bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3783: Oral squamous carcinoma, LN metastasis
Authors: Kawai Hotaka , Eain Htoo Shwe , Ohara Toshiaki , Oo May Wathone , So Yamin , Nagatsuka Hitoshi 
Published: March 2024

Abstract
Due to genetically unstable nature of cancer cells, they give rise to genetically different variant subclones inside a single tumor. To enable the development of more efficacious therapies, it is crucial to understand cancer heterogeneity and subclone characteristics. Oral squamous cell carcinoma (OSCC) has high heterogeneity and plasticity. C-X3-C motif ligand 1 (CX3CL1) is the chemokine with anti- and pro-tumor functions. Our study reported CX3CL1 functions on cancer subclones with different phenotypes, both in vivo and in vitro. We found that Mouse OSCC (MOC) 1 and MOC2 cells responded in similar manners to CX3CL1 in vitro. However, in vivo, CX3CL1 increases cellular differentiation in indolent cancer (MOC1) while increasing metastasis in aggressive cancer (MOC2). These phenomena are influenced by different phenotypic tumor microenvironments created by indolent and aggressive cancer. From there, we established that when aggressive cancer cells gain CX3CL1 expression, they stimulate protumor immune system, promoting cancer metastasis via lymphatic vessels. A similar phenomenon was observed in metastatic OSCC patient samples, where CX3CL1 expression became intense in metastasis regions, consistent with aggressive subclone (MOC2) character; we correctly predicted patient outcomes by using CX3CL1 as prognostic indicator for long-term follow-up in metastatic OSCC patients. In conclusion, CX3CL1 is the key factor for stimulating aggressive cancer subclones to create new lymphatic networks for lymph node metastasis.
Citation Format: Hotaka Kawai, Htoo Shwe Eain, Toshiaki Ohara, May Wathone Oo, Yamin So, Hitoshi Nagatsuka. Oral squamous carcinoma, LN metastasis [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 3783.
Abstract 3820: Impact of primary site in early-stage follicular lymphoma on patient outcomes: Analysis of a large national database
Authors: Davis Olivia , Kasht Rana , Cohoon Andrew , Day Silas , Ibrahimi Sami , Asch Adam , Al-Juhaishi Taha 
Published: March 2024

Abstract
Introduction: Follicular lymphoma (FL) is the most common indolent Non-Hodgkin lymphoma and is associated with better outcomes compared to other types of lymphoma. Despite this, cure is usually elusive and most patients experience multiple relapses within their lifetime. Previous studies have identified risk factors associated with worse outcomes, but little is known about the role of primary disease site in FL. We sought to investigate the outcomes of patients with extranodal early-stage FL compared to nodal disease using a large national cancer database.
Methods: The Surveillance, Epidemiology, and End Results (SEER) public database was used to identify and extract data for patients with FL. Early-stage disease was defined as stage I or II by the Ann Arbor staging system. Most patients in the database were diagnosed after 2000 so this was used as the diagnosis year cutoff and also to reflect the impact of recent management strategies on outcomes. Patients were divided into two groups based on their primary disease site. These two groups were nodal (includes spleen) and extranodal. Treatment effect (surgery, radiation, or chemotherapy) was analyzed when available. Survival was estimated using the Kaplan-Meier method and compared using log-rank tests. Cox proportional hazards models were used for adjusted survival analyses.
Results: A total of 13,400 patients with FL of all histologic grades diagnosed between 2000 and 2015 were identified in the SEER database. The median age at diagnosis was 65 years (2-100). A majority of patients were Caucasian (81%), had stage I disease (62%), and belonged to the nodal FL group (79%). Median overall survival (OS) for patients with nodal FL was 181 months [95% CI (175-187)]. Median OS for extranodal FL was 189 months [95% CI (179-195)]. Extranodal FL was associated with better OS compared to the nodal group [HR=0.89, 95% CI (0.84-0.96); p-value =0.00012] even after adjusting for age and race [HR=0.84, 95% CI (0.79-0.90); p-value &lt;0.0001].
Conclusions: In this analysis of a large national cancer database, early-stage FL presenting as extranodal disease can be seen in about 20% of patients and is associated with slightly better outcomes.
Citation Format: Olivia Davis, Rana Kasht, Andrew Cohoon, Silas Day, Sami Ibrahimi, Adam Asch, Taha Al-Juhaishi. Impact of primary site in early-stage follicular lymphoma on patient outcomes: Analysis of a large national database [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 3820.
Abstract 3840: Can serum exosomal content predict response to immunotherapy in hepatocellular carcinoma
Authors: Savaraj Niramol , Puente Pablo , Li Ying-Ying , Wu Chunjing , Nguyen Jonathan D. , Wangpaichitr Medhi , Hosein Peter J. , Feun Lynn G. 
Published: March 2024

Abstract
While atezolizumab and bevacizumab combination has received FDA approval for the treatment of unresectable hepatocellular carcinoma (HCC), and recently durvalumab + tremelimumab also showed activity over sorafenib, there is no biomarker which can guild which patients can benefit from these regimens. The traditional PD-L1 positivity in the tumor by immunohistochemical staining which can predict possible response to immune checkpoint inhibitor in other solid tumors, such as melanoma and NSCLC, does not appear to apply to HCC. Thus, we attempt to explore whether exosomal content can be useful to predict response. HCC tumors exist in a complex microenvironment and serum exosomes can be generated from either tumor cells, macrophages, or other immune cells. Exosome act as new mediators for cell-cell communication transporting molecules such as lipids, proteins, and RNAs in vivo. Exosomal PD1 and PD-L1 have been implicated for possible biomarkers for immune checkpoint sensitivity. We isolated exosome from serum of unresectable HCC patients who underwent treatment with atezolizumab and bevacizumab. Blood sample was obtained prior to treatment, and then on cycle 3 and at the time of disease progression. Exosomes were isolated using the kit from System BioScience. Twenty patients were entered into the study. Five patients were not treated (received SBRT or other regional treatment), one was lost to follow up and one had atezolizumab only. In terms of antitumor response, eight patients had stable disease, three patients had partial response and two patients had progressive disease. Serum exosomal content data was available in 16 patients. Both PD1 and PDL1 are lowest in the three patients who had response followed by the group who had stable disease. In the two patients who had progressive disease, both exosomal PD-L1 and PD1 appeared to be the highest and did not change during treatment. Unlike in melanoma patients we have studied, other proteins in the antiapoptotic family such as Bcl-2 do not show any differences. While the number of patients are small and accrual is still ongoing, it appears that exosomal PD-L1/PD1 may have clinical value in predicting response to atezolizumab + bevacizumab therapy. Supported by Sylvester Comprehensive Cancer Center grant.
Citation Format: Niramol Savaraj, Pablo Puente, Ying-Ying Li, Chunjing Wu, Jonathan D. Nguyen, Medhi Wangpaichitr, Peter J. Hosein, Lynn G. Feun. Can serum exosomal content predict response to immunotherapy in hepatocellular carcinoma [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 3840.
Abstract 3847: Dual targeting of EGFL6 and VEGF-A to overcome immune suppression in ovarian cancer
Authors: Umamaheswaran Sujanitha , Mangala Lingegowda S. , Joseph Robiya , Jennings Nicholas B. , Kim Mark S. , Wen Yunfei , Bayraktar Emine , Zhang Ningyan , An Zhiqiang , Sood Anil K. 
Published: March 2024

Abstract
Background: Ovarian carcinomas are known to have a high degree of immune suppression, which may be related, in part, to high levels of vascular endothelial growth factor-A (VEGF-A). Bevacizumab (anti-VEGF antibody) has been shown to increase infiltration of T-cells in the tumor microenvironment (TME). We have also identified EGFL6 as an important angiogenic protein. Here, we examined the biological effects of blocking EGFL6 and VEGF-A in ovarian cancer models.
Methods: We studied the in vitro (endothelial tube formation and migration assays) and in vivo (ID8KO-Trp53;Brca2 and SKOV3-ip1 models) biological effects of EGFL6 and VEGF-A blockade. Tumor-infiltrating immune cells were studied by flow cytometry and immunohistochemistry staining.
Results: Blocking EGFL6 and VEGF-A simultaneously with monoclonal antibodies in RF24 endothelial cells decreased tube formation and migration significantly, in comparison to VEGF-A blockade alone (p&lt;0.001). EGFL6 monotherapy in ID8KO-Trp53;Brca2 tumor bearing syngeneic mice decreased tumor burden (~2.5 fold, p&lt;0.0001) and increased the infiltration of IFNγ+ (~2.75 fold, p&lt;0.0001) and GzmB+ (~1.75 fold, p&lt;0.01) CD8+ T-cells and IFNγ+ (~2 fold, p&lt;0.0001) and GzmB+ (~2 fold, p&lt;0.01) CD4+ T-cells while decreasing PD-L1+ cells (~1.8 fold, p=0.01). Dual blockade of EGFL6 and VEGF-A in SKOV3-ip1 tumor bearing nude mice significantly decreased tumor burden (~3.72 fold, p&lt;0.01) and angiogenesis (~2.36 fold, p&lt;0.05) compared to controls and single-agent blockade. Similar blockade in ID8KO-Trp53;Brca2 tumor bearing mice significantly decreased tumor burden (~4.2 fold, p=0.0004), improved CD8+ (~3.32 fold, p=0.0004) and CD4+ (~2.81 fold, p&lt;0.0001) T-cell infiltration, NK cell infiltration (~2.3 fold, p=0.0005) and decreased myeloid-derived suppressor cells (MDSCs) (~1.92 fold,
p=0.0278) compared to EGFL6 and VEGF-A blockade alone.
Conclusions: Our results demonstrate that simultaneously targeting the angiogenesis drivers EGFL6 and VEGF-A in ovarian cancer significantly decreased tumor burden in vivo and increased the infiltration of T lymphocytes compared to single-agent blockade.
AACR Category: Tumor Microenvironment and Immune Oncology
Key words: ovarian cancer, immune suppression, angiogenesis, VEGF-A, EGFL6
Citation Format: Sujanitha Umamaheswaran, Lingegowda S. Mangala, Robiya Joseph, Nicholas B. Jennings, Mark S. Kim, Yunfei Wen, Emine Bayraktar, Ningyan Zhang, Zhiqiang An, Anil K. Sood. Dual targeting of EGFL6 and VEGF-A to overcome immune suppression in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3847.
Abstract 385: Stress-induced pentraxin 3 enhances anoikis resistant-associated metastasis and post-chemotherapeutic recurrence in head and neck cancer
Authors: Chang Ting-Wei , Chang Wen-Chang , Chen Ben-Kuen 
Published: March 2024

Abstract
Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive cancer with the properties of local recurrence and lymphatic metastasis. During metastatic process in blood circulation, cancer cells lose the interaction with extracellular matrix and encounter the anoikis stress, resulting in successfully extravasate and form micrometastasis in distal organs. However, most patients develop chemo-drug resistance during the metastatic recurrence which leading to poor prognosis. Thus, it is a pressing matter to elucidate the molecular mechanisms involved in cancer metastasis and the behaviors of the post-chemotherapy treated HNSCC cells. Our previous studies suggest that growth factor signaling stimulated HNSCC cells metastasis by the expression of pentraxin 3 (PTX3). Moreover, recent findings also reveal that chemotherapy mediated oxidative stress induce PTX3 expression and poor progression. Here, we raise the hypothesis that the expression of PTX3 through stress signal may promote cancer cells against from anoikis and promote the post-chemotherapeutic survival. The first, we identified that the secondary messenger-reactive oxygen species (ROS) dominate the gene activation of PTX3 by spheroid culture and platium-based agents’ treatment. The ROS scavenger, NAC, inhibited cisplatin (CDDP)-induced PTX3 expression and rescue the cell viability by decreasing the ROS level. The oxidative stress inducer-H2O2 treatment also verify the PTX3 expression through AKT and NF-κB pathways. In addition, both the spheroid selection and CDDP-induced PTX3 regulated the EMT phenotype and further strengthen the growth factor signaling. In addition, we found that PTX3 also regulate the survival during spheroid selection and drug treatment. The post-selected cells also exhibit the unique glycosylated modification on PTX3. Disrupted the PTM modification of PTX3 could inhibit the spheroid survival and cell invasion. The animal studies revealed that both spheroid selection and CDDP-treated HNSCC cells had stronger extravasation ability than parental cells in NOD-SCID mice. Depletion of PTX3 also repressed the HNSCC cells extravasation ability. The results indicate that PTX3 were essential for oxidative stress-induced tumor metastasis and recurrence. It also speculates that the combination of antioxidants and PTX3 antibody may prevent tumor metastatic recurrence after chemotherapy in HNSCC.
Citation Format: Ting-Wei Chang, Wen-Chang Chang, Ben-Kuen Chen. Stress-induced pentraxin 3 enhances anoikis resistant-associated metastasis and post-chemotherapeutic recurrence in head and neck 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 385.
Abstract 386: BACH1 is a key regulator of the tumor hypoxia response
Authors: Nguyen Long Chi , Dann Christopher , Yang Dongbo , Henn Madeline , Shi Emily , Li Thomas , Stock Letícia , Liu Wenchao , Matossian Margarite , Valdespino Andrea , Han Yoo Jane , Zhang Jing , Yerradoddi Geetha Priyanka , Li Yan , Matsumoto Mitsuyo , Olopade Olufunmilayo I. , Igarashi Kazuhiko , Rosner Marsha R. 
Published: March 2024

Abstract
Hypoxia is an important hallmark of aggressive solid tumors and a key driver of metastasis and resistance to therapy. Hypoxic stress induces the activation of various factors, such as hypoxia-inducible factors (HIFs), which facilitate cellular adaptation and promote tumorigenesis. Given the complexity of this mechanism, identifying novel targets that sensitize hypoxic tumors to therapy could have significant clinical impact. Here we show that the pro-metastatic BTB and CNC homology 1 (BACH1) transcription factor is prolyl-hydroxylated by the HIF Prolyl Hydroxylase (PHD), similar to HIFs, in an oxygen-dependent manner. We describe two major prolyl hydroxylation sites in BACH1 and demonstrate that prolyl hydroxylation increases protein turnover and decreases DNA binding in normoxia. We further demonstrate HIF-independent induction of BACH1 within multiple TNBC (Triple-Negative Breast Cancer) cell lines and patient-derived organoids under hypoxic conditions. Utilizing ChIP-seq, bulk, single-cell and spatial transcriptomics across diverse BACH1 knockout tumor models, our study revealed that BACH1 selectively and directly modulates the transcriptional response associated with hypoxia and stress in TNBC. Our findings identify BACH1 as a clinically relevant target for attenuating hypoxia induced, pro-metastatic signaling and therapeutic resistance in cancers.
Citation Format: Long Chi Nguyen, Christopher Dann, Dongbo Yang, Madeline Henn, Emily Shi, Thomas Li, Letícia Stock, Wenchao Liu, Margarite Matossian, Andrea Valdespino, Yoo Jane Han, Jing Zhang, Geetha Priyanka Yerradoddi, Yan Li, Mitsuyo Matsumoto, Olufunmilayo I. Olopade, Kazuhiko Igarashi, Marsha R. Rosner. BACH1 is a key regulator of the tumor hypoxia response [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 386.
Abstract 3873: Understanding spatial organization of cellular plasticity in pancreatic ductal adenocarcinoma
Authors: Zamora Izabella , Parikh Milan , Patel Bidish K. , Bi Lynn , Haviv Doron , Cao Jingyi , Shiau Carina , Hemberg Martin , Hwang William L. , Hacohen Nir , Ting David T. , Mehta Arnav 
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is notorious for poor survival rates, underscoring the urgency of understanding factors that drive tumor progression. A key player in this process is epithelial-mesenchymal transition (EMT), known for its role in enhancing cancer cell adaptability, resistance to treatment, and metastasis. Our study focuses on EMT within PDAC, using single-cell spatial transcriptomics to explore how the tumor microenvironment influences changes in cellular states. We introduce a novel method involving Gaussian mixture models (GMM) to categorize EMT stages in single-cell data and utilize deep learning for label transfer of these tumor cell states, including intermediate cell states, onto spatial transcriptomic data with limited gene panels and sparse count profiles. We find strong spatial autocorrelation of classical cells and a dispersion of basal cells alongside other cells at intermediate stages of the EMT spectrum. By leveraging the spatial proximity of clonally related cells, we confirm that cells transition along the EMT spectrum in a gradient and infer transition rates. We next leverage density gradients of tumor cells in different states to identify distinct neighborhoods with varying EMT subtype composition. We observe significant variations in cell density among different EMT states. A focus on cancer-associated fibroblasts (CAFs) and macrophages reveals differences in these cells across density contours. We also examine differential ligand-receptor interactions across cell state gradients to better understand the cellular interactions that drive EMT transitions and alter the tumor environment. By leveraging spatial transcriptomics, this research aims to provide new biological insights into PDAC intratumoral heterogeneity, potentially leading to the identification of novel therapeutic targets to disrupt treatment resistance.
Citation Format: Izabella Zamora, Milan Parikh, Bidish K. Patel, Lynn Bi, Doron Haviv, Jingyi Cao, Carina Shiau, Martin Hemberg, William L. Hwang, Nir Hacohen, David T. Ting, Arnav Mehta. Understanding spatial organization of cellular plasticity in pancreatic ductal adenocarcinoma [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 3873.
Abstract 3903: Discovery of ULBP6 as a novel immuno-oncology target using pleiotropic signals from 23andMe’s genetic and health survey database
Authors: Tilk Susanne , Fontanillas Pierre , Chung Wei-Jen , Hom Clifford , Shi Shi , Diep Anh , Gerrick Kim , Poggio Mauro , Sood Pranidhi 
Published: March 2024

Abstract
23andMe has assembled one of the largest platforms for human genetics research that combines genotypes from 14 million individuals, 80% of which are consented to participate in research, with billions of phenotypic data points collected from health survey data. Using these large scale genetic and phenotypic datasets, we have developed a unique target discovery platform that has identified hundreds of pleiotropic genetic variants with opposing directionality of effects in cancer and immune diseases. These immune-oncology (I/O) genetic associations point to already clinically validated immune checkpoint receptors (e.g., CTLA4) and those currently in clinical trials (e.g., CD200R1). This suggests that these I/O genetic associations could be linked to genes that are broadly utilized by tumor cells to evade the immune system and could be used to identify novel therapeutic targets involved in regulating anti-tumor immune response. Here, we utilized expression quantitative trait loci (eQTLs) and annotation of coding single nucleotide polymorphisms (SNPs) to link one of these signals to a causal gene, and identified ULBP6, a stress-induced ligand for the activating immunoreceptor NKG2D found on NK and T cells. ULBP6 is known to be shed from the cell surface of tumor cells to block its interaction with NKG2D to evade immune surveillance. Expression profiling of ULBP ligands in various tumor types using MSD, IHC, bulk and single-cell RNA-seq revealed tumor-intrinsic up-regulation of ULBP6 in squamous cancer subtypes. Collectively, these data suggest that ULBP6 is a promising therapeutic target, and that can potentially enhance anti-tumor immunity.
Citation Format: Susanne Tilk, Pierre Fontanillas, Wei-Jen Chung, Clifford Hom, Shi Shi, Anh Diep, Kim Gerrick, Mauro Poggio, Pranidhi Sood. Discovery of ULBP6 as a novel immuno-oncology target using pleiotropic signals from 23andMe’s genetic and health survey database [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 3903.