bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA20: Lymph protects metastasizing melanoma cells from ferroptosis
Authors: Morrison Sean J. 
Published: December 2020

Abstract
Cancer cells, including melanoma, often metastasize regionally through lymphatics before metastasizing systemically through the blood; however, the reason for this is unclear. We discovered that melanoma cells in lymph experience less oxidative stress and form more metastases than melanoma cells in blood. Immunocompromised mice with patient-derived melanomas and immunocompetent mice with mouse melanomas had more melanoma cells per microliter of tumor-draining lymph than tumor-draining blood. Cells metastasizing through blood, but not lymph, became dependent on the ferroptosis inhibitor GPX4. Cells pre-treated with chemical ferroptosis inhibitors formed more metastases than untreated cells after intravenous, but not intralymphatic, injection. We observed multiple differences between lymph fluid and blood plasma that may contribute to decreased oxidative stress and ferroptosis in lymph, including higher levels of glutathione and oleic acid, and less free iron, in lymph. Oleic acid protected melanoma cells from ferroptosis in an Acsl3-dependent manner and increased their capacity to form metastatic tumors. Melanoma cells from lymph nodes were more resistant to ferroptosis and formed more metastases after intravenous injection than melanoma cells from subcutaneous tumors. Exposure to the lymphatic environment thus protects melanoma cells from ferroptosis and increases their ability to survive during subsequent metastasis through the blood.
Citation Format: Sean J. Morrison. Lymph protects metastasizing melanoma cells from ferroptosis [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr IA20.
Abstract PO-001: xCT expression alters the epigenome and induces genomic instability
Authors: Hill Dalton , Rahman Jamshedur , Kluwe Christien , Massion Pierre P. 
Published: December 2020

Abstract
Metabolic reprogramming, remodeling of the epigenetic landscape, and genomic instability are three processes that drive tumorigenesis. While each has been investigated individually, there is a growing interest in the interplay between each process during early cancer development. High expression of the cystine/glutamate antiporter SLC7A11 (xCT) is frequently seen in lung cancer. Our lab previously demonstrated overexpression of xCT in normal bronchial airway epithelial cells is sufficient to induce metabolic reprogramming. In this study, we investigated the effects of xCT overexpression in normal bronchial airway epithelial cells. We hypothesize that xCT overexpression both induces genomic instability and alters the epigenome in normal bronchial airway epithelial cells through the perturbation of intracellular metabolite levels. Through utilizing an alkaline comet assay, we discovered that xCT overexpression induces DNA damage, increasing the percentage of DNA in the comet tail by 15.1% (P=0.002). Furthermore, we found that xCT overexpression induces alterations to the histone modification landscape, most notably increasing H3K9me3 and H3K9ac by 3.2 and 3.9-fold (P=0.08) respectively. Finally, xCT overexpression shows higher tumorigenic potential through increased colony formation in a soft agar assay. Taken together, xCT overexpression in normal bronchial airway epithelial cells increases tumorigenic potential, induces metabolic reprogramming, causes higher levels of DNA damage, and alters the epigenetic landscape. Future experiments elucidating the links between these processes, including ChIP-seq and whole-genome bisulfite sequencing are currently underway. Establishing causal links between metabolic reprogramming, epigenetic alterations, and genomic instability are imperative in elucidating an effective, potentially multifaceted approach to treating early-stage lung cancer.
Citation Format: Dalton Hill, Jamshedur Rahman, Christien Kluwe, Pierre P. Massion. xCT expression alters the epigenome and induces genomic instability [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-001.
Abstract PO-005: Tet2 inactivation enhances the anti-tumor efficiency of tumor-infiltrating lymphocytes (TILs)
Authors: Lee Minjung , Li Jiangfang , Fang Shaohai , Han Wei , Moczygemba Margarita , Zhou Yubin , Li Jia , Sun Deqiang , Huang Yun 
Published: December 2020

Abstract
Inactivation of tumor infiltrating lymphocytes (TILs) is one of the mechanisms mitigating anti-tumor immunity during tumor onset and progression. Epigenetic abnormalities are regarded as a major culprit contributing to the dysfunction of TILs within tumor microenvironments. In this study, we used a murine model of melanoma to discover that Tet2 inactivation significantly enhances the anti-tumor activity of TILs, with the efficacy comparable to immune checkpoint inhibition imposed by anti-PD-L1 treatment. Single-cell RNA-seq analysis further revealed that Tet2-deficient TILs exhibit effector-like features. Transcriptomic and ATAC-seq analysis further demonstrated that Tet2 deletion reshapes the chromatin accessibility and favors the binding of transcription factors geared toward CD8+ T cell activation. In summary, our study establishes that Tet2 constitutes one of the epigenetic barriers contributing to dysfunction of TILs, and that Tet2 inactivation could benefit anti-tumor immunity to boost tumor suppression.
Citation Format: Minjung Lee, Jiangfang Li, Shaohai Fang, Wei Han, Margarita Moczygemba, Yubin Zhou, Jia Li, Deqiang Sun, Yun Huang. Tet2 inactivation enhances the anti-tumor efficiency of tumor-infiltrating lymphocytes (TILs) [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-005.
Abstract PO-040: The role of mTOR in epigenetic regulation in cancer
Authors: Kim HaEun , Papadopoli David , Topisirovic Ivan 
Published: December 2020

Abstract
Changes in gene expression, including those caused by epigenetic dysregulation, represent a hallmark of cancer. The mechanistic/mammalian Target of Rapamycin (mTOR) is a serine/threonine kinase that coordinates nutrient availability to the regulation of cell growth and metabolism, which is frequently perturbed in cancer. mTOR exists in two structurally and functionally divergent complexes, mTOR complex 1 and 2 (mTORC1 and 2). mTORC1 regulates many metabolic pathways, including the serine-glycine-one carbon network (SGOC), a pathway modulating the production of S-adenosyl methionine (SAM) and α-ketoglutarate (α-KG). The latter two metabolites constitute essential co-substrates of histone methyltransferases and demethylases, respectively. However, how mTOR signaling controls epigenetic dynamics remains largely unknown. To address this important gap in knowledge, we treated two breast cancer cell lines (MCF7 and T47D) with allosteric (rapamycin) and active-site (INK128) mTOR inhibitors to study how mTOR may influence global histone methylation. We found that mTOR inhibitors significantly increased histone 3 lysine 9 tri-methylation (H3K9me3) and histone 3 lysine 27 tri-methylation (H3K27me3) but not histone 3 lysine 4 tri-methylation (H3K4me3) suggesting this effect was selective. Metabolomic tools were employed to decipher changes of epigenetic metabolites α-KG, SAM, S-Adenosyl homocysteine (SAH), methionine, and serine upon mTOR inhibition. These findings provide bases for my future work which will focus on establishing the role of alterations in mTOR signaling on epigenetic programs which drive tumorigenesis. A better understanding of this network may help identify new therapeutic targets to improve current cancer treatments.
Citation Format: HaEun Kim, David Papadopoli, Ivan Topisirovic. The role of mTOR in epigenetic regulation in cancer [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-040.
Abstract PO-053: Investigating intra-tumour metabolic heterogeneity in triple-negative breast cancer
Authors: Fukano Marina , Deblois Geneviève , Zuo Dongmei , Martinez Constanza , Yang Yang , Ragoussis Ioannis , Kleinman Claudia , Park Morag 
Published: December 2020

Abstract
Intra-tumour heterogeneity is a great challenge in cancer treatment. Cancer cells presenting different metabolic profiles can mutually support each other through metabolic symbiosis mechanism, which contributes to tumour proliferation, metastasis, and therapeutic resistance. Triple-negative breast cancer (TNBC) shows poor clinical outcomes due to a high level of heterogeneity and a lack of targeted therapies. Through multiplex immunofluorescence tissue section staining of TNBC patient-derived xenografts (PDX), we identified two mutually exclusive and metabolically distinct cell populations within a TNBC tumour. One cancer cell population expresses glucose transporter 1 (GLUT1) and is located in hypoxic areas, whereas another specifically expresses glutamine synthetase (GS) and is located near vasculatures. Single-cell RNA sequencing data from a TNBC PDX with mutually exclusive GLUT1- and GS-positive cells shows that GLUT1-positive cells are enriched for hypoxic and glycolytic gene signatures, while GS-positive cells are associated with glutathione, pyrimidine and purine metabolism. Importantly, our data suggest that GLUT1- and GS-positive cells exchange glutamate and lactate metabolites as part of metabolic symbiosis and targeting this mechanism could successfully impair the growth of TNBC.
Citation Format: Marina Fukano, Geneviève Deblois, Dongmei Zuo, Constanza Martinez, Yang Yang, Ioannis Ragoussis, Claudia Kleinman, Morag Park. Investigating intra-tumour metabolic heterogeneity in triple-negative breast cancer [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-053.
Abstract PO-057: Breast cancer cell metabolism: Effect of beta-hydroxybutyrate on glucose deprived breast cancer cells
Authors: Maldonado Rylee , Talana Chloe Adrienna , Uehara Kahealani , Weichhaus Michael 
Published: December 2020

Abstract
Ketogenic diets have the potential to lower glucose availability to cancer cells. The effect that the resulting increase in ketone bodies has on cancer cells is not fully understood. Here we explored the effect of beta-hydroxybutyrate (BHB) on glucose deprived MCF-7 and T47D breast cancer cells. Cell proliferation was decreased with lower glucose conditions which could not be rescued by either 10 mM or 25 mM BHB supplementation. Gene expression changes were altered when cells were glucose deprived. Smaller changes were observed when gene expression changes were compared between glucose deprived cells and those treated with BHB. Pathway enrichment analysis demonstrated that glucose deprivation decreased activity of the Hippo-Yap cell signaling pathway in MCF-7 breast cancer cells, while it increased expression of genes of the NRF2-pathawy and genes regulating ferroptosis in T47D breast cancer cells. No significant pathway enrichment was found when glucose deprived cells were treated with BHB. Both cell lines expressed the enzymes (OXCT1/2, BDH1, ACAT1/2) responsible for metabolizing BHB to acetyl-CoA, yet expression of these enzymes does not change with either glucose deprivation or BHB treatment. In the publicly available Cancer Genome Atlas increased expression compared to healthy tissue of enzymes responsible for metabolizing BHB to acetyl-CoA was also observed, however only a small subset of patients showed alterations in these enzymes. This alteration was linked to a significant decrease in overall survival. In conclusion, neither MCF-7 nor T47D breast cancer cells were affected by BHB during glucose deprivation, however screening of the patient’s tumor for activation of ketone bodies metabolizing enzymes may be indicated to identify who will benefit from ketogenic diet interventions.
Citation Format: Rylee Maldonado, Chloe Adrienna Talana, Kahealani Uehara, Michael Weichhaus. Breast cancer cell metabolism: Effect of beta-hydroxybutyrate on glucose deprived breast cancer cells [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-057.
Abstract PR10: Alterations in carbon and nitrogen metabolism in lung cancer
Authors: Kim Jiyeon 
Published: December 2020

Abstract
Lung cancer is the leading cause of cancer death worldwide. The critical barrier in lung cancer treatment is a lack of effective therapies at later stages of the disease. Lung cancer genome sequencing supports the idea that combinations of mutations act in concert to foster malignancy and disease progression. Among these, KRAS and LKB1 mutations represent “driver” changes in tumor development. Importantly, mutations in these genes also perturb signal transduction to promote a form of metabolism conducive to tumor growth. Metabolic reprogramming is considered to be fundamental to malignant transformation; thus, identifying molecular links between these mutations and metabolism, and targeting the resulting metabolic pathways, may produce better therapies. To gain broader insight into metabolic reprogramming and potential dependencies in different KRAS/LKB1 co-mutant (KL) model systems, we analyzed metabolome and gene expression profiling of tumors derived from genetically engineered mouse models of lung cancer. These two datasets independently revealed that both mouse and human KL co-mutants are associated with elevated hexosamine biosynthesis pathway (HBP) expression, a metabolic pathway that requires the interplay between nitrogen and carbon metabolism. Upregulation of the HBP in co-mutants resulted in enhanced global N-acetyl glucosamine modification (O-GlcNAcylation) and glycosylation, modification involved in important processes occurring in cancer, such as cell signaling and communication, cell-matrix interactions, immune modulation and metastasis formation. KL cells have elevated HBP metabolites and higher hexosamine biosynthesis rates. By small scale RNAi screening and chemical inhibition of the HBP, we uncovered that KL co-mutants are dependent on Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2), a rate-limiting enzyme in the pathway. GFPT2 inhibition selectively reduced KL cell growth in culture and xenografts. Importantly, high GFPT2 expression predicts poor prognosis in human NSCLC patients, considerably more so than low LKB1 expression alone. Our study illuminates the functional significance of the interplay between carbon and nitrogen metabolism in cancer, not only for primary cancer growth but also for tumor aggressiveness and may lead to new avenues for developing novel targeted therapeutics.
Citation Format: Jiyeon Kim. Alterations in carbon and nitrogen metabolism in lung cancer [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PR10.
Abstract A12: Expression of GPR41, GPR43, and GPR109A in breast tissue in relation to breast cancer development
Authors: Kump Annie , Herrera Daniel , Stiemsma Leah T. 
Published: December 2020

Abstract
Introduction: There is evidence to suggest that the human microbiome may play a key role in the development of breast cancer. There is a unique microbial signature in mammary tissue that is associated with breast cancer. Further, there is mounting evidence to support the role of the gut microbiome in promoting or preventing breast cancer. Consequently, specific compositional and/or functional shifts in either of these microbiomes may promote the growth of breast tumors. Short chain fatty acids (SCFAs) are microbial metabolites produced in the large intestine by bacterial fermentation of complex carbohydrates. These metabolites exit the gut and interact with many different cell types throughout the human body, including those in the breast, via g-protein coupled receptors; GPR41, GPR43, and GPR109A. These metabolites have been identified as a potential functional connection between the gut microbiome and breast cancer but have not been studied in breast tissue in the context of breast cancer. To assess the interaction between the microbiome and breast tumor development, we analyzed the expression of these receptors in tissue collected from women who donated healthy, prediagnostic, or cancerous tissue to the Susan G. Komen and Indiana University Simon Cancer Center Tissue Banks.
Methods: DNA and RNA (n=60, n = 15 for each tissue subset: healthy, prediagnostic, adjacent normal, and tumor tissue) was copurified from these tissues using the Qiagen AllPrep® PowerFecal® DNA/RNA Kit. The RNA was then reverse transcribed into complementary DNA. Quantitative PCR was performed on the cDNA using four validated primer sets: GPR41, GPR43, GPR109A, and ribosomal 18S (housekeeping gene).
Results/Cconclusions: We did not identify any significant differences in expression levels of these receptors between the participant groups, suggesting that cancer status is not associated with increased metabolic activity of the microbiome. We are currently conducting sensitivity analyses to determine the role of clinical factors such as age, menopausal status, BMI, etc., on the expression of these receptors in breast tissue. We are also investigating the expression of enzymes and transporters in breast tissue related to host cell metabolism of the most bioactive SCFAs (acetate, propionate, and butyrate). This work will yield valuable information regarding the interaction between the human microbiome and breast tumor development. Ultimately, it may be possible to target SCFA-producing bacteria or SCFA catabolic pathways in breast tissue to prevent or treat breast cancer.
Citation Format: Annie Kump, Daniel Herrera, Leah T. Stiemsma. Expression of GPR41, GPR43, and GPR109A in breast tissue in relation to breast cancer development [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr A12.
Abstract A17: Human papillomavirus type 16 and 18 viral loads as predictors associated with abnormal cervical cytology among women in Saudi Arabia
Authors: Obeid Dalia , Almatrrouk Shihana , Khayat Hadeel , Al-Muammer Turfah , Tullbah Asma , Albadawi Ismail , Alahdal Mohammed , Alhamlan Fatimah 
Published: December 2020

Abstract
The present study aimed to screen for and genotype HPV among Saudi women; develop sensitive quantitative polymerase chain reaction (qPCR) assays to detect the viral load for the two most common HPV types, namely 16 and 18; and assess whether HPV viral load could be used as a marker for cervical abnormality and disease progression. This study examined 733 specimens (both formalin-fixed, paraffin-embedded specimens and PAP smear samples) from women who underwent cervical screening. The specimens and samples were processed for DNA extraction and then tested for HPV DNA. Approximately 165 specimens (18%) were positive for HPV. Those specimens were genotyped using a reverse line blotting hybridization assay. The results indicated that the most common HPV types detected were a single infection with HPV 16 (51%) or with HPV 18 (28%) followed by infections with multiple HPV types (~7%). A qPCR TaqMan assay developed in-house was used to determine the viral load for HPV genotypes 16 (n=80) and 18 (n=45). Viral loads for both HPV types were significantly associated with cervical cytology grade (P &lt; 0.05). The odds ratio (OR) for the HPV 16 viral load was high for specimens with cervical cancer (OR, 18.8; 95% CI, 4.3–82.9) or for those with high-grade squamous intraepithelial lesions (OR, 14.7; 95% Cl, 2.43–88.49). For the HPV 18 viral load, the OR was significant only for specimens with cervical cancer (OR, 11.1; 95% Cl, 2.2–54.9). Logistic regression models for HPV 16 and for HPV 18 viral load levels were significant, with higher viral load associated with cervical abnormalities. These findings indicate that viral load is a predictor significantly associated with cytology abnormality in women who are positive for high-risk HPVs and suggest integrating a viral load test into current clinical screening practices for HPV-positive women.
Citation Format: Dalia Obeid, Shihana Almatrrouk, Hadeel Khayat, Turfah Al-Muammer, Asma Tullbah, Ismail Albadawi, Mohammed Alahdal, Fatimah Alhamlan. Human papillomavirus type 16 and 18 viral loads as predictors associated with abnormal cervical cytology among women in Saudi Arabia [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr A17.
Abstract A22: A mechanism of γδ T cell-mediated antitumor immunity against brain cancer
Authors: Park Jang Hyun , Lee Heung Kyu 
Published: December 2020

Abstract
Glioblastoma multiforme (GBM) is one of the less survivable and most malignant brain tumors. The average survival period is less than 2 years despite multiple therapies including chemotherapy and radiation. Furthermore, GBM showed severe resistance against immunotherapies such as immune checkpoint blockade mainly targeting CD8 T cells (1). Recently, several studies showed that γδ T cells can be an alternative target of immunotherapy. Unlike conventional T cells, γδ T cells recognize stress-induced surface antigens such as NKG2D-ligands and phosphor-antigens (2). Because GBM cells highly express NKG2D-ligands, γδ T cells could be proper targets for immunotherapy. However, a basic understanding of γδ T cell-mediated antitumor immunity remains unclear. Using single-cell transcriptomic analysis, we analyzed the characteristics of GBM-infiltrating γδ T cells. γδ T cells are highly suppressed by oxygen tension of tumor microenvironment in the brain tumor. We inhibited respiration of tumor cells by metformin, which is the drug for type 2 diabetes. Inhibition of tumor cell respiration sufficiently reinvigorated γδ T cells. Reinvigorated γδ T cells highly expressed NKG2D and multiple cytokines. In conclusion, this study highlights the importance of γδ T cells and the druggable pathways through reinvigoration of γδ T cells.
Citation Format: Jang Hyun Park, Heung Kyu Lee. A mechanism of γδ T cell-mediated antitumor immunity against brain cancer [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr A22.