bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 315: Cell death of AML blasts induced by cytarabine and enhanced by the Vitamin D2/Carnosic acid cell differentiating combination involves apoptosis signal-regulating kinase 1 (ASK1) activation
Authors: Wang Xuening , Harrison Jonathan S. , Studzinski George P. 
Published: August 2018

Abstract
Acute Myeloid Leukemia (AML) is a disease with a grim prognosis and limited curative treatment options. The principal agent used to induce disease remissions is Cytarabine (AraC), typically combined with an anthracycline, though multiple other combinations have been explored. We have previously reported that the exposure of AML blasts, in which the DNA is already damaged by AraC, to the Vitamin D2 analog Doxercalciferol combined with Carnosic Acid (D2/CA) enhances AraC cytotoxicity, resulting in an increased cell kill of the blasts. To obtain an understanding of the underlying mechanisms, and thus facilitate the translation of this finding to the clinic, we conducted in vitro studies on HL60, U937 cell lines and on AML blasts in primary culture. The initial findings were that the kinases BRAF and JNK1 and the pro-apoptotic protein BIM participate in the enhancement of AraC action. We now report that the kinase activity of ASK1 (MAP3K5) is upregulated by both AraC and D2/CA, and this appears to be additive thus increasing the apoptosis by this sequential combination regimen. Interestingly, we also noted that BRAF directly binds to ASK1, and since it is a kinase, this raises the possibility that it activates ASK1 in this experimental system. This possibility is strengthened by the report that JNK activation which leads to apoptosis is dependent on BRAF. The ongoing investigation of additional details of the molecular events responsible for enhanced cell death may provide clues for the improvement of the therapy of AML. (Supported by NIH grant R01CA044722-26 from NCI).
Citation Format: Xuening Wang, Jonathan S. Harrison, George P. Studzinski. Cell death of AML blasts induced by cytarabine and enhanced by the Vitamin D2/Carnosic acid cell differentiating combination involves apoptosis signal-regulating kinase 1 (ASK1) activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 315.
Abstract 3154: Harnessing the adaptive potential of mechanoresponsive proteins to overwhelm pancreatic cancer dissemination and invasion
Authors: Surcel Alexandra , Schiffhauer Eric S. , Thomas Dustin G. , Zhu Qingfeng , DiNapoli Kathleen , Herbig Maik , Otto Oliver , Guck Jochen , Jaffee Elizabeth , Iglesias Pablo A. , Anders Robert A. , Robinson Douglas N. 
Published: August 2018

Abstract
Metastatic disease is often characterized by altered cellular contractility and deformability, lending cells and groups of cells the flexibility to navigate through different microenvironments. This ability to change cell shape is driven in large part by the structural elements of the mechanobiome, which includes cytoskeletal proteins that sense and respond to mechanical stimuli. Here, we demonstrate that key mechanoresponsive proteins (those that accumulate in response to mechanical stress), specifically nonmuscle myosin IIA and IIC, α- actinin 4, and filamin B, are highly upregulated in pancreatic ductal adenocarcinoma cancer (PDAC) and in patient-derived pancreatic cancer cell lines. Their less responsive sister paralogs (myosin IIB, α-actinin 1, and filamin A) show a smaller dynamic range or disappear with PDAC progression. We demonstrate that these mechanoresponsive proteins directly impact cell mechanics using knockdown and overexpression cell lines. We further quantify the nonmuscle myosin II family members in patient-derived cell lines and identify a role for myosin IIC in the formation of transverse actin arcs in single cells and cortical actin belts in tissue spheroids. We harness the upregulation of myosin IIC and its impact of cytoskeletal architecture through the use of the mechanical modulator 4-hydroxyacetophenone (4-HAP), which increases myosin IIC assembly and stiffens cells. Here, 4-HAP decreases dissemination, induces cortical actin belts, and slows retrograde actin flow in spheroids. Finally, mice having undergone hemisplenectomies with PDAC cells and then treated with 4-HAP have a reduction in liver metastases. Thus, increasing the activity of these mechanoresponsive proteins (in this case, by increasing myosin IIC assembly) to overwhelm the ability of cells to polarize and invade may be an effective strategy to improve the five-year survival rate of pancreatic cancer patients, currently hovering around 6%.
Citation Format: Alexandra Surcel, Eric S. Schiffhauer, Dustin G. Thomas, Qingfeng Zhu, Kathleen DiNapoli, Maik Herbig, Oliver Otto, Jochen Guck, Elizabeth Jaffee, Pablo A. Iglesias, Robert A. Anders, Douglas N. Robinson. Harnessing the adaptive potential of mechanoresponsive proteins to overwhelm pancreatic cancer dissemination and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3154.
Abstract 316: Cancer cell apoptosis is induced by soluble factors secreted from normal mammary fibroblasts
Authors: Tsegaye Matyas Abel , Nemera Mati , Schafer Zachary T. 
Published: August 2018

Abstract
The tumor microenvironment (TME), comprised of a heterogeneous population of transformed and non-transformed cells, plays a crucial role in cancer growth. Studies have shown that there is continuous bidirectional communication between cancer cells and the different cell populations within the TME. This communication can either work to promote tumor growth, as seen with carcinoma associated fibroblasts (CAFs), or inhibit tumor growth, as observed with tumor infiltrating lymphoid cells. To date, the majority of research focusing on understanding the role of fibroblasts in the TME has been on CAFs and their ability to enhance tumorigenesis. Although the majority of studies have focused on CAFs, some studies have shown that certain fibroblast populations can antagonize tumor growth. Despite this evidence for an inhibitory role of normal fibroblasts, the precise molecular mechanism by which these cells modulate cancer cell growth has yet to be elucidated. Here, we show that normal mammary fibroblasts (fibroblasts isolated from normal breast tissue) secrete soluble factors that induce caspase mediated cell death in a variety of cancer cell lines. This phenotype was observed in MDA-MB-231s as well as T47D, and BT474 cell lines. Further verification of this phenotype was performed in MDA-MB-231s using Annexin V staining and flow cytometry. When examining the mechanism of apoptotic induction, we observed a substantive increase in the cleavage of caspase 8, evidence that the extrinsic apoptotic pathway is activated. We are currently working to further elucidate the signaling pathways activated in the aforementioned cancer cell lines resulting in the induction of apoptosis by normal mammary fibroblasts. Our research reveals a novel and potentially tumor suppressive function of normal mammary fibroblasts in the tumor microenvironment through secretion of soluble factors that induce apoptosis in cancer cells.
Citation Format: Matyas Abel Tsegaye, Mati Nemera, Zachary T. Schafer. Cancer cell apoptosis is induced by soluble factors secreted from normal mammary fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 316.
Abstract 3162: Endothelin-1 receptor/beta-arrestin-1 pathway promotes invadopodia and metastatic process by integration with hMENA in human serous ovarian cancer
Authors: Caprara Valentina , Modugno Francesca Di , Chellini Lidia , Tocci Piera , Spadaro Francesca , Sacconi Andrea , Blandino Giovanni , Nisticò Paola , Bagnato Anna , Rosanò Laura 
Published: August 2018

Abstract
Aberrant activation of the endothelin-1 receptor (ET-1R) elicits pleiotropic effects relevant for serous ovarian cancer (SOC) cell invasion. The network activated by this receptor might be finely, spatially and temporary orchestrated by β-arrestin1 (β-arr1)-driven interactome. Recently, we uncovered a novel role for ET-1R/β-arr1 as regulator of cytoskeletal remodelling and invasive protrusions, invadopodia. Emerging evidence demonstrated that hMENA protein, an Ena/Vasp family member, is a key invadopodia component. In this study, we set out to molecularly dissect whether hMENA might represent a novel interacting partner of β-arr1 necessary for invadopodial function downstream of ET-1R in SOC cells. ENAH mRNA is significantly upregulated in OC tissues, and in particular in high-grade (HG)-SOC tumors, compared with normal tissues. In a panel of SOC cells, the expression hMENA, along with the spliced isoform hMENAΔv6, is upregulated by ET-1, at mRNA and protein levels, through β-arr1, restricted to mesenchymal phenotype. This effect is inhibited by treatment with the dual ETAR/ETBR antagonist macitentan. As shown by biochemical and imaging assays, ET-1 promotes a physical association between hMENA and β-arr1 as well PDZ-RhoGEF, which in turn activate RhoC. Most importantly, ET-1 induces localization of hMENA in F-actin-containing puncta, which co-localize with cortactin, and extracellular matrix degradation sites, thus promoting invadopodia maturation. Silencing of hMENA, as well as of β-arr1, or treatment with macitentan, impairs ET-1-dependent invadopodia activity, MMP secretion and activation, invasion, transendothelial migration and cell plasticity. In vivo, macitentan is able to inhibit SOC metastatic dissemination and hMENA expression along with other invadopodia markers. Finally, high ETAR/ARRB1/ENAH gene expression is associated with a poor prognosis in SOC patients. Collectively, these data define a pivotal function of hMENA/ hMENAΔv6, which is required for ET-1/β-arr1-induced invadopodial function and metastatic spreading of SOC.
Citation Format: Valentina Caprara, Francesca Di Modugno, Lidia Chellini, Piera Tocci, Francesca Spadaro, Andrea Sacconi, Giovanni Blandino, Paola Nisticò, Anna Bagnato, Laura Rosanò. Endothelin-1 receptor/beta-arrestin-1 pathway promotes invadopodia and metastatic process by integration with hMENA in human serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3162.
Abstract 3163: Wnt7a promotes bladder cancer cell invasion via canonical Wnt/β-Catenin signaling
Authors: Huang Ruimin , Huang Xiaojing , Zhu Hongwen , Zhuang Junlong , Dong Yu , Zhou Hu , Guo Hongqian , Yan Jun 
Published: August 2018

Abstract
The mortality rate of urinary bladder cancer (UBC) increases dramatically, once low grade non-muscle invasive bladder cancer develops into muscle invasive bladder cancer. Hence, understanding the mechanisms underlying UBC invasion/metastasis and identification of biomarkers for invasion/metastasis will help clinicians to determine how to treat patients. Herein we generated two sublines from parental 5637 UBC cells with low invasive and high invasive capacities, which were designated as 5637 NMI and 5637 HMI, respectively. Mass spectrometry analysis was performed to identify the invasion-associated proteins. 5,987 proteins were quantified across all six samples with the coefficients among different channels all nearly 1.00, suggesting good biological repeatability and minor differences between 5637 HMI and NMI samples. Fold change &gt; 1.2 and p value &lt;0.05 were set as the cut-off standard, and 16 upregulated proteins and 26 downregulated proteins were identified in 5637 HMI cells. Among them, Wnt7a overexpression was confirmed in 5637 HMI cells compared to 5637 NMI cells, which was also associated with metastasis potential and worse clinical outcome in UBC patients.
Depletion of Wnt7a in 5637 HMI and T24 cells reduced UBC cell invasion, with the reduction of active β-Catenin and its downstream target genes involved in epithelial-to-mesenchymal transition (EMT) and extracellular matrix (ECM) degradation. Consistently, introduction recombinant Wnt7a protein to 5637 NMI and J82 cells induced cell invasion, EMT, and the expression of ECM degradation-associated genes. Using luciferase reporter driven by the wildtype or mutants of matrix metalloproteinase 10 (MMP10) promoter, a canonical Wnt/β-Catenin regulation pattern was demonstrated.
Four miRNAs downregulated in UBCs were predicted directly targeting Wnt7a using bioinformatics analysis. miRNA mimic could decrease Wnt7a expression, reduce the activation of MMP 10 reporter and suppress the invasion of 5637 HMI cells. Treatment of UBC cells with Wnt7a partially abrogated such miRNAs-induced invasion suppression.
Taken together, our data identify a new miRNA/Wnt7a axis to mediate cell invasion and metastasis of UBC through canonical Wnt/β-Catenin pathway, which may offer prognostic and therapeutic opportunity.
Citation Format: Ruimin Huang, Xiaojing Huang, Hongwen Zhu, Junlong Zhuang, Yu Dong, Hu Zhou, Hongqian Guo, Jun Yan. Wnt7a promotes bladder cancer cell invasion via canonical Wnt/β-Catenin signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3163.
Abstract 3166: The HU177 cryptic collagen epitope selectively regulates melanoma cell behavior by a CDK5 and PTPN12 associated mechanism
Authors: Han Xianghua , Caron Jennifer M. , Brooks Peter C. 
Published: August 2018

Abstract
Previous studies indicate that selectively inhibiting cellular interactions with the HU177 cryptic collagen epitope, which can be generated in vivo during structural remodeling of the extracellular matrix (ECM), inhibits tumor growth and metastasis. However, a detailed understanding of the mechanisms by which antagonists of the HU177 collagen epitope inhibit these pathological processes is not fully understood. Uncovering the molecular mechanisms by which cellular interactions with this collagen epitope regulate tumor cell behavior may allow the development of more effective clinical strategies targeting tumor cell-ECM interactions. Here we provide evidence for the first time, that specific targeting of the HU177 cryptic collagen epitope reduces phosphorylation of cyclin-dependent kinase (CDK5) and in addition, reduces the expression of the phosphatase PTPN12 in melanoma cells attached to denatured collagen. Importantly, both CDK5 &lt; PTPN12 play a functional role in the ability of the HU177 collagen epitope to regulate migration of melanoma cells as reducing expression of these molecules inhibited the anti-migratory activity of the anti-HU177 antibody. Surprisingly, reduction in either CDK5 or PTPN12 also inhibited nuclear accumulation of YAP. These novel findings help define a previously unknown signaling mechanism by which both CDK5 &lt; PTPN12 may play a selective role in controlling nuclear accumulations of the transcriptional co-activator YAP following melanoma cell interactions with the HU177 cryptic collagen epitope. Taken together, these studies provide new molecular insight into the role of the HU177 collagen epitope in controlling melanoma cell behavior. Given that direct targeting of integrin receptors that mediate tumor cellular interactions with the ECM have demonstrated only limited anti-tumor activity in human clinical trials, a more detailed molecular understanding of how generation of biologically relevant cryptic elements of the ECM control melanoma cell behavior will likely facilitate the development of more effective new clinical strategies to control tumor progression.
Citation Format: Xianghua Han, Jennifer M. Caron, Peter C. Brooks. The HU177 cryptic collagen epitope selectively regulates melanoma cell behavior by a CDK5 and PTPN12 associated mechanism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3166.
Abstract 3167: Loss of HP1α alters the integrity of the nuclear lamina, thereby promoting invasion
Authors: Hale Tracy K. , Solomon Raoul 
Published: August 2018

Abstract
Malignant cell invasion is accompanied by complex changes in nuclear morphology and chromatin patterning that have been utilized by pathologists to determine malignancy. Members of the HP1 family modulate chromatin plasticity, with the HP1α paralog required to maintain the condensation of transcriptionally silent heterochromatin and to sequester it at the nuclear periphery. While increased expression of HP1α is proposed to aid the onset of malignancy, the acquisition of an invasive phenotype correlates with the loss of this architectural protein in many solid tumors including those of the thyroid, kidney, colon and breast. We have shown in a Drosophila model of epithelial cell invasion that loss of HP1α synergistically enhances invasion in cells with an activated oncogenic pathway. In the poorly invasive MCF7 breast cells, loss of HP1α increases their invasive potential and promotes epithelial plasticity. These phenotypic changes are associated altered nuclear morphology including increased nuclear grooves and indentations, diffuse chromatin patterning and a loss of heterochromatin at the nuclear periphery. Since during metastatic invasion, the nucleus, the largest and most rigid cellular of organelle, becomes malleable enough to squeeze through interstitial spaces in the surrounding tissue. This lead us to propose that loss of HP1α causes a remodelling of nuclear periphery thereby increasing nuclear malleability. Here we demonstrate that HP1α knockdown in MCF7 cells decreases mechanical stability of the nuclei and altering the integrity of nuclear lamina. While total levels of Lamin A/C, Lamin B1 and Lamin B2 are unchanged within the cell, their solubility and thus localization within the nucleus is altered. We also demonstrate how this change in the lamina effects other proteins that function at the nuclear periphery. Together, these findings suggest that when loss of HP1α increases invasive potential there is a corresponding disruption to the nuclear periphery, creating a weakness in these cells that could be exploited for therapeutic benefit.
Citation Format: Tracy K. Hale, Raoul Solomon. Loss of HP1α alters the integrity of the nuclear lamina, thereby promoting invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3167.
Abstract 3174: PLK4 is a rational target for very high-risk medulloblastoma
Authors: Nor Carolina , Bray Mark , Mak Tak , Taylor Michael 
Published: August 2018

Abstract
Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite aggressive therapy (maximal safe surgical resection, craniospinal irradiation and/or chemotherapy) only 65% of patients survive, and survivors are left with severe neuro-cognitive sequelae. MB is comprised of at least four distinct molecular subgroups (SHH, Wnt, Group 3 and Group 4). Within the Sonic hedgehog (SHH) subgroup, a subset harboring inactivating mutations within TP53 represent a very high-risk group with almost universally fatal outcome. TP53 mutated SHH tumors have a high degree of genomic instability with frequent chromothripsis and are resistant to the current generation of SHH pathway inhibitors. The protein PLK4 has a key role in the maintenance of chromosome numeral integrity and as such dysregulation of PLK4 expression causes genomic instability. The PLK4 inhibitor (CFI-400945, produced by the Campbell Family Institute for Breast Cancer Research) was shown to increase genomic instability in aneuploid cells from adult solid tumors and induce these cells to die through mitotic catastrophy. Here we leverage a sporadic transposon based metastatic mouse model (Ptch+/-/Math1-SB11/T2Onc) that faithfully mimics very high-risk MB in children. In order to mimic treatment in children, tumors are microsurgically subtotally resected, followed with the oral administration of CFI-400945 and cranial MRI to monitor response. Blood brain barrier penetration of CFI-400945 was confirmed using mass spectroscopy, specifically pharmacokinetics study revealed an expected availability of CFI-400945 in the circulating blood and concentrated compound in the tumor compared to the normal brain. The administration of CFI-400945 confers an advantage of survival to the mice in this model, median of 18.5 days for surgery group and 49 days for surgery plus CFI-400945 group (p=0.005). In human tumor datasets PLK4 is highly expressed across a variety of malignancies, including MB. Specifically, across two independent, non-overlapping datasets higher PLK4 levels correlate with a trend toward worse outcome, however, when restricting this analysis only to SHH tumors, there is a significant survival difference between high and low PLK4 expression (p=0.012). In paired primary-metastatic MB PLK4 expression is retained at the time of recurrence, specifically in metastatic recurrences, suggesting PLK4 inhibition is a suitable treatment option at the time of recurrence. Taken together, the data reveals PLK4 inhibition as a novel and rational therapeutic target for a subset of very high risk MB and a broad range of other pediatric cancers.
Citation Format: Carolina Nor, Mark Bray, Tak Mak, Michael Taylor. PLK4 is a rational target for very high-risk medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3174.