bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4309: Mode of action of LTX315-induced cell death
Authors: ZHOU HENG , Sauvat Allan , Durand Sylvère , Forveille Sabrina , Yamazaki Takahiro , Souquere Sylvie , Sica Valentina , Rekdal Øystein , Kepp Oliver , Kroemer Guido 
Published: July 2017

Abstract
The experimental anticancer agent LTX-315 is an amphipathic cationic peptide that efficiently eradicates cancer cells in vitro and in vivo. Attracted by its efficacy we launched an in depth mechanistic study on LTX-315. First we focused on the mode of action of LTX-315 and found that the agent failed to induce morphological signs of apoptosis but evoked necrotic phenotypes. Accordingly, LTX-315 failed to stimulate the activation of caspases, and the pan-caspase inhibitor Z-VAD-fmk was unable to reduce cell killing. We then studied its subcellular localization by fractionation of LTX-315-treated cells, and revealed that the agent was enriched in mitochondria and caused an immediate arrest of mitochondrial respiration without any major uncoupling effect. LTX-315 disrupted the mitochondrial network, dissipated the mitochondrial inner transmembrane potential, and caused the release of mitochondrial intermembrane proteins into the cytosol. Cells lacking the two pro-death multidomain proteins BAX and BAK, were less susceptible to LTX-315-mediated killing. Moreover, cells engineered to lose their mitochondria were resistant against LTX-315, underscoring the importance of this organelle for LTX-315-mediated cytotoxicity. Further, we observed that LTX-315 induced all known characteristics of immunogenic cell death, including calreticulin exposure, ATP secretion, HMGB1 exodus and type-1 interferon induction. When injected into established cancers, LTX-315 caused a transiently hemorrhagic focal necrosis that was accompanied by massive release of HMGB1 (from close-to-all cancer cells), as well caspase-3 activation in a fraction of the cells. Collectively, these results support the idea that LTX-315 triggers unregulated necrosis, and kills cancer cells by virtue of its capacity to permeabilize mitochondrial membranes. In addition, LTX-315 can induce ICD, hence explaining its capacity to mediate immune-dependent therapeutic effects.
Citation Format: HENG ZHOU, Allan Sauvat, Sylvère Durand, Sabrina Forveille, Takahiro Yamazaki, Sylvie Souquere, Valentina Sica, Øystein Rekdal, Oliver Kepp, Guido Kroemer. Mode of action of LTX315-induced cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4309. doi:10.1158/1538-7445.AM2017-4309
Abstract 4311: Targeting specific regulatory subunits of protein phosphatase 1 phenocopies estrogen-induced apoptosis
Authors: Sevigny Catherine , Sengupta Surojeet , Bouker Kerrie B. , Clarke Robert 
Published: July 2017

Abstract
The growth of estrogen receptor positive (ER+) breast cancers is considered to be dependent on estrogen and its actions can be blocked by selective estrogen receptor modulators (SERMS), like tamoxifen, or by inhibiting the synthesis of estrogen, by aromatase inhibitors (AIs). Both of these classes of drug are used to treat ER+ breast cancers in the clinic. Paradoxically, before the discovery of SERMs and AIs, high dose estrogen was the choice of endocrine therapy to treat post-menopausal breast cancers. Recent clinical trials have confirmed a 30% clinical benefit rate with high, as well as low, doses of estrogen therapy in AI- resistant breast cancers. However, the underlying mechanism by which estrogen triggers the tumor regression remains unknown. Using an in vitro cell model MCF7:5C cells, that undergo estrogen-induced apoptosis, we demonstrate that sustained phosphorylation of eukaryotic initiation factor 2-alpha (eIF2-α), a downstream target of PERK activation, is crucial in estrogen-induced apoptosis. Growth arrest and DNA damage inducible-34 (GADD34) and constitutive repressor of eIF2α phosphorylation (CReP) are two regulatory subunits of protein phosphatase 1 (PP1) complex, that provides substrate specificity towards eIF2α, and are responsible for its de-phosphorylation. Our results show that pharmacological inhibition of GADD34 and CReP, or their genetic depletion, can enhance the phospho-eIF2α (p-eIF2α) levels and promote apoptosis. Elevated levels of p-eIF2α attenuated global translation but preferentially allowed high expression of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) that are involved in apoptosis. Both estrogen and inhibition of GADD34 and CReP promote apoptosis by an identical mechanism. Importantly, inhibition of GADD34 and CReP induced apoptosis in another estrogen-independent breast cancer cell line, LCC9, which is resistant to both tamoxifen and fulvestrant but does not undergo estrogen mediated apoptosis. Overall, our study provides crucial evidence that inhibiting specific regulatory subunits (GADD34 and CReP) of PP1 complex, can mimic estrogen-induced apoptosis in breast cancer cells that are not susceptible to estrogen mediated apoptosis. Therefore, GADD34 and CReP can be targeted for potential therapeutic intervention in endocrine therapy resistant breast cancers.
Citation Format: Catherine Sevigny, Surojeet Sengupta, Kerrie B. Bouker, Robert Clarke. Targeting specific regulatory subunits of protein phosphatase 1 phenocopies estrogen-induced apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4311. doi:10.1158/1538-7445.AM2017-4311
Abstract 4312: Targeting FoxM1 in inducing anticancer effects in triple-negative breast cancer cells
Authors: Bu Rong , Siraj Abdul K. , Ahmed Maqbool , Al-Dayel Fouad , Al-Kuraya Khawla S. 
Published: July 2017

Abstract
Triple-negative breast cancer (TNBC) is highly aggressive and a major threat to survival due to absence of molecular targets. Invasion, metastasis and chemoresistance are the greatest obstacles to the successful tumor treatment in breast cancer patients. In this study, over-expression of Forkhead box transcription factor M1 (FoxM1) was observed in 79% (770/975) of breast cancers from Saudi Arabia. FoxM1 over-expression was found to be an independent prognostic marker in multivariate analysis in late stage (Stage 3 and 4) breast cancer (p=0.0110). Our in vitro results show that treatment with thiostrepton, a dual FoxM1 and proteasome inhibitor caused cell viability loss and induce apoptosis in a dose dependent manner in triple-negative breast cancer cell lines. Thiostrepton treatment also inhibited colony formation and invasion/migration capabilities of triple-negative breast cancer cells. In vivo, thiostrepton treatment regressed TNBC cells; MDA-MB-231 generated xenografts via down-regulation of FoxM1 and its downstream targets. Altogether, our results suggest that FoxM1 and its associated signaling pathway may be a potential target for therapeutic intervention in the treatment of aggressive breast cancer.
Key words: Triple-negative breast cancer, FoxM1, Apoptosis and Invasion
Citation Format: Rong Bu, Abdul K. Siraj, Maqbool Ahmed, Fouad Al-Dayel, Khawla S. Al-Kuraya. Targeting FoxM1 in inducing anticancer effects in triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4312. doi:10.1158/1538-7445.AM2017-4312
Abstract 4317: EGLN1/c-Myc induced lymphoid-specific helicase inhibits ferroptosis through lipid metabolic gene expression changes
Authors: Tao Yongguang , Liu Shuang , Jiang Yiqun 
Published: July 2017

Abstract
Ferroptosis has emerged as a new form of non-apoptotic cell death in multiple human diseases. However, the epigenetic mechanisms of ferroptosis remain poorly defined. We demonstrate that Lymphoid-specific helicase (LSH), a DNA methylation modifier, interacts with WDR76 to inhibit ferroptosis by activating lipid metabolism-associated genes, including GLUT1, and ferroptosis related genes SCD1 and FADS2. These effects are dependent on iron and lipid reactive oxygen species. We further show that EGLN1 and c-Myc directly activate LSH expression by inhibiting HIF-1α. Finally, we demonstrate that LSH functions as an oncogene in lung cancer in vitro and in vivo. Therefore, our study elucidates the molecular basis for a c-Myc/EGLN1-mediated induction of LSH expression to inhibit ferroptosis, which can be exploited for the development of therapeutic agents to target ferroptosis in cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Yongguang Tao, Shuang Liu, Yiqun Jiang. EGLN1/c-Myc induced lymphoid-specific helicase inhibits ferroptosis through lipid metabolic gene expression changes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4317. doi:10.1158/1538-7445.AM2017-4317
Abstract 4321: TNF receptor 2 is essential for RIP1-dependent cell death in refractory leukemia
Authors: Aguadé-Gorgorio Julia , McComb Scott , Eckert Cornelia , Dobay Maria Pamela , Cario Gunnar , Mezzatesta Caterina , Stackelberg Arend Von , Stanulla Martin , Martin Schrappe , Bourquin Jean-Pierre , Bornhauser Beat C. 
Published: July 2017

Abstract
The identification of molecular determinants that regulate sensitivity to specific agents is essential for the development of new therapeutic approaches in cancer. We have earlier shown that a subset of refractory acute lymphoblastic leukaemia (ALL) samples respond to SMAC-mimetic (SM) induced IAP depletion by concurrently inducing RIP1-dependent apoptosis and necroptosis. Comparative gene expression profiling indicated a correlation of sensitivity to SM with the expression of TNF receptor 2 (TNFR2) in primary ALL. Using an independent cohort of primary chemotherapy-resistant ALL samples, we found that presence of high TNFR2 expression identified by qPCR predicted ex vivo-sensitivity to SM. High TNFR2 levels also correlated with higher expression of TNFR1. Deletion of either TNFR1 or TNFR2 using CRISPR/Cas9 in primary ALL conferred resistance to treatment with SM, indicating that TNFR1 and 2 are both functionally required for cell death. Concomitant with an important role for TNFR2 in the response to SM, the overexpression of TNFR2 leads to increased sensitivity to TNF through increased activation of the TNFR1/RIP1 death axis. On the mechanistic level, SM induced recruitment of RIP1 to TNFR1, which was abolished in cells deficient for TNFR2. Taken together, our data reveal a novel function of TNFR2 in cell death signalling, as TNFR2 predicts sensitivity to SMAC mimetics and plays a key role in modulating a switch from RIP1-controlled cell survival to cell death.
Citation Format: Julia Aguadé-Gorgorio, Scott McComb, Cornelia Eckert, Maria Pamela Dobay, Gunnar Cario, Caterina Mezzatesta, Arend Von Stackelberg, Martin Stanulla, Schrappe Martin, Jean-Pierre Bourquin, Beat C. Bornhauser. TNF receptor 2 is essential for RIP1-dependent cell death in refractory leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4321. doi:10.1158/1538-7445.AM2017-4321
Abstract 433: Glycogen accumulation in aggressive breast cancers during hypoxic exposure
Authors: Altemus Megan , Yates Joel , Wu ZhiFen , Bao LiWei , Merajver Sofia 
Published: July 2017

Abstract
Isolation of specific metabolic alterations in aggressive triple negative and inflammatory breast cancers represents a compelling avenue for the development of treatments for these diseases. The ability of cancer to utilize diverse metabolic pathways to modulate increased survival and proliferation is well established. Indeed, we have previously described a series of metabolic adaptations in the triple negative inflammatory breast cancer cell line SUM149 and demonstrated a role for the small GTPase RhoC in the metabolic phenotype of the cell line.
In this work we seek to describe a survival mechanism for cancer cells that are subjected to hypoxic environments. Hypoxic survival or growth is often necessitated at the center of a growing tumor mass or if the tumor is growing in the lymphatic system, as is often the case for inflammatory breast cancers. Here we investigate the regulation of glycogen levels in breast cancer and normal-like cell lines in atmospheric and 1% oxygen environments. Reserves of glucose are typically stored in liver and muscle cells as the polysaccharide glycogen. Elevated levels of glycogen have previously been observed in various cancers, and recent studies have implicated the importance of glycogen metabolism in promoting cancer cell survival. We hypothesize that aggressive breast cancers utilize modifications of the glycogen synthesis and degradation pathways to provide nutritional flexibility as they proliferate and invade into diverse environments. MCF10A, SUM149, and SUM190 cell lines demonstrate a greater than 10-fold increase in glycogen accumulation when subjected to hypoxic growth conditions. MDA-MB-231 cells also increase glycogen storage, though at levels on the order of 2-3 times higher in hypoxia when compared to normoxic growth. Conditioned media for all cell lines in normoxic and hypoxic conditions were analyzed for glucose and lactate levels to determine changes in metabolite consumption.
The data presented indicate an unexpected accumulation of glycogen in response to hypoxic conditions. Studies to determine the mechanisms through which these changes occur and why they are important for continued survival and growth of the cancer cells are ongoing and will be presented.
Citation Format: Megan Altemus, Joel Yates, ZhiFen Wu, LiWei Bao, Sofia Merajver. Glycogen accumulation in aggressive breast cancers during hypoxic exposure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 433. doi:10.1158/1538-7445.AM2017-433
Abstract 4331: Novel Wnt-SCD-LRP5/6 pathway linking liver fibrosis to cancer
Authors: Lai Keane , Kweon Soo-Mi , Chi Feng , Hwang Edward , Wu Raymond , Kabe Yasuaki , Murali Ramachandran , Mishra Lopa , Ntambi James , Tsukamoto Hidekazu 
Published: July 2017

Abstract
Activated hepatic stellate cells (HSCs) are primarily responsible for the genesis of liver fibrosis which promotes liver tumor development. Stearoyl-CoA desaturase (SCD) which synthesizes monounsaturated fatty acid (MUFA such as oleic acid or palmitoleic acid), is implicated in metabolic syndrome, tumorigenesis and stemness. Indeed, we demonstrate SCD upregulation in both HSCs and liver tumor cells in patients. Further, SCD correlates with the advancing grade of HCC and mortality in patients. However, its causality in tumorigenesis and mesenchyme-tumor crosstalk, and underlying mechanisms, are unknown. The present study aimed to determine whether and how SCD promotes and links liver fibrosis and cancer. In both HSCs and liver tumor-initiating stem cell-like cells (TIC), we reveal that the Wnt effector β-catenin is a potent co-activator for SREBP-1-dependent Scd transcription as demonstrated by promoter-reporter assay and re-ChIP analysis. We also discover β-catenin which drives SCD expression is in turn stabilized by SCD-derived MUFA. To identify molecular targets of MUFA mediating this SCD-β-catenin positive loop, we performed MUFA-nano-beads pull-down assay with TIC lysate, ESI-MS based identification of MUFA interacting proteins, computational docking analysis, co-IP and ribonucleoprotein-IP. These analyses reveal that MUFA is essential for LRP5/6 expression: MUFA interferes Transportin-1 and Ran-1 interaction, resulting in suppressed nuclear import of the mRNA binding protein HuR, HuR cytoplasmic accumulation, and increased HuR binding to and stabilization of Wnt co-receptor Lrp5/6 mRNA. As such, genetic or pharmacologic SCD inhibition reduces cytosolic HuR, LRP5/6 expression, β-catenin stabilization, HSC activation and TIC self-renewal and attenuates liver fibrosis and tumorigenesis in mice. Moreover, conditional genetic ablation of Scd2 in HSCs not only abrogates HSC-mediated promotion of TIC-derived tumorigenesis in a xenograft mouse model but also inhibits DEN-induced liver tumor development in Col1a1-Cre; Scd2flox/flox mice (tumor volume reduced to 21.5 + 7.9 vs. 360.9 + 193 mm3 in Scd2flox/flox mice; tumor multiplicity decreased to 18 + 5.4 vs. 45 + 8.4 in Scd2flox/flox mice, both p&lt;0.05). Collectively, our findings support that a newly disclosed Wnt-SCD-LRP5/6 loop may serve as a novel therapeutic target for liver cancer and underlies a known crosstalk between liver mesenchyme and liver tumor development.
Citation Format: Keane Lai, Soo-Mi Kweon, Feng Chi, Edward Hwang, Raymond Wu, Yasuaki Kabe, Ramachandran Murali, Lopa Mishra, James Ntambi, Hidekazu Tsukamoto. Novel Wnt-SCD-LRP5/6 pathway linking liver fibrosis to cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4331. doi:10.1158/1538-7445.AM2017-4331
Abstract 4336: Human mesodermal-derived CNS metastasis-associated stromal cells induce a fibrotic response to limit tumor growth
Authors: Legendre Christophe , Gooden Gerald C. , Johnson Kyle N. , Martinez Rae Anne , Bernstein Mark , Glen Jennifer , Kiefer Jeffrey , Hinek Aleksander , Toms Steven A. , Salhia Bodour 
Published: July 2017

Abstract
Metastasis to the central nervous system (CNS) remains a major cause of mortality and morbidity in patients with systemic cancer. However, the mechanistic interactions of the neural niche with disseminated tumors cells in CNS metastases (CM) are still poorly understood. To better understand the cross-talk between the neural niche and metastatic tumors, we generated five different patient-derived cell lines (PDCs) originating from surgically resected CM. To assess the genetic and epigenetic characteristics of each PDC, DNA and RNA sequencing, and DNA methylation analysis was performed. Non-tumoral PDCs revealed normal copy number profiles, and retention of germline mutations as seen in patient-matched germline DNA. In contrast, one PDC (CM04) resembled its patient tumor, showing numerous copy number and somatic alterations. RNA-seq and DNA methylation analysis demonstrated that non-tumoral PDCs highly resembled each other, suggestive of a common cell of origin. Additionally, PDCs revealed gene expression signatures associated with cancer associated fibroblasts, epithelial to mesenchymal transition, and mesenchymal stem cells. Further in vivo studies demonstrated that CM04 cells were tumorigenic, whereas non-tumoral PDC (CM08) cells were unable to form tumors in mice. However, CM04:CM08 mixed tumors were significantly smaller than CM04 only tumors and revealed induction of a fibrotic response by immunohistochemistry. These data offer the first evidence that CNS metastasis-associated stromal cells (cMASCs) produce a collagen and fibronectin-rich extracellular matrix constituting a protective host response, which impedes growth of tumor cells. The therapeutic potential of these cells merits further exploration.
Citation Format: Christophe Legendre, Gerald C. Gooden, Kyle N. Johnson, Rae Anne Martinez, Mark Bernstein, Jennifer Glen, Jeffrey Kiefer, Aleksander Hinek, Steven A. Toms, Bodour Salhia. Human mesodermal-derived CNS metastasis-associated stromal cells induce a fibrotic response to limit tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4336. doi:10.1158/1538-7445.AM2017-4336
Abstract 4348: Methylation analysis of uveal melanoma reveals definitive patterns in tumors harboring BAP1 mutations
Authors: Durante Michael , Field Matthew , Kurtenbach Stefan , Bussies Parker , Decatur Christina , Harbour J. William 
Published: July 2017

Abstract
Introduction: Uveal melanoma (UM) is the most common primary intraocular malignancy and can be classified by gene expression profiling into two distinct molecular classes that correspond to metastatic risk: Class 1 (low risk) and Class 2 (high risk). The less aggressive Class 1 UMs express a more differentiated phenotype and exhibit numerous characteristics of normal uveal melanocytes, while the metastasizing Class 2 UMs display loss of melanocytic differentiation and have acquired a primitive, stem-like phenotype. The majority of Class 2 UMs harbor loss of chromosome 3 in addition to inactivating mutations of the tumor suppressor BAP1, which also catalyzes ubiquitin removal from histone H2A and modulates gene expression. Histone modifications have been shown to be associated with DNA methylation and this study investigates the global methylation and gene expression changes in BAP1 mutant tumors.
Methods: RNA-Sequencing data and Illumina Human Methyl 450K BeadChip Array data obtained from 92 primary uveal melanoma tumors was analyzed using optimized pipelines.
Results: This analysis revealed that the more aggressive Class 2 tumors exhibit a distinct pattern of hypermethylation and silencing of developmental genes involved in neural crest migration and differentiation. Chromosomal regions that were significantly enriched for hypermethylated genes with decreased gene expression in Class 2 tumors included chromosome 3p14-26, 3q12-29 and 8p12-22, whereas the only significantly enriched region for genes that were hypomethylated with increased gene expression in Class 2 tumors was chromosome 8q22-24. Additionally, BAP1 itself was differentially hypermethylated in Class 2 UMs, suggesting that it may regulate its own transcription.
Conclusions: Class 2 UMs harboring BAP1 mutations displayed distinct regions of differential hypermethylation in comparison to Class 1 UMs. In these tumors, the most significantly hypermethylated regions occurred on chromosome 3 and in regions that were enriched for genes encoding neural crest guidance cue proteins that regulate homing, migration and invasion. These findings suggest that BAP1 mutations are associated with marked reorganization of the DNA methylome, providing new insights into the pathophysiology of UM and suggesting that methylation may serve as a diagnostic to further stratify metastatic risk. Furthermore, these findings may open new opportunities for targeted therapy of Class 2 UMs.
Citation Format: Michael Durante, Matthew Field, Stefan Kurtenbach, Parker Bussies, Christina Decatur, J. William Harbour. Methylation analysis of uveal melanoma reveals definitive patterns in tumors harboring BAP1 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4348. doi:10.1158/1538-7445.AM2017-4348