bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1236: Direct interaction between cancer cells and fibroblasts drives epithelial-to-mesenchymal plasticity (EMP)
Authors: Dhungel Nilu , Dragoi Ana-Maria 
Published: April 2023

Abstract
The tumor microenvironment (TME), composed of immune cells and fibroblasts, blood vessels, signaling molecules and extracellular matrix, is the source of important cues that govern epithelial-to-mesenchymal (EMT) transition and facilitate the acquisition of aggressive traits by cancer cells. It is now recognized that EMT is not a binary program, and cancer cells rarely switch to a fully mesenchymal phenotype. Rather, cancer cells exist in multiple hybrid epithelial/mesenchymal (E/M) states responsible for cell population heterogeneity, which is advantageous for the ever-changing environment during tumor development and metastasis. How are these hybrid states generated and maintained is not fully understood. We show that direct interaction between small cell lung carcinoma cells (SCLC) and lung fibroblasts induces a hybrid EMT phenotype in cancer cells in which several mesenchymal genes involved in receptor interaction with the extracellular matrix (ECM) and ECM remodeling are upregulated while epithelial genes such as E-cadherin remain unchanged. We also demonstrate that several core EMT-regulating transcription factors (EMT-TFs) are upregulated in cancer cells during direct contact with fibroblasts, as is Yes-associated protein (YAP1), a major regulator of the Hippo pathway. Further, we show that these changes are transient and reverse to the initial state once the interaction is disrupted. Altogether, our results provide evidence that tumor cells’ direct contact with the fibroblasts in the TME initiates a signaling cascade responsible for hybrid E/M states of cancer cells. These hybrid states are maintained during the interaction and possibly contribute to therapy resistance and immune evasion, while interference with direct contact will result in slow recovery and a switch to the initial states.
Citation Format: Nilu Dhungel, Ana-Maria Dragoi. Direct interaction between cancer cells and fibroblasts drives epithelial-to-mesenchymal plasticity (EMP) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1236.
Abstract 1254: Acetyl-coA distribution devote STAT3 related neuronal methylation phenotype and pro-inflammatory niche in gastric cancer
Authors: Low Jie-Ting , Chuang Yu-Ming , Lee Yu-Ting , Chan Michael Wing-Yan 
Published: April 2023

Abstract
STAT3 activation is important in the development of gastric cancer (GCA), but its role in DNA methylation is not fully understood. STAT3-mediated DNA methylation is controlled by K685 acetylation, we therefore hypothesized that distribution of acetyl-CoA could affect the role of STAT3 in DNA methylation. Here, by methylation microarray from GCA patients and cells depleted with STAT3, we identified a STAT3-related CpG island methylator phenotype (CIMP), located at neuronal genes (neuronal CIMP). Further TCGA RNA-Seq identified neuronal CIMP+ve to be positively associated with the expression and higher cyto/mito ratio of acetyl-CoA synthetase (ACSS2). Intriguingly, patients with neuronal-CIMP +ve or higher cyto/mito ratio of ACSS were associated with a better survival, suggesting a different role of acetyl-STAT3. As STAT3 pathway plays a key role in chemokine response, we also analyze whether neuronal-CIMP contributes to anti-tumor immune response. Surprisingly, CIMP +ve patients correlated with pro-inflammatory niche, including activated CD4 + T cells and M1 macrophages. In conclusion, neuronal-CIMP may be a biomarker to predict patient’s immune responses in GCA.
Citation Format: Jie-Ting Low, Yu-Ming Chuang, Yu-Ting Lee, Michael Wing-Yan Chan. Acetyl-coA distribution devote STAT3 related neuronal methylation phenotype and pro-inflammatory niche in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1254.
Abstract 1288: NRP1 exon 4-skipping variant promotes colorectal cancer metastasis by secreted exosomes and activated endosomal signals
Authors: Gu Yiwei , Huang Xiuping , Ye Qing , She Qing-Bai 
Published: April 2023

Abstract
Neuropilin-1 (NRP1) is a transmembrane glycoprotein that acts as a critical co-receptor for tyrosine kinase receptors in growth factor signaling in both physiological and pathological context. The characterization of the NRP1 variants generated by alternative splicing mechanisms has provided profound insights into our understanding of the regulation of NRP1 function in cancer growth, angiogenesis, invasion and metastasis as well as for the modulation of therapeutic outcomes. Here, we identified a novel human NRP1 splice variant resulting from the skipping of exon 4 (NRP1-ΔE4) in colorectal cancer (CRC). We found that NRP1-ΔE4 was largely expressed in CRC and significantly correlated with CRC progression. Furthermore, NRP1-ΔE4 exhibited increased endocytosis/recycling activity via secreted exosomes and decreased levels of degradation, leading to accumulation on endosomes. In addition, NRP1-ΔE4 enhanced interactions with the Met and β1-integrin receptors, resulting in Met/β1-integrin co-internalization and co-accumulation on endosomes. This provided persistent endosomal signals to activate the FAK/p130Cas pathway, thereby promoting CRC cell migration, invasion and metastasis. Blocking exosome secretion, endocytosis or endosomal Met/β1-integrin/FAK signaling using genetic and pharmacological approaches profoundly inhibited the oncogenic effects of NRP1-ΔE4. Taken together, these findings reveal a unique function of NRP1-ΔE4 in the regulation of endocytic trafficking for CRC cell dissemination.
Citation Format: Yiwei Gu, Xiuping Huang, Qing Ye, Qing-Bai She. NRP1 exon 4-skipping variant promotes colorectal cancer metastasis by secreted exosomes and activated endosomal signals [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1288.
Abstract 1291: Signaling pathways modulated by lncRNA UCA1 during anchorage-independent growth in colorectal cancer
Authors: Leslie Sophia , Doxtater Kyle D. , Lopez Samantha , Ezell Kristopher , Anilkumar Adithya , Sanchez Amayrani , Hafeez Bilal , Oraby Tamer , Jaggi Meena , Loy Timothy , Chauhan Subhash , Tripathi Manish K. 
Published: April 2023

Abstract
Colorectal cancer (CRC) is the second deadliest cancer, and over 40-50% of patients develop metastasis during their fight against the disease. CRC survival rate drops from 90% to 14% when the condition is contained within the colon vs. when found at distant sites within the body. Metastasis is a multistep process and one of the critical steps for cancer cells to acquire anoikis resistance to survive after detachment from the primary sites and travel through the circulatory and lymphatic systems to distant target organs. Thus, understanding the molecular players involved in the anoikis process and metastasis could be vital for improving the survival of CRC patients. The aberrant expression of a long noncoding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) has been identified in CRC. However, its role in metastasis processes is not yet well defined. Our preliminary results in the anchorage-independent growth (anoikis model) demonstrate increased expression of lncRNA UCA1. Moreover, the overexpression of lncRNA UCA1 led to high expression of stemness markers SOX2 and Kaiso, along with increased survival of anchorage-independent cells, which indicates a potential mechanistic role of UCA1 in anoikis resistance. Thus, in this study, we propose elucidating the role(s) of UCA1 and its associated signaling pathways during anoikis resistance. We hypothesize that the overexpression of lncRNA UCA1 enhances CRC metastasis through anoikis resistance-associated signaling pathways. We will utilize Isogenic CRC cell lines SW480 (oncogenic) and SW620 (metastatic) to understand the mechanistic regulation of anoikis resistance. Lentiviral transduced stable overexpression (SW480+UCA1//GFP) and knockdown (SW620+CRISPRgUCA1) cell lines have been utilized for this study. After subjecting these cell lines (along with control) to anchorage-independent growth conditions, cell cycle, pro-survival, anti-apoptotic, stemness, and glucose metabolism factors will be analyzed through RT-PCR, Digital Droplet PCR (ddPCR), western blot, and FACS analyses. Utilizing the same model, we will examine lncRNA UCA1 linked anoikis resistance specific phosphorylation profiles of kinases, their protein substrates using the Proteome Profiler Phospho-Human Phospho-Kinase Array.
Citation Format: Sophia Leslie, Kyle D. Doxtater, Samantha Lopez, Kristopher Ezell, Adithya Anilkumar, Amayrani Sanchez, Bilal Hafeez, Tamer Oraby, Meena Jaggi, Timothy Loy, Subhash Chauhan, Manish K. Tripathi. Signaling pathways modulated by lncRNA UCA1 during anchorage-independent growth in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1291.
Abstract 1298: Single cell analysis of breast cancer progression and metastasis to lymph nodes reveals cancer cell plasticity and MHC class II-mediated immune regulation
Authors: Lei Pin-Ji , Pereira Ethel , Andersson Patrik , Amoozgar Zohreh , Van Wijnbergen Jan Willem , O'Melia Meghan J. , Zhou Hengbo , Chatterjee Sampurna , Ho William Wee , Posada Jessica M. , Kumar Ashwin Srinivasan , Morita Satoru , Chuang Charlie , Ergin Ilgin , Jones Dennis , Huang Peigen , Beyaz Semir , Padera Timothy P. 
Published: April 2023

Abstract
Tumor-draining lymph nodes are critical sites for generating tumor antigen-specific T cells and are associated with durable immune responses. However, lymph nodes are often the first site of metastasis and lymph node metastases portend worse outcomes. Through cross species single cell gene expression analysis of breast cancer progression and metastasis to lymph nodes, we uncovered features that define the heterogeneity, plasticity, and immune evasion of cancer cells. Notably, a subpopulation of metastatic cancer cells in the lymph node were marked by high levels of MHC class II (MHC-II) gene expression both in mice and humans. Mechanistically, the IFN-γ and JAK/STAT signaling pathways mediate MHC-II expression in cancer cells. Ablation of IFNGR1/2 or CIITA, the transactivator of MHC-II, in cancer cells prevented tumor progression. Interestingly, MHC-II+ cancer cells lacked co-stimulatory molecule expression, engendered the expansion of regulatory T cells and blunted CD4+ effector T cells in the tumor draining lymph nodes and favor tumor progression. Overall, our data suggests that cancer cell plasticity during breast cancer progression and metastasis to lymph nodes endows metastatic cells with the ability to avoid immune surveillance. These data provide the basis for new opportunities to therapeutically stimulate anti-cancer immune responses against local and systemic metastases.
Citation Format: Pin-Ji Lei, Ethel Pereira, Patrik Andersson, Zohreh Amoozgar, Jan Willem Van Wijnbergen, Meghan J. O'Melia, Hengbo Zhou, Sampurna Chatterjee, William Wee Ho, Jessica M. Posada, Ashwin Srinivasan Kumar, Satoru Morita, Charlie Chuang, Ilgin Ergin, Dennis Jones, Peigen Huang, Semir Beyaz, Timothy P. Padera. Single cell analysis of breast cancer progression and metastasis to lymph nodes reveals cancer cell plasticity and MHC class II-mediated immune regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1298.
Abstract 1347: PAUF stimulates monocytes and induces their differentiation into tumor-associated macrophages
Authors: Jiang Fen , Kim Yeon Jeong , Park Yun Yong , Kang Tae Heung , Koh Sang Seok 
Published: April 2023

Abstract
Background: One of the main reasons for the failure of cancer treatments is that the biological function of therapeutic target molecules is only studied in cancer cells. Therefore, the dynamic and complex interactions between cancer and stromal cells in the tumor microenvironment (TME) should be investigated. TME-specific stromal cells include various cells, with tumor-associated macrophages (TAMs) being one of the major players. TAM are differentiated from monocytes, as immature monocytes recognize molecules derived from infected cells or foreign substances, become activated, and may differentiate into anti-tumoral M1 macrophages or pro-tumoral M2 macrophages (called TAMs). TAMs induce immune evasion of cancer cells in the TME, leading to active proliferation and metastasis of cancer cells. The presence of TAMs in the TME is associated with poor prognosis in various cancers.
PAUF is a protein that is secreted by cancer cells, and it exerts tumor-promoting effects through autocrine and paracrine mechanisms. Compared to the autocrine actions, the paracrine effects of PAUF on immune cells in the TME are less understood.
Objective: This study aimed to evaluate 1) the role of PAUF as a TME modulator, and specifically, a TAM inducer and 2) the potentiality of PAUF antibody as a blocker of TAM transformation.
Methods and Results: In a monocyte-PAUF co-culture system, PAUF (tested at two concentrations, 0.1 and 0.5 μg/mL) demonstrated strong chemoattractant effects on monocytes (~400% of that caused by PBS), which were blocked by TLR2/4 inhibitors. PAUF also induced differentiation of monocytes into macrophages, which were identified to be TAM, using flow cytometric analysis and ELISA method. Moreover, these PAUF-induced TAM demonstrated T cell suppressing capacities. Finally, in a CFPAC-1 human cancer orthotopic mouse model, a humanized monoclonal PAUF-antibody diminished 60-70% of infiltrated TAM (p&lt;0.01), quantified using an immunofluorescence assay (IFA).
Conclusion: In conclusion, this study provides direct evidence that PAUF can differentiate monocytes into TAM of immune-suppressing functions, and the PAUF neutralization-induced TAM infiltration blocking suggests potential combination use of PAUF antibody with immunotherapeutics for cancer treatments.
Citation Format: Fen Jiang, Yeon Jeong Kim, Yun Yong Park, Tae Heung Kang, Sang Seok Koh. PAUF stimulates monocytes and induces their differentiation into tumor-associated macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1347.
Abstract 1373: Cell-in-cell mediated entosis reveals a progression mechanism in pancreatic cancer
Authors: Song Jianlu , Ruze Rexiati , Chen Yuan , Xu Ruiyuan , Yin Xinpeng , Wang Chengcheng , Zhao Yupei 
Published: April 2023

Abstract
Pancreatic cancer (PC) is a deadly malignancy with high intra-tumoral heterogeneity and lacks effective therapeutics. Entosis is a non-apoptotic regulated cell death mediated by cell-in-cell (CIC) structures. However, the impact of entosis on PC progression needs to be determined. This study analyzes the expression levels and prognostic values of entosis-related regulators in public datasets. It identifies that these regulators are commonly upregulated in PC and associated with worse prognosis. We further find that the entotic CIC structures detected in PC specimens have a possible correlation with PC metastases. We enrich a cell population of PC cells undergoing entotic CIC using fluorescence-activated cell sorting (FACS), and several oncogenes, such as NET1, ALDH3A1, PLAT, GALNT5, and FAM3C, were defined as the marker genes of this population using single-cell RNA sequencing (scRNA-seq) analysis. Functionally, this population demonstrates enhanced cell proliferation, migration, invasion, anoikis resistance, sphere formation in vitro, and tumorigenicity in vivo. Moreover, NET1 (neuroepithelial cell transforming gene 1) overexpression promotes cell proliferation, migration, invasion, anoikis resistance, CIC formation, cell competition in vitro, and tumorigenicity in vivo of PC cells. NTE1 is also associated with unfavorable prognosis for PC patients. These results indicate that entosis may play a vital oncogenic role in PC progression. PC cells generate a highly “progressive” subpopulation marked by NET1 via entotic CIC. NET1 is a newly validated gene related to entosis. Targeting entotic processes may be a potential therapeutic option for PC.
Citation Format: Jianlu Song, Rexiati Ruze, Yuan Chen, Ruiyuan Xu, Xinpeng Yin, Chengcheng Wang, Yupei Zhao. Cell-in-cell mediated entosis reveals a progression mechanism in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1373.
Abstract 1383: Mechanisms of ATG9 mediated aggrephagy initiation
Authors: Madhusanka Deshan , McEwan Colton , Broadbent David , Schmidt Jens , Andersen Joshua 
Published: April 2023

Abstract
Highly biosynthetic cancer cells produce proteins at a rate that may exceed the capacity of protein folding machinery, resulting in an accumulation of misfolded proteins that are poly-ubiquitinated and clustered into phase-separated ‘ubiquitin-rich’ condensates. These condensates are the initiation point for a form of autophagy called aggrephagy, which maintains cancer cell homeostasis by degrading the misfolded protein condensates via the lysosome. Aggrephagy is a cancer cell vulnerability, yet its mechanisms are poorly understood, particularly the mechanisms by which autophagy machinery recognizes the ubiquitin-rich condensates to initiate aggrephagy. Among 15 core autophagy proteins, ATG9A is the only multi-pass transmembrane protein and is essential for all known forms of autophagy. Recent evidence indicates that ATG9A is a lipid scramblase, in complex with ATG2A, that channels lipids to a growing autophagosome, which ultimately engulfs the ubiquitin-rich condensate. However, the mechanism of ATG9A recruitment to these condensates is not understood. Our data indicate that genetic or chemical manipulations of cells that cause ubiquitin-rich condensates to accumulate causing a corresponding accumulation of ATG9A. Furthermore, the induction of artificial ubiquitin-rich condensates, composed of chains of M1-linked ubiquitin, is sufficient to recruit ATG9A. Using a CRISPR knockout and reconstitution approach, we show that ATG9A is essential for assembling other autophagy machinery at ubiquitin-rich condensates. Together, our data support a model in which ATG9A recruitment is the initiating step for aggrephagy. Furthermore, our data suggest a signal or molecular pattern within the condensate promotes ATG9A recruitment to initiate aggrephagy. Our current work focuses on identifying features of ATG9A and components of the ubiquitin-rich condensate that cooperate to recruit ATG9A to these sites of aggrephagy initiation.
Citation Format: Deshan Madhusanka, Colton McEwan, David Broadbent, Jens Schmidt, Joshua Andersen. Mechanisms of ATG9 mediated aggrephagy initiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1383.
Abstract 1396: The HOX family gene signature predicts prognosis and indicates immune infiltrates in pediatric gliomas
Authors: Zhao Qianhao , Su Junyan 
Published: April 2023

Abstract
Background: Pediatric gliomas (PGs) are highly aggressive and predominantly occur in young children. Homeobox (HOX) family genes are transcription factors that play a crucial role in anterior-posterior body axis patterning during embryonic development. This study aimed to propose a novel HOX-related signature of PGs to predict patients’ prognosis and immune infiltrate characteristics.
Methods: Multiple levels of data (whole-exome sequencing, mRNA-sequencing, and single-cell RNA-sequencing) of 571 PGs obtained from publicly available databases were utilized to reveal the relationship among abnormal expression of HOX family genes, prognosis, tumor immune infiltration, clinical features, and genomic features in PGs. A total of 39 HOX family genes were utilized to identify heterogeneous subtypes using consensus clustering. Then a random forest-supervised classification algorithm and a nearest shrunken centroid algorithm were performed to develop a prognostic signature in the training group and validated in two test groups and an independent cohort.
Results: Here, we first identified 39 HOX family genes significantly differentially expressed in PGs compared to adjacent normal tissues. Then the individuals with PGs were then divided into two heterogeneous clusters (cluster 1 and cluster 2) based on HOX family gene expression profiles. Cluster 2 showed higher total mutation counts, lower immune infiltration, and worse prognosis than cluster 1. Finally, we constructed a four-hub-HOX gene signature (including HOXA2, HOXA6, HOXC5, and HOXC6) based on the cluster for subtype prediction applying a random forest supervised classification algorithm and a nearest shrunken centroid algorithm. The signature was revealed to be an independent prognostic factor for patients with PGs by multivariable Cox regression analysis.
Conclusion: Our results provide a novel method for the prognosis classification of PGs. The findings also suggest that the four-hub-HOX gene signature is a new biomarker for the prognosis of patients with PGs, allowing for more accurate survival prediction.
Citation Format: Qianhao Zhao, Junyan Su. The HOX family gene signature predicts prognosis and indicates immune infiltrates in pediatric gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1396.