bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PO-020: Targeting metabolism to improve response to immune-checkpoint inhibition in melanoma
Authors: Tiersma Jiske F. , Evers Bernard , Bakker Barbara M. , de Jong Steven , Jalving Mathilde 
Published: December 2020

Abstract
Immune checkpoint inhibitors improve long term survival of advanced melanoma patients, however, 40-50% of patients do not benefit. Reprogrammed tumor metabolism may hinder immune cell function. We aimed to reverse metabolic reprogramming in melanoma cells by inhibiting pyruvate dehydrogenase (PDK), thereby reducing lactate secretion, while preserving or enhancing immune cell activity. In addition, we strived to elucidate metabolic vulnerabilities arising during PDK inhibitor treatment by co-treating cells with other metabolically targeted inhibitors. We treated a panel of melanoma cell lines with genetic backgrounds similar to those most frequently found in the clinic with PDK inhibitor dichloroacetate (DCA) to determine effects on viability, expression of metabolic proteins and oxygen consumption/lactate secretion. IC50 values for DCA were 14.9 ± 1.0 for A375, 13.3 ± 0.6 for MeWo, 20.0 ± 1.4 for SK-MEL-28 and 27.3 ± 1.7 mM for SK-MEL-2 cells. PDK inhibition decreased expression of the phosphorylated (inactive) form of PDH (pPDH) in melanoma cells. DCA treatment led to an up to threefold increase in the oxygen consumption rate:extracellular acidification rate (OCR:ECAR) ratio in melanoma cells. Growth inhibition of DCA synergized with other metabolic inhibitors CB-839 (glutaminase inhibitor) and metformin. The combination index (CI) was less than 0.5, indicating strong synergy, for DCA with CB-839 or DCA with metformin in several models. DCA at concentrations affecting OCR:ECAR ratio of melanoma cells (7 mM) had only minimal effects on proliferation of activated T cells and peripheral blood mononuclear cells (PBMCs). Interestingly, the interferon-γ level as a marker of cytotoxicity was increased by DCA in culture media of both T cells and PBMCs. We conclude that PDK inhibition through DCA reverses metabolic programming in melanoma cells. Also, DCA toxicity was enhanced by other metabolic inhibitors, showing that DCA treatment leads to dependency on other metabolic pathways. DCA treatment was non-toxic to immune cells and even enhanced cytotoxicity. Therefore, DCA may be a valuable tool in improving response to immunotherapy in melanoma patients.
Citation Format: Jiske F. Tiersma, Bernard Evers, Barbara M. Bakker, Steven de Jong, Mathilde Jalving. Targeting metabolism to improve response to immune-checkpoint inhibition in melanoma [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-020.
Abstract PO-021: Cell identity determines TCA cycle dynamics
Authors: Arnold Paige K. , Jackson Benjamin T. , Alibeckoff Sydney , Drill Esther , Sullivan Lucas B. , Finley Lydia W.S. 
Published: December 2020

Abstract
Cells utilize diverse metabolic strategies to support cell type-specific bioenergetic requirements. The enzymes that mediate cellular metabolic processes have been well studied. However, how cells coordinate these factors into metabolic networks remains poorly understood. Here we use measurements of gene dependency across hundreds of cancer cell lines to cluster metabolic genes into co-dependent modules. These analyses identified two distinct tricarboxylic acid (TCA) cycle modules with specific genetic dependencies. Isotope tracing combined with genetic manipulation of TCA cycle modules revealed that both normal stem cells and cancer cells can engage two different modes of TCA cycle metabolism. Enforcing self-renewal or differentiation induced preferential use of one TCA cycle module over another, indicating that TCA cycle dynamics are determined by cell state. In turn, the mode of TCA cycle metabolism employed by cells dictated nutrient dependencies, enabling cell-type specific responses to nutrient deprivation. Collectively, these studies reveal that TCA cycle behavior is dynamic and can be rerouted to confer a selective advantage to cells under different nutrient conditions.
Citation Format: Paige K. Arnold, Benjamin T. Jackson, Sydney Alibeckoff, Esther Drill, Lucas B. Sullivan, Lydia W.S. Finley. Cell identity determines TCA cycle dynamics [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-021.
Abstract PO-022: The NKX3.1 homeoprotein functions in the mitochondria to protect against oxidative stress-dependent prostate tumorigenesis
Authors: Papachristodoulou Alexandros , Panja Sukanya , Mitrofanova Antonina , Dutta Aditya , Abate-Shen Cory 
Published: December 2020

Abstract
The NKX3.1 homeobox gene is a key regulator of prostate differentiation, whose loss-of-function predisposes to prostate cancer. Here, we uncover an unexpected role for NKX3.1 in mitochondrial function and bioenergetics that regulates cancer initiation under conditions of oxidative stress. To investigate whether NKX3.1 plays a direct functional role in protection against oxidative stress, we studied the consequences of its loss- or gain-of-function in tumorigenic and non-tumorigenic human prostate cells, mutant mice, and primary human prostate cultures. Utilizing redox compounds to exogenously induce and study oxidative stress responses in our models, we show that NKX3.1 localizes to the mitochondria to protect against oxidative stress, while its loss-of-function leads to deregulation of mitochondrial-encoded oxidative phosphorylation genes, elevated reactive oxygen species, and accelerated prostate cancer initiation. Importantly, our studies reveal that cells lacking NKX3.1 have impaired intracellular energetics under oxidative stress, warranting further investigation into the role of NKX3.1 loss in cancer metabolism. These observations uncover a novel function for a tissue-specific differentiation regulator in mitochondria and demonstrate its functional relevance for suppressing prostate cancer initiation.
Citation Format: Alexandros Papachristodoulou, Sukanya Panja, Antonina Mitrofanova, Aditya Dutta, Cory Abate-Shen. The NKX3.1 homeoprotein functions in the mitochondria to protect against oxidative stress-dependent prostate tumorigenesis [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-022.
Abstract PO-025: Mitochondrial elongation through Drp1 deletion increases CD8 T cell oxidative phosphorylation and memory formation
Authors: Gonzales Marissa A. , Bullock Timothy NJ 
Published: December 2020

Abstract
Despite the positive effects of tumor infiltrating lymphocytes (TIL) seen in patients with melanoma and other tumor types, TIL often fail to completely control disease progression even with immune responses enhanced by checkpoint blockade or other immunotherapy. These TIL exhibit characteristics of exhaustion such as poor proliferation, poor effector function, and an increase in inhibitory receptor expression. By flow cytometry, we find that TIL have lower mitochondrial mass as well as lower mitochondrial membrane potential when compared to functional effector T-cells. During the activation and differentiation of T cells, the metabolic demands fluctuate between the necessity for glycolysis or oxidative phosphorylation (OXPHOS), which is supported by shifting of the mitochondrial network state. Using mice lacking Drp1, a mitochondrial fission protein, in T cells as a model of elongated mitochondria, we see increased spare respiratory capacity and OXPHOS as compared to WT T cells with fission capability. We find that these mice are more likely to generate memory precursor CD8 T cells as represented by KLRG1 lo and CD127 hi during a primary response to anti-CD40, PolyI:C, and ovalbumin protein. As indicated by the increase in memory precursors, we find that Drp1 −/− T cells form more memory than WT animals after a 28-day rest period. At this time, mice were challenged with an adenovirus expressing ovalbumin to elicit a recall response. This recall response of CD8 T cells is greater in animals lacking Drp1 in the T cells. In addition to the increase in T cell numbers, we anticipate an increase in the metabolic and possibly cytokine function of these cells, which is still under investigation. We aim to exploit mitochondrial dynamics to enforce elongation of the mitochondrial network of TIL in order to improve TIL functions and have begun investigations into mitochondrial elongation in T cells in mice bearing B16OVA melanoma tumors.
Citation Format: Marissa A. Gonzales, Timothy NJ Bullock. Mitochondrial elongation through Drp1 deletion increases CD8 T cell oxidative phosphorylation and memory formation [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-025.
Abstract PO-026: Analysis of metabolic adaptations in HeLa cells as a function of energy status using a novel, direct ATP chelation methodology
Authors: Brown Ashley P. , Muhammad Taha , Martinez Selina , Korch Shaleen B. , Norris Jeffrey 
Published: December 2020

Abstract
Introduction: Since pioneering studies by Otto Warburg demonstrated that cancer cells had markedly reduced oxidative phosphorylation under conditions of high oxygen tension (Warburg Effect/aerobic glycolysis), metabolic reprogramming has become a well-recognized hallmark of cancer. While numerous discoveries have revealed highly specific metabolic differences between cancer cells, utilization of aerobic glycolysis as the primary means of ATP generation remains one of the most common metabolic alterations observed across a range of cancers. Gain-of-function mutations in p53 (mutp53) occur with a frequency of greater than 50% in many types of cancers and promote aerobic glycolysis by activation of glycolysis and inhibition of the tricarboxylic acid cycle. However, the manner by which these mutp53 regulates metabolic shifts in response to energy strain is only beginning to be elucidated. Hypothesis: Increased energy demand by cells caused by direct chelation of ATP by the novel, synthetic ATP-binding protein DX will be met by increases primarily in oxygen consumption. Methods: A cationic lipid mixture was complexed with active, purified DX protein to generate a DX/lipid complex. HeLa cells were incubated with the DX/lipid complex to allow efficient delivery of DX into the cytoplasm of the HeLa cells. The XF Real-Time ATP Rate Assay using Seahorse XF label-free technology was used to measure the rate of ATP production following DX expression and estimate the relative contributions of glycolysis and oxidative phosphorylation to the total ATP production rate. Results: HeLa cells transfected with DX had reduced viability, altered morphology, and decreased bioavailable intracellular ATP following DX expression. Unexpectedly, in response to DX expression and reduction in ATP, total ATP production rates in HeLa cells significantly decreased over time. Importantly, this drop in total ATP production was associated with a metabolic pathway utilization shift. Conclusion: The synthetically derived DX protein is a tool that allows for direct control of the ATP levels in cancer cells and has the potential to reveal novel metabolic adaptive responses to energy stress. Following regulated ATP reduction in HeLa cells, changes observed in the OXPHOS/glycolytic balance represent an overall cellular metabolic shift.
Citation Format: Ashley P. Brown, Taha Muhammad, Selina Martinez, Shaleen B. Korch, Jeffrey Norris. Analysis of metabolic adaptations in HeLa cells as a function of energy status using a novel, direct ATP chelation methodology [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-026.
Abstract PO-031: MetMap: A map of metastatic potential of human cancer cell lines
Authors: Jin Xin , Demere Zelalem , Nair Karthik , Ali Ahmed , Ferraro Gino B. , Natoli Ted , Deik Amy , Petronio Lia , Tang Andrew A. , Zhu Cong , Wang Li , Rosenberg Danny , Mangena Vamsi , Roth Jennifer , Chung Kwanghun , Jain Rakesh K. , Clish Clary B. , Vander Heiden Matthew G. , Golub Todd R. 
Published: December 2020

Abstract
Most deaths from cancer are explained by metastasis, and yet large-scale metastasis research has been impractical due to the complexity of in vivo models. Here, we introduce an in vivo barcoding strategy capable of determining the metastatic potential of human cancer cell lines in murine xenografts at scale. We validated the robustness, scalability and reproducibility of the method, and applied it to 500 cell lines spanning 21 solid cancer types. We created a first-generation Metastasis Map (MetMap) that reveals organ-specific patterns of metastasis and allows relating those patterns to clinical and genomic features. We demonstrated the utility of MetMap by exploring the molecular basis of breast cancers capable of metastasizing to the brain – a principal cause of death in these patients. We found that breast cancers capable of metastasizing to the brain had unexpected evidence of altered lipid metabolism. Perturbing lipid metabolism curbed brain metastasis development, suggesting a therapeutic strategy to combat the disease and demonstrating the utility of MetMap as a public resource to support metastasis research.
Citation Format: Xin Jin, Zelalem Demere, Karthik Nair, Ahmed Ali, Gino B. Ferraro, Ted Natoli, Amy Deik, Lia Petronio, Andrew A. Tang, Cong Zhu, Li Wang, Danny Rosenberg, Vamsi Mangena, Jennifer Roth, Kwanghun Chung, Rakesh K. Jain, Clary B. Clish, Matthew G. Vander Heiden, Todd R. Golub. MetMap: A map of metastatic potential of human cancer cell lines [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-031.
Abstract PO-051: Metabolic alterations reveal epigenetic vulnerabilities in breast cancer
Authors: Deblois Genevieve 
Published: December 2020

Abstract
Tumor progression and therapeutic resistance in cancer are characterized by changes in cell identity, which is regulated in part by the epigenetic landscape of the cells. Alterations in metabolic profiles can contribute to changes in cell fate during tumor progression through remodelling of chromatin landscapes. We show that chemoresistance in triple-negative breast cancer is characterized by altered cellular metabolism, impacting the levels of metabolites required for DNA and histone methylation. Using models of chemotherapy resistance breast cancer, we have identified metabolic and epigenetic dependencies specific to drug-resistant breast cancer cells. We show that the remodelling of epigenetic states upon chemotherapy-induced metabolic stress can contribute to drug resistance in breast cancer cells by enabling the maintenance of transposable element repression and preventing the induction of cytotoxic stress-induced viral mimicry. While these metabolic and epigenetic changes contribute to the enhanced tumorigenic fitness of chemo resistant breast cancer, they reveal epigenetic vulnerabilities that can be therapeutically targeted in drug-resistant tumors.
Citation Format: Genevieve Deblois. Metabolic alterations reveal epigenetic vulnerabilities in 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-051.
Abstract PR02: Integrated metabolic and epigenomic reprograming by H3K27M mutations in diffuse intrinsic pontine gliomas
Authors: Chung Chan , Sweha Stefan , Pratt Drew , Tamrazi Benita , Panwalkar Pooja , Banda Adam , Bayliss Jill , Hawes Debra , Yang Fusheng , Lee Ho-Joon , Shan Mengrou , Cieslik Marcin , Qin Tingting , Werner Christian , Wahl Daniel , Lyssiotis Costas , Yadav Viveka Nand , Koschmann Carl , Chinnaiyan Arul , Blüml Stefan , Judkins Alexander , Venneti Sriram 
Published: December 2020

Abstract
H3K27M-midline gliomas are fatal tumors that mainly harbor H3.3K27M mutations resulting in global H3K27me3 reduction that impacts neuroglial-differentiation. However, the exact mechanisms by which H3.3K27M mutations promote cancer are poorly understood. Metabolic reprogramming is a hallmark of cancer and we hypothesized that H3.3K27M mutations can reprogram metabolism to support uncontrolled growth. We demonstrate that H3.3K27M-mutant cells show elevated levels of critical enzymes related to glycolysis and TCA cycle metabolism including hexokinase-2, isocitrate dehydrogenase (IDH)-1 and glutamate dehydrogenase. H3.3K27M cells also demonstrated enhanced glycolysis, glutamine and TCA-cycle metabolism accompanied by increased alpha-ketoglutarate (α-KG) production. Mutant IDH (mIDH)1/2 converts α-KG to D-2-hydroxyglutarate (D-2HG). D-2HG increases H3K27me3 by inhibiting α-KG’s function to drive H3K27-demethylases. We discovered that H3.3K27M cells use α-KG in an opposing manner to maintain low H3K27me3. Inhibiting enzymes related to α-KG generation including hexokinase-2, glutamate-dehydrogenase and wild type-IDH1 increased global H3K27me3, altered chromatin accessibility at neuroglial-differentiation factors, lowered tumor cell proliferation, and increased overall survival in vivo in two independent H3.3K27M animal models (p&lt; 0.0001). H3K27M and mIDH1 were mutually exclusive in-patient tumor samples and D-2HG treatment or forced-mIDH1 expression in H3.3K27M cells increased global H3K27me3 and cell death. Finally, H3.3K27M and mIDH1 were synthetic lethal in vitro. Our data suggest that H3.3K27M and mIDH1 hijack a critical and conserved metabolic pathway in opposing manners to regulate global H3K27me3. These results have implications for understanding the pathogenesis of fatal H3K27M-gliomas and for developing therapeutic strategies by disruption of an integrated metabolic/epigenetic-axis.
Citation Format: Chan Chung, Stefan Sweha, Drew Pratt, Benita Tamrazi, Pooja Panwalkar, Adam Banda, Jill Bayliss, Debra Hawes, Fusheng Yang, Ho-Joon Lee, Mengrou Shan, Marcin Cieslik, Tingting Qin, Christian Werner, Daniel Wahl, Costas Lyssiotis, Viveka Nand Yadav, Carl Koschmann, Arul Chinnaiyan, Stefan Blüml, Alexander Judkins, Sriram Venneti. Integrated metabolic and epigenomic reprograming by H3K27M mutations in diffuse intrinsic pontine gliomas [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 PR02.
Abstract PR03: Metabolic control of Polycomb Repressive Complex 2 in Lung Disease and Lung Cancer
Authors: Bakhtiari Mojtaba , Byrd Aria L. , Chen Fan , Lukyanchuk Alexsandr , DuCote Tanner J. , Brainson Christine Fillmore 
Published: December 2020

Abstract
Dysregulated epigenetic control of lung lineage fate is believed to be a major driver of lung disease, including plasticity in lung cancer. Our laboratory has observed a marked decrease in Polycomb Repressive Complex 2 (PRC2) activity in bronchiolar epithelium of COPD patients, poorly differentiated adenocarcinomas and the majority of squamous cell carcinomas. Interestingly, the PRC2 methyltransferase EZH2 is still highly expressed in many of these tissues, suggesting a de-coupling of EZH2 and PRC2 activity. A mouse model of lineage switching from adenocarcinoma to squamous lung cancer clearly showed that loss of PRC2 activity was a catalyst to epigenetic reprogramming. This model also showed increased infiltration of neutrophils, which are known to produce large amounts of superoxide. Our current hypothesis is that oxidative stress, in part through neutrophil recruitment to lung tissue, drives the loss of PRC2 activity through metabolic changes. To support this hypothesis, we have shown that a redox-sensitive enzyme in the methionine pathway, cystathionine beta synthase (CBS), is expressed in COPD and lung cancer and modulates PRC2 activity. Enforced CBS expression drives global decrease in the PRC2-mediated histone marked, H3K27me3, and increased expression of genes expressed by basal cells of the lung, including KRT5, SOX2 and PD-L1. Furthermore, we have found that PRC2 activity can be stabilized through restriction of methionine levels or knock-down of CBS, leading to increased sensitivity of cells to chemotherapy and radiation treatments. PRC2-low epigenetic states can also be exploited – either pharmacological or genetic perturbation of EZH2 led to sensitivity to several classes of drugs, including immunotherapies. Our future studies include using Stable Isotope Resolved Metabolomics (SIRM) to understand how oxidative stress alters the methionine cycle and ultimately changes the stability and function of the PRC2 complex, and to use this information to design better therapeutic strategies. Work supported by AACR Innovation and Discovery Grant, American Cancer Society 133123-RSG-19-081-01-TBG and IRG-85-001-25, NCI R01 CA237643, NIGMS P20 GM121327-03, NIEHS T32 5T32ES007266-30, NCI T32 CA165990 and NHLBI F31 HL151111-01.
Citation Format: Mojtaba Bakhtiari, Aria L. Byrd, Fan Chen, Alexsandr Lukyanchuk, Tanner J. DuCote, Christine Fillmore Brainson. Metabolic control of Polycomb Repressive Complex 2 in Lung Disease and 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 PR03.