activation in NRF2-negative SCLCs can significantly inhibit their growth. Further, human SCLC gene expression data showed reduced levels of a NRF2 signature as hSCLC neuroendocrine SCLC transforms to non-neuroendocrine subtypes. As an anti-inflammatory pathway, NRF2 is known to inhibit immune cell gene signature. Our in vivo and invitro studies showed that NRF2 inhibits immune cell infiltration in SCLC; and increases PDL1 protein expression. Currently, we are investigating the effect of NRF2 activation in hSCLC growth, neuroendocrine differentiation and immune gene activation in vitro and in vivo. We are also using immune checkpoint inhibitors to determine the best therapeutic options for each SCLC subtype.
Citation Format: Samera Hamad, Hansa Joshi, Yahui Li, Helen Toma, Nasrine Bendjilali, Stuart Jefferys, David Corcoran, Weam Elbezanti, Ben Major, Weissman Bernard, Francis Spitz. Neuroendocrine differentiation and treatment of human SCLC: NRF2 has a role [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 3842.
Abstract 3851: Beta-lapachone promotes tumor associated neutrophils (TANs) polarized towards anti-tumor (N1) phenotype
Authors: Huang Xiumei , Tumbath Soumya , Jiang Liangxiang , Fu Yang-Xin 
Published: March 2024

Abstract
NAD(P)H:quinone oxidoreductase1 (NQO1) is overexpressed in most solid cancers, emerging as a promising target for tumor selective killing. β-lapachone (β-lap), an NQO1bioactivatable drug, exhibits significant antitumor effects on NQO1+ human solid cancer cell lines. It also induces immunogenic cell death in the tumor microenvironment (TME)and synergizes with anti-PD-L1 immunotherapy. However, the interaction between β-lap-mediated anti-tumor immune response and neutrophils, a novel antigen presenting cells(APCs), remains unknown. This study found β-lap treatment increased intracellular ROS formation and DNA damage to kill NQO1+ murine tumor cell lines and dicoumarol spared the lethality. Furthermore, flow cytometric analysis of immune cells in TME of subcutaneous tumor models indicated that there is a significant infiltration of neutrophils(CD11b+ Gr1high cells) or Tumor Associated Neutrophils (TANs) following β-lap treatment. Depletion of neutrophils by co-addition of anti-Ly6G antibody abolished β-lap-induced anti-tumor efficacy in immune competent mice. Neutrophil mediated tumor cell killing determined ex vivo using bone marrow derived neutrophils and it was observed that in the presence of β-lap induced antigen, neutrophils were killing murine tumor cells. Moreover, exposure of these neutrophils to β-lap induced antigen medium induce antitumor N1-like properties, include increase in certain surface markers such as CD95(Fas) and CD54 (ICAM-1) as well as increase in intracellular cytokine IFN-β and decrease in TGF-β revealed by flow cytometric analysis. Corroborating to this, there is a significant increase of CD95 and IFN-β and a decrease in TGF-β were observed with TANs infiltrated into β-lap treated TME compared to vehicle treated tumors. Additionally, TLR/MyD88signaling deficiency decreased β-lap induced neutrophil tumor infiltration. BlockingHMGB1, depleting neutrophils, or TLR4/MyD88 deficiency lessened the antigen-specific T cell response. This study highlights that β-lap kills NQO1+ murine tumor cells through ROS production and DNA damage, and neutrophils play a pivotal role in its antitumor effects.
Citation Format: Xiumei Huang, Soumya Tumbath, Liangxiang Jiang, Yang-Xin Fu. Beta-lapachone promotes tumor associated neutrophils (TANs) polarized towards anti-tumor (N1) phenotype [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 3851.