bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2793: The role of IL-10 in obesity-induced T-cell polarization in the prostate tumor microenvironment
Authors: Kappel Margaret , Adkison Michael , De Angulo Alejandra , Travis Peyton , Harlow Brittany , Jolly Christopher , deGraffenried Linda 
Published: July 2021

Abstract
Background: Prostate cancer remains the second leading cause of cancer related deaths in men and obesity has been shown to severely impact its prognosis. Previous studies in our laboratory have shown that CD4+ T cells polarized under obese conditions are prostate cancer promoting and that this is due in part to suppression of IFNγ and induction of IL-6 in the T cells.
Objective: The goal of this study is to determine the role of IL-10 in mediating the impact of obese conditions on T cell phenotype.
Methods: A series of in vitro studies were conducted to evaluate the effects of obesity on T cell function and polarization. Splenic CD4+ T-cells from 10-week-old, male, C57BI/6 mice were isolated and stimulated with anti-CD3+/CD28+ antibodies under obese conditions. Gene expression was measured using qPCR and AKT phosphorylation was measured using Western blot analysis. In vivo T-cell function was compared between obese and non-obese male mice. Deletion assays were used to determine the role of IL-10 in mediating the effects observed on T cell phenotype in response to obese conditions.
Results: For both the in vitro and in vivo studies, obese conditions suppressed the expression of Th1 biomarkers (IFNγ, IL-2, and T-bet) and upregulated the expression of Th2 biomarkers (IL-6, IL-10, and GATA-3) in CD4+ T cells. Likewise, obese conditions in vitro and in vivo were associated with decreased AKT phosphorylation. Studies are on-going to determine whether inhibiting the IL-10 pathway restores proper T cell activation under obese conditions.
Conclusion: Obesity induces T cell dysfunction characterized by a Th1 to Th2 phenotypic shift, resulting in a pro-tumorigenic phenotype, potentially mediated by paracrine IL-10 signaling. These results are important in understanding the mechanisms by which obesity promotes a more aggressive disease, thereby identifying potential targets for improving outcomes. The results from these studies will provide a better understanding of the role of IL-10 as a novel target for preventing prostate cancer in obese subjects and improving overall survival.
Citation Format: Margaret Kappel, Michael Adkison, Alejandra De Angulo, Peyton Travis, Brittany Harlow, Christopher Jolly, Linda deGraffenried. The role of IL-10 in obesity-induced T-cell polarization in the prostate tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2793.
Abstract 2818: In vivo imaging of mitochondrial bioenergetics in lung cancer
Authors: Han Mingqi , Momcilovic Milica , Bushong Eric , Stiles Linsey , Shirihai Orian , Koehler Carla , Sadeghi Saman , Ellisman Mark , Shackelford David B. 
Published: July 2021

Abstract
Non-small cell lung cancer (NSCLC) is a histologically, genetically and metabolically heterogeneous disease. The mitochondria are essential regulators of cellular energy and metabolism and they play a critical role in sustaining growth and survival of lung tumor cells. However, our understanding of mitochondrial metabolism in cancer at an in vivo level has been limited thus leaving a large gap in our knowledge of how mitochondrial bioenergetics support tumor growth. To better study mitochondrial bioenergetics in lung tumors, we recently developed and validated a voltage sensitive, positron emission tomography (PET) tracer known as 4-[18F]fluorobenzyl triphenylphosphonium (18FBnTP) that we used to profile mitochondrial bioenergetics in autochthonous K-Ras driven mouse models of lung cancer (Momcilovic et al., (2019) Nature). The use of 18FBnTP PET imaging enabled us to functionally profile mitochondrial bioenergetics in live tumors and discover distinct functional mitochondrial heterogeneity conserved across different NSCLC tumor subtypes. In order to study mitochondria at the level of ultrastructure we coupled 18FBnTP PET with 3D serial block-face scanning electron microscopy (3D SBEM). By coupling these two techniques we are able to image and quantify mitochondria heterogeneity from whole tumors down to the ultrastructures of individual mitochondria within tumor cells. Our study reveals distinct organization of mitochondrial structure and function as lung tumors adapt during tumorigenesis. We anticipate that coupling 18FBnTP PET imaging with 3D SBEM will have dynamic applications beyond that of lung cancer and enrich our understanding how mitochondria impact human disease.
Citation Format: Mingqi Han, Milica Momcilovic, Eric Bushong, Linsey Stiles, Orian Shirihai, Carla Koehler, Saman Sadeghi, Mark Ellisman, David B. Shackelford. In vivo imaging of mitochondrial bioenergetics in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2818.
Abstract 2827: Inactivating calcium-sensing receptor polymorphisms at rs1801725 are associated with increased risk of secondary malignancies
Authors: Beasley Heather K. , Actkins Ky'Era V. , Faucon Annika B. , Davis Lea K. , Sakwe Amos M. 
Published: July 2021

Abstract
The dysregulation of systemic calcium homeostasis during malignancy is common in most patients with high-grade tumors. The associated comorbidity is known as cancer-induced hypercalcemia (CIH) which affects up to 30% of cases, in the absence of metastasis. In the course of breast cancer progression, the secretion of parathyroid hormone-related protein (PTHrP) by tumor cells and the associated destruction of bone tissues, leads to a progressive increase in systemic calcium or CIH. The increase in circulating Ca2+ is sensed by the calcium-sensing receptor (CaSR), which plays a significant role in maintaining Ca2+ homeostasis. More than 200 mutations and single nucleotide polymorphisms (SNPs) in the CaSR gene have been described, including the A986S CaSR at rs1801725 and Q1011E CaSR at rs1801726 SNPs with reduced sensitivity to Ca2+. Interestingly, high circulating Ca2+ is associated with aggressive breast tumors in premenopausal women and larger tumors in postmenopausal women; however, the contribution of the CaSR in breast cancer progression remains poorly understood. Unlike SNPs at rs1801726, up to 20% of breast cancer patients with SNPs at rs1801725 may be predisposed to higher circulating Ca2+ in the course of their disease. Since breast cancer frequently metastasizes to Ca2+ rich skeletal tissues, we hypothesize that the development of CIH and subsequent desensitization of the CaSR by sustained high Ca2+ is critical for both the adaptation of TNBC cells to CIH in Ca2+ rich microenvironments and TNBC progression. Our preliminary data reveal that the expression level and mutational status of the CaSR is cell type-specific, and that sustained high Ca2+ desensitizes the receptor, but promotes tumor cell growth and motility. In addition, our preliminary data show that the A986S SNP is associated with hypercalcemia, secondary malignancy of bone and respiratory organs, and deficiency of humoral immunity. This study provides novel insights into not only the adaptation of TNBC cells to high circulating Ca2+, but also suggests that mutations of the CaSR at rs1801725 are predictive of the likelihood for metastasis to lungs and bone.
Citation Format: Heather K. Beasley, Ky'Era V. Actkins, Annika B. Faucon, Lea K. Davis, Amos M. Sakwe. Inactivating calcium-sensing receptor polymorphisms at rs1801725 are associated with increased risk of secondary malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2827.
Abstract 283: Target cell-derived, G401-CLENs for selective delivery of model therapeutics to rhabdoid tumors
Authors: Bourdeau Lindsay , Cruz Carlos , Williams Taylor 
Published: July 2021

Abstract
One of the rarest and most aggressive pediatric cancers to date is the malignant rhabdoid tumor (MRT), maintaining a survival rate of 16%. Considered a renal cancer, approximately 20-25 new cases are diagnosed in the USA each year, with the average age of diagnosis being about 11 months old. Conventional strategies for treating MRT are limited due to several factors including off-target associated toxicities, patient population, age, metastasis to brain tissue, and diminished survival rates. CLENs (cell membrane lipid-extracted nanoliposomes), a novel drug delivery system, was previously developed and evaluated for selective delivery of cytotoxic drug agents to breast cancer cells and compared to more conventional liposomes. The purpose of this investigation was to optimize and characterize G401-CLENs for selective targeting and delivery of model payloads to a cellular model of rhabdoid tumors. The MRT cell line (G-401 [G401] (ATCC® CRL-1441™) was cultured in McCoy's 5A Medium (ATCC® 30-2007™), supplemented by 10% FBS. The G401 cellular lipid materials (otherwise known as lipid extracts (LE)) were derived from G401 cells. Follow up studies include the incorporation of G401-LE in liposomes to form G401-CLENs. For development, special consideration was given to distinct determinants of targeting (i.e., particle size and zeta potential) and cellular uptake by G401-CLENs. Other analyses include a comparison of delivery of model and functional siRNA (BRD9 Silencer Select Pre-designed, siRNA ID s35295, Ambion) to G401 target cells using G401-CLENs, and conventional nano-preparations in vitro. G401-LE cell membrane components were extracted from rhabdoid G401 cells. On-going physiochemical characterization studies of G401-CLENs and functional in vitro and fluorescence microscopic analyses are currently underway.
Citation Format: Lindsay Bourdeau, Carlos Cruz, Taylor Williams. Target cell-derived, G401-CLENs for selective delivery of model therapeutics to rhabdoid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 283.
Abstract 2831: Exosome gene signatures characterize metastatic dynamicity
Authors: Gonda Amber , Shah Jay V. , Siebert Jake N. , Zhao Nanxia , Kwon Mi Jung , Moghe Prabhas V. , Francis Nicola , Ganapathy Vidya 
Published: July 2021

Abstract
Early diagnosis and effective tumor monitoring can significantly alter clinical outcomes of ovarian cancer patients. Innovative tools are needed to enhance the sensitivity and specificity of current monitoring modalities. Extracellular vesicles, or exosomes, have shown to be promising conduits of diagnostic biomarkers to aid in tumor detection as evidenced by Exosome Diagnostics' new ExoDx Prostate (IntelliScore) test that uses exosomal markers to differentiate between benign prostate disease and early cancer (Tutrone, R., Donovan, M.J., Torkler, P. et al. Clinical utility of the exosome based ExoDx Prostate(IntelliScore) EPI test in men presenting for initial Biopsy with a PSA 2-10 ng/mL. Prostate Cancer Prostatic Dis 23, 607-614 (2020)). The potential of these vesicles however goes beyond simple diagnostic power of cancer detection. Due to the onco-specific contents packaged and the minimally invasive, low risk accessibility, exosomes have the capacity to be used as longitudinal monitoring tools to characterize early molecular changes at all stages of the disease. We hypothesized that the dynamicity of ovarian tumors during progression and metastatic development is reflected in exosomes. In order to test this we isolated exosomes and used qPCR to analyze exosomal gene signatures from a mouse model of ovarian cancer. SKOV3 ovarian cancer tumor cells were injected into mice and allowed to grow for 3 weeks. Plasma was collected from mice at 5-7 day increments and exosomes were extracted. Multiple established metastatic genes in ovarian cancer were evaluated and 4 genes, Lox, THBS1, TIMP3, and β-actin, were found to be differentially expressed in correlation with 3 translationally pertinent assessments: presence or absence of tumors, levels of metastatic burden, and longitudinal tumor progression. Gene expression patterns were compared with exosomal gene signatures extracted from human ovarian patient plasma and found to express similar patterns. These results support the diagnostic potential of using exosomal genetic signatures to detect early metastatic development and to facilitate longitudinal tracking of tumor progression.
Citation Format: Amber Gonda, Jay V. Shah, Jake N. Siebert, Nanxia Zhao, Mi Jung Kwon, Prabhas V. Moghe, Nicola Francis, Vidya Ganapathy. Exosome gene signatures characterize metastatic dynamicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2831.
Abstract 2836: Effect of autophagy inhibition on epithelial mesenchymal transition in breast cancer cell lines
Authors: Rojas Guadalupe , Pazos Nidia , Maycotte Paola 
Published: July 2021

Abstract
The aim of our work is to evaluate potential undesirable effects of autophagy inhibition in breast cancer subtypes which are not sensitive to the inhibition of autophagy. Worldwide, BC is the most frequent cancer in women. Despite recent advances in diagnosis, molecular stratification and targeted therapy, BC is still the leading cause of cancer-related death in women. Thus, it is a public health issue that must be attended. In cancer, autophagy has a pro-tumorigenic role that helps tumor cells survive metabolic stress and growth factor deprivation, hypoxia, maintain tumor initiating cells, confer therapy resistance and modulate epithelial mesenchymal transition (EMT). Because tumor cells benefit from autophagy, it has been proposed that autophagy inhibition could be beneficial for cancer treatment. Nowadays, there are clinical trials where autophagy is being inhibited with promising results that encourage this approach. However, in these clinical trials, cancer types are not been stratified and autophagy is being inhibited in many solid tumor types. In this regard, there is also in vitro evidence in which autophagy inhibition in some cancer types induces EMT, which in the clinic could be detrimental for patients. This highlights the urgency for stratifying patients that will benefit the most from autophagy inhibition. In this work, autophagy inhibition in MCF7 ER+ cell line increased secretion, inflammation and EMT related pathways suggesting induction of malignancy. Autophagy inhibition induced changes in cell morphology in ER+ breast cancer cell lines (MCF7 and T47D) when evaluated by aspect ratio estimation changing from a cobblestone -like epithelial morphology to a fibroblast-like morphology. No changes in cell morphology were found in MCF10A and MDAMB231 cell lines. Changes in morphology were accompanied by a decrease in E-cadherin protein levels suggesting induction of EMT. Our results suggest that CQ treatment in ER+ BC cells could induce a malignant process related to EMT. Thus, ER+ BC patients may not benefit from autophagy inhibition. Nowadays, there are clinical trials where autophagy is being inhibited and no subtype stratification is being done, so we encourage to stratify patients to determine who will be benefited the most from autophagy inhibition and who will not.
Citation Format: Guadalupe Rojas, Nidia Pazos, Paola Maycotte. Effect of autophagy inhibition on epithelial mesenchymal transition in breast cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2836.
Abstract 2837: NR2F1 is a barrier to early dissemination of pre-malignant mammary cells
Authors: Sosa Maria Soledad , Rodriguez-Tirado Carolina , Kale Nupura , Carlini Maria , Shrivastava Nitisha , Khalil Bassem , Bravo-Cordero Javier , Alexander Melissa , Ji Jiayi 
Published: July 2021

Abstract
Cancer cells disseminate during very early and sometimes asymptomatic stages of tumor progression. Granted that biological barriers to tumorigenesis exist, there must also be limiting steps to early dissemination, all of which remain largely unknown. We report that the orphan nuclear receptor NR2F1/COUP-TF1 serves as a barrier to early dissemination. High-resolution intravital imaging revealed that loss of function of NR2F1 in HER2+ early cancer cells increased in vivo dissemination without accelerating mammary tumor formation. NR2F1 expression was positively regulated by the tumor suppressive MMK3/6-p38-MAPK pathway and downregulated by HER2 and Wnt4 oncogenic signaling. NR2F1 downregulation by HER2 in early cancer cells led to decreased E-cadherin expression and β-catenin membrane localization, disorganized laminin 5 deposition, and increased expression of CK14, TWIST1, ZEB1 and PRRX1. Our findings reveal the existence of an inhibitory mechanism of dissemination regulated by NR2F1 downstream of HER2 signaling.
Citation Format: Maria Soledad Sosa, Carolina Rodriguez-Tirado, Nupura Kale, Maria Carlini, Nitisha Shrivastava, Bassem Khalil, Javier Bravo-Cordero, Melissa Alexander, Jiayi Ji. NR2F1 is a barrier to early dissemination of pre-malignant mammary cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2837.
Abstract 2849: Shc1 as a potential metastasis driver gene of breast cancer
Authors: Majocha Megan , Hunter Kent , Ross Christina 
Published: July 2021

Abstract
In the US, women diagnosed with non-metastatic breast cancer have a 5-year survival rate of approximately 98.8%. However, if women develop metastases the survival rate drops to 27.4%, highlighting the need for a better understanding of the mechanisms that regulate and drive metastasis. Somatically acquired mutations that drive metastasis were originally hypothesized by Nowell in the 1970s; however, to date few candidate metastasis driver mutations have been identified and the role of these mutations in metastasis are not well-understood. Using the PyMT genetically engineered mouse model of luminal metastatic breast cancer, previous work by our group performed whole exome sequencing on pairs of matched primary tumor and metastatic tissues from 65 mice. Analysis of this sequencing data identified recurrent metastasis-specific mutations in members of the Ras signaling pathway. One of the members was the SHC Adaptor Protein 1 (Shc1). Five PyMT animals carried different nucleotide substitutions within the same proline 561 codon that falls within the SH2 domain, suggesting an activating role in metastasis. Furthermore, changing this proline mutation to another amino acid could induce a critical change to the Shc1 protein structure and its function. To investigate the role of Shc1 in breast cancer metastasis, CRISPR was performed engineer Shc1 P561 mutations for in vitro and in vivo assays using a series of mouse mammary cancer cell lines and allograft mouse models. Preliminary evidence suggests the P561 mutations have a role in metastasis. Future experiments will address the consequences of the P561 mutation on Shc1 binding partner interactions and downstream signaling and its effects on breast cancer metastasis.
Citation Format: Megan Majocha, Kent Hunter, Christina Ross. Shc1 as a potential metastasis driver gene of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2849.
Abstract 2856: GLI3-mediated HH regulates prostate cancer progression
Authors: Duong Thu Minh , Burleson Marieke Oldenbroek , Deng J J. , Qin T , D Das , Sun L-z , Boyer T G. 
Published: July 2021

Abstract
Although prostate cancer patients initially respond to androgen deprivation therapy, they eventually progress to lethal castration resistant prostate cancer (CRPC), characterized by restoration of the androgen receptor (AR) signaling despite castrate levels of circulating androgens. Mechanisms proposed to underlie CRPC include AR crosstalk with alternative signaling pathways. Among these, the Sonic hedgehog (SHH)Hedgehog (HH) pathway, an essential signaling axis in prostate development and homeostasis, has been implicated in prostate cancerCRPC progression. SHH pathway is regulated by transcription factors and effectors Glioma-associated oncogene family zinc finger (GLI) proteins 1, 2, and 3. Previous studies reported that GLI1 and GLI2 drive androgen-independent growth of prostate cancer by upregulating androgen-stimulated genes. However, whether and how GLI3 plays a role in prostate cancer progression remains unclear. In the present study, we investigated the role of GLI3 in the progression of prostate cancer cells. Like GLI2, GLI3 is the a downstream transcriptional factor effector of the SHH signaling pathway that can exist as a full-length activator form or a cleaved repressor form. Our data showed an increase in GLI3 expression in prostate cancer cells growing under androgen deprived conditions. Thuserefore, we hypothesize that androgen deprivation leads to activation of the SHH signaling pathway which consequently activates GLI3 to promote androgen-independent growth of prostate cancer cells. We showed that knockdown of GLI3 repressed while overexpression of GLI3 promoted androgen-independent growth of prostate cancer cells. GLI3 knockdown also resulted in regression of castration-resistant outgrowth of xenograft tumors in mice. Additionally, transcriptomic analysis of GLI3 knockdown cells revealed that the SHH signaling pathway and epithelial mesenchymal transition (EMT) genes are altered suggesting that GLI3 regulates androgen-independent growth of prostate cancer cells through canonical SHH signaling pathway and likely contributes to prostate cancer metastasis. Lastly, our data demonstrated a physical and functional relationship between GLI3 and AR suggesting a functional crosstalk between SHH signaling and AR signaling pathways in advanced prostate cancer.
Citation Format: Thu Minh Duong, Marieke Oldenbroek Burleson, J J. Deng, T Qin, Das D, L-z Sun, T G. Boyer. GLI3-mediated HH regulates prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2856.