bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1941: Cell surface vimentin is a novel marker for CTC detection in neuroblastoma
Authors: Batth Izhar S. , Li Heming , Sholler Giselle Saulnier , Li Shulin 
Published: July 2017

Abstract
Among children in the United States, brain cancers now account for most number of cancer-related deaths. Neuroblastomas (NB) and sarcomas account for 13% of all childhood cancers in the United States. Despite significant progress yielding increased 5-year survival, 1250 deaths are expected this year from childhood cancers and cancer incidence has been steadily increasing. One of the key contributors to cancer mortality is tumor metastasis. It is generally believed that CTCs are shed into the circulation from primary tumors and contain unique driver mutations enabling their aggressive phenotype. However, detection of CTCs from NB is difficult as there is no direct method. Our lab has developed a monoclonal antibody targeting vimentin on the cells’ surface. Cell surface vimentin (CSV) is only observed in tumor cells; it remains intracellular in normal cells. We have published data demonstrating the superior specificity and sensitivity of our approach in breast, colon, and prostate cancer. Here, we report direct CTC detection in NB using our CSV mAb. As part of our collaborative effort analyzing NB blood samples from a multicenter Phase II trial, we present novel discoveries regarding treatment of NB with difluoromethylornithine (DFMO) and its effects on CTC release into the circulation in patients under remission. Among our observations, approximately ~1/3 patients have low or no CTCs while ~1/4 with high numbers of CTC are responding to DFMO treatment. Remaining patients show oscillating CTC numbers. Further, treatment with DFMO showed a statistically significant decline in CTCs after the beginning of therapy. Ongoing work including whole genome analysis can possibly reveal new insight into CTCs’ entering the circulation. These data demonstrate that our CTC capture using CSV is a novel and unique approach for detection in NB.
Citation Format: Izhar S. Batth, Heming Li, Giselle Saulnier Sholler, Shulin Li. Cell surface vimentin is a novel marker for CTC detection in neuroblastoma [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 1941. doi:10.1158/1538-7445.AM2017-1941
Abstract 1957: Molecular pathogenesis and drug synergism in a zebrafish model of high risk neuroblastoma
Authors: He Shuning , Mansour Marc R. , Zimmerman Mark W. , Layden Hillary M. , Look A. Thomas 
Published: July 2017

Abstract
We have developed a transgenic zebrafish model that overexpresses MYCN and harbors loss-of-function mutations of the nf1 tumor suppressor. In this model, loss of nf1 leads to aberrant activation of RAS-MAPK signaling, promoting both increased tumor cell survival and rapid tumor cell proliferation. These neuroblastomas are very aggressive in that almost all of the fish develop neuroblastoma by 3 weeks of age. Three-week old juvenile fish are very small, making it feasible to test the effectiveness of many drugs and drug combinations in vivo for activity against the primary tumors. We demonstrate these advantages of the model by showing marked synergistic anti-tumor effects of a MEK inhibitor (trametinib) and a retinoid (isotretinoin) in vivo at several different dosage combinations by in vivo isobologram analysis. Thus, inhibition of RAS-MAPK signaling can significantly improve the treatment of this very aggressive form of neuroblastoma when it is combined with the inhibition of other key pathways. Because of the very high penetrance and rapid onset of neuroblastoma in our nf1-deficient, MYCN-transgenic zebrafish model, it is one of the only model systems in which extensive analysis of the synergistic activity of two or more drugs can be evaluated in primary tumors in vivo. This capability is especially valuable given that mutations causing RAS-MAPK pathway hyperactivation have been shown to arise frequently at the time of relapse of childhood neuroblastomas, indicating the need to eliminate these mutated tumor cells as a component of the primary treatment.
Note: This abstract was not presented at the meeting.
Citation Format: Shuning He, Marc R. Mansour, Mark W. Zimmerman, Hillary M. Layden, A. Thomas Look. Molecular pathogenesis and drug synergism in a zebrafish model of high risk neuroblastoma [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 1957. doi:10.1158/1538-7445.AM2017-1957
Abstract 197: Anti-cancer activity of extract from the Jamaican round-leaf yellow yam (RLY2) (Dioscorea cayenensis)
Authors: Wright Sasha-Gay A. , Gray Wesley G. , Asemota Helen 
Published: July 2017

Abstract
The Jamaican Round-Leaf yellow yams (RLY2), Dioscorea cayenensis, are edible tubers, bulbils or rhizomes that are of considerable economic value and possess several health benefits. These RLY2 are a rich source of anti-oxidants, vitamins and phytochemicals. In addition to its nutritional value, the Jamaican populace regards RLY2 as an herbal medicine useful in treatment of diabetes mellitus, hypertension and certain kind of cancers. Chemical analysis of RLY2 revealed the presence of a myriad of bioactive ingredients that are likely to be lost due to the method of preparation for consumption. Thus, we hypothesized that mild extraction of RLY2 will preserved the bioactive analytes that give RLY2 its anti-cancer property. To test this hypothesis, different ethanolic extracts of RLY2 were prepared, and their bioactivity demonstrated in two models of prostate cancer. The present study demonstrates dosage and time-dependence inhibition in both the androgen sensitive LNCaP and androgen insensitive DU-145 prostate cancer cell lines. We observed that DU-145 was three-times more sensitive to RLY2 ethanol extract than LNCaP. Growth of LNCaP for 3-days with varying concentration of RLY2 ethanol extract resulted in an IC50 of 750 ppm (95% C.I. 726-791ppm), whereas DU-145 resulted in an IC 50 of 250 ppm (95% C.I. 236-281ppm). The maximum growth inhibition by RLY2 extract occurs within twenty-four hours for both LNCaP and DU-145 with no significant changes after 5-days. To determine the mechanism of toxicity by RLY2, we induced both LNCaP and DU-145 with RLY2 for 0-24h and prepared cells for flow cytometer analysis. The effect of RLY2 on cell cycle and degree of apoptosis will be discussed. Our data indicated that the ethanol extract of RLY2 was more sensitive toward androgen-insensitive prostate cancer. Thus, this study suggests that RLY2 contain bioactive chemical that may be used in grade II prostate adenocarcinoma represented by the DU-145 phenotype.
Citation Format: Sasha-Gay A. Wright, Wesley G. Gray, Helen Asemota. Anti-cancer activity of extract from the Jamaican round-leaf yellow yam (RLY2) (Dioscorea cayenensis) [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 197. doi:10.1158/1538-7445.AM2017-197
Abstract 1975: FAM83B: A novel regulator of cell plasticity in breast cancer
Authors: Bartel Courtney A. , Junk Damian J. , Jackson Mark W. 
Published: July 2017

Abstract
Epithelial to mesenchymal transition (EMT) is an important process in both metastasis and cancer stem cell (CSC) enrichment. Recent studies suggest that instead of simply transitioning from one cell state to another, cancer cells exist along a continuum of epithelial and mesenchymal cell states. Identifying novel regulators of tumor cell plasticity will be critical to fully understand this continuum and to target metastasis and CSC phenotypes in the future. FAM83B is a novel oncogene identified by the Jackson Laboratory in a forward genetic screen for drivers of Human Mammary Epithelial Cell (HMEC) transformation. Previous work showed that FAM83B expression is elevated in triple negative breast cancers and that FAM83B also activates key cell signaling pathways (EGFR, MAPK, and PI3K) in breast cancers. Here, we implicate FAM83B as a novel regulator of epithelial-mesenchymal plasticity using a HMEC transformation model. Transformation of primary HMEC by expressing shp16, shp53, c-Myc, and RAS results in the generation of two distinct transformed cell populations. One population retains epithelial characteristics, while an emergent population spontaneously acquires a mesenchymal morphology and a CD24LOCD44HI (CSC) cell surface marker profile. Moreover, isolation of epithelial, CD24HICD44LO cells (non-CSC) and exposure to Oncostatin M (OSM), an EMT-inducing cytokine, can also generate cells with a mesenchymal/CSC phenotype. Interestingly, FAM83B expression was significantly elevated in the epithelial/non-CSC population compared to the mesenchymal/CSC population. Moreover, treatment of purified epithelial/non-CSC cells with OSM resulted in decreased FAM83B expression levels, indicating FAM83B expression is suppressed as the cells move through EMT. FAM83B expression also correlated with an epithelial phenotype in a panel of breast cancer cell lines. shRNA-mediated knock-down of FAM83B from epithelial/non-CSC resulted in increased spontaneous EMT, concomitant with elevated expression of the mesenchymal marker Vimentin and master EMT transcription factor Zeb1. Following treatment with OSM, sh83B cells maintain prolonged, elevated p-Stat3 and p-ERK signaling, known contributors to the mesenchymal/CSC phenotype. Conversely, OSM-induced EMT was blunted in epithelial/non-CSC expressing exogenous FAM83B. Thus, FAM83B expression is a determinant in maintaining an epithelial phenotype, while suppression of FAM83B is important during EMT. Future work will seek to define novel FAM83B-mediated signaling pathways important for regulating cellular plasticity.
Citation Format: Courtney A. Bartel, Damian J. Junk, Mark W. Jackson. FAM83B: A novel regulator of cell plasticity in breast 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 1975. doi:10.1158/1538-7445.AM2017-1975
Abstract 1978: Identification of the metastatic cell populations in a spontaneous mouse model of melanoma
Authors: Li Xiaoshuang , Torres Raul , Kos Lidia 
Published: July 2017

Abstract
Melanoma is the deadliest form of skin cancer due to its high propensity to metastasize and resistance to current therapies. We have created a spontaneous mouse model of metastatic melanoma (Dct-Grm1/K5-Edn3) where metastasis to the lungs is 80% penetrant. The primary tumors of these mice present cellular heterogeneity with cells at varying levels of differentiation. The main goal of this study is to determine the metastatic potential of the primary tumor resident Tyrosinase positive cells and evaluate the dynamic pattern of gene expression as those cells move from the primary tumors to the sites of metastasis. To accomplish this aim we crossed the Dct-Grm1/K5-Edn3 mice to CreERT2/ ROSAmT/mG mice to indelibly label Tyrosinase cell populations within the primary tumor by topical application of 4-hydroxytamoxifen at the tumor site. In vivo lineage tracing and characterization of those labeled cells was performed in the metastatic lesions. We found that Tyrosinase positive cells enter the circulation before the appearance of any noticeable tumor or nevus and establish close interactions with the vasculature as single cells. Metastatic cells in close association with the inner wall of the vasculature lose pigmentation and do not express melanocytic markers. Interestingly, those intravascular cells mimic endothelial cell properties with the expression of platelet endothelial cell adhesion molecule (PECAM-1, also known as CD31). In the lung tissue, the primary tumor derived Tyrosinase positive cells or their progeny can survive and establish successful metastases with pigmentation. This in vivo lineage tracing system in mouse will be a powerful model to evaluate and help us understand the etiology and pathogenesis of melanoma metastasis. Further characterization of those more aggressive cells in melanoma will allow for the development of new prognostic tests and novel therapeutic strategies to eliminate metastasis.
Citation Format: Xiaoshuang Li, Raul Torres, Lidia Kos. Identification of the metastatic cell populations in a spontaneous mouse model of melanoma [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 1978. doi:10.1158/1538-7445.AM2017-1978
Abstract 1981: Tissue-engineered bone for longitudinal intravital microscopy of solid tumor growth and therapy response
Authors: Dondossola Eleonora , Alexander Stephanie , Holzapfel Boris , Logothetis Christopher J. , Hutmacher Dietmar W. , Friedl Peter 
Published: July 2017

Abstract
Bone metastases are the initial site of progression and account for many of the complications experienced by men with metastatic prostate cancer (PCa), including therapy resistance. Besides cell intrinsic mechanisms, the interaction between PCa cells and the bone microenvironment critically contributes to lesion expansion and drug sensitivity. We here developed a mouse model amenable to intravital multiphoton microscopy (iMPM) to longitudinally study PCa-stromal cell interactions and therapy response in a partially humanized neobone, established in the dermis of the mouse. Tissue engineered bone constructs, TEBCs, were generated by functionalizing polymeric polycaprolactone scaffolds with human mesenchymal stem cells (hMSCs) differentiated to osteoblasts followed by cell-derived calcification of the inter-scaffold space. 30 days after implantation of functionalized scaffolds under the skin of the mouse, bone and bone marrow maturation resulted in a 30mm3 cavity surrounded by optically transparent cortical bone of 50-60 μm thickness, as monitored by microCT and iMPM. Intra-bone tumor growth and osteolysis dynamics caused by human fluorescent PCa cells (PC3) were three-dimensionally reconstructed by multi-parameter detection through a body window, including collagen and bone matrix (SHG), calcified bone (fluorescent bisphosphonates), osteoclasts (cathepsin K), bone surface (THG), blood vessels and stromal phagocytes (fluorescent dextran), and PC3 cells (nuclear H2B/eGFP, cytoplasmatic DsRed2). As a proof of concept, the efficacy to halt bone remodeling during bisphosphonate therapy was detected, revealing the composition and kinetics of the bone-tumor interface. Combining engineered neobone with an optical window is suited to detail the 3D organization and dynamics of cancer lesions in bone and provides mechanistic insight and efficacy predictions for therapy response. Thus, this strategy will be implied to dissect the therapeutic effect of radium 223, a radioisotope with bone seeking properties, and the first agent that improves the duration and quality of life of advanced metastatic PCa patients. By using this model we will test the hypothesis that 223Ra alters stromal niches, structurally and molecularly, in a manner that accounts for the clinical observations in established macroscopic lesions.
Citation Format: Eleonora Dondossola, Stephanie Alexander, Boris Holzapfel, Christopher J. Logothetis, Dietmar W. Hutmacher, Peter Friedl. Tissue-engineered bone for longitudinal intravital microscopy of solid tumor growth and therapy response [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 1981. doi:10.1158/1538-7445.AM2017-1981
Abstract 1985: Tbk1 loss in pancreatic cancer leads to changes in epithelial plasticity
Authors: Burton Victoria Haley , Brekken Rolf A. , Gross Melissa , Bremauntz Alberto 
Published: July 2017

Abstract
Effective therapies are needed to enhance the long-term survival of patients with pancreatic ductal adenocarcinoma (PDA), which is the fourth leading cause of cancer-related deaths in the United States and eighth worldwide. Initial stages of PDA are commonly characterized by an activating mutation in K-RAS, yet direct inhibition of K-RAS through pharmacological means remains a challenge. Higher levels of TANK Binding Kinase 1 (TBK1) mRNA, a critical downstream effector of mutant active K-RAS in lung cancer, are associated with poorer overall survival in a cohort of human PDA patients. We hypothesize that TBK1 is also an effective mediator of K-RAS driven pancreatic cancer.
Here we report that TBK1 is expressed and more active in human PDA cell lines relative to immortalized pancreatic epithelial lines (HPNE) and fibroblasts. We found that human PDA cell lines are sensitive to a small molecule inhibitor of TBK1 in the low micromolar range. Further mice engineered to express a mutant kinase dead form of TBK1 (Tbk1Δ/Δ) are viable and fertile yet display smaller tumors at early time points in a genetically engineered mouse model of PDA. Interestingly, tumors from Tbk1Δ/Δ: PDA mice are more epithelial in gene expression and show significantly less collagen deposition compared to Tbk1+/+: PDA tumors. Additionally, cell lines isolated from Tbk1Δ/Δ: PDA tumors are more epithelial in morphology and less migratory and invasive relative to Tbk1+/+: PDA cell lines. Current work is focused on delineating the functional contribution of TBK1 to tumor cell motility in vivo as well as mechanistic understanding of the epithelial phenotype in Tbk1Δ/Δ: PDA tumors. These results will further our understanding of Ras signaling in pancreatic cancer and are critical for exploring a new avenue of targeted therapy.
Citation Format: Victoria Haley Burton, Rolf A. Brekken, Melissa Gross, Alberto Bremauntz. Tbk1 loss in pancreatic cancer leads to changes in epithelial plasticity [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 1985. doi:10.1158/1538-7445.AM2017-1985
Abstract 1988: Exosome-mediated ovarian cancer tumorigenesis mediated by miR1246/Rb/Cav1 axis
Authors: Kanlikilicer Pinar , Bayraktar Recep , Rashed Mohammed , Aslan Burcu , Calin George A. , Sood Anil K. , Lopez-Berestein Gabriel 
Published: July 2017

Abstract
Exosomes are secreted from many cell types and play an important role in the tumor microenvironment. The most impressive breakthrough in exosomes research was that they contain the genetic material of the host cell. However, whether cancer cells use their exosomes to transfer their oncogenic material to recipient cells, or to get rid of their tumor suppressor material is not well understood. We previously identified that miR-1246 was hundreds of folds higher expressed in six different ovarian cancer exosomes compared to their originating cells. Here, we showed that miR-1246 co-localized in the exosomes in ovarian cancer cells. miR-1246 act as an oncogenic miRNA and the levels were elevated in ovarian cancer patients compared to health donors. We also demonstrated that miR-1246 inhibitor treatment in combination with paclitaxel was significantly inhibited tumor burden in SKOV3-ip1 orthotopic ovarian cancer model. Our results suggest that miR-1246 inhibited RB tumor suppressor protein and regulate Cav-1 and platelet-derived growth factor receptor beta precursor signaling in ovarian cancer. In addition Inhibiting miR-1246 led a significant decrease in exosome release. Together, our findings provide strong evidence that oncogenic miR-1246 can be targeted as a potential novel therapeutic approach in the treatment of ovarian cancer.
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Note: This abstract was not presented at the meeting.
Citation Format: Pinar Kanlikilicer, Recep Bayraktar, Mohammed Rashed, Burcu Aslan, George A. Calin, Anil K. Sood, Gabriel Lopez-Berestein. Exosome-mediated ovarian cancer tumorigenesis mediated by miR1246/Rb/Cav1 axis [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 1988. doi:10.1158/1538-7445.AM2017-1988
Abstract 1990: Single cell co-expression profiles of immunotherapy targets in the tumor microenvironment of NSCLC samples
Authors: Kim Jeffrey , Su Nan , Ma Xiao-Jun , Park Emily 
Published: July 2017

Abstract
Cancer immunotherapies have made great strides in recent years, yet identifying key molecules in the tumor microenvironment is necessary to develop improved approaches to achieve more durable responses in a greater number of patients. Obstacles such as adaptive resistance to individual checkpoint marker blockade, such as PD1 and CTLA4, have led researchers down the path of pursuing multiple immune targets that may be upregulated on the same lymphocyte as a consequence of mono-antibody therapies. While several clinical trials taking a combinatorial approach are currently in progress, including targeting multiple checkpoint markers, it is clear that these new strategies may rely on the pre-existing immune system, regardless of being treatment naïve or previously treated. The challenge now is to identify the relevant biomarkers and to stratify patients to provide the most appropriate treatment. As a proof of concept, here we evaluate single cell co-expression profiles of key therapeutic targets in archived tissues of non-small cell lung cancer (NSCLC) samples using the RNAscope® Duplex Assay, an advanced in situ hybridization platform that allows for the visualization of single cell gene expression of mRNA targets directly in tissue.
In our investigation of 60 archived formalin-fixed paraffin embedded NSCLC tissues, co-expression profiles of PD1 or PD-L1 coupled with another therapeutic target (IDO1, LAG3, 4-1BB, GITR, and TIM3) were assessed, bringing to light substantial variations in the tumor microenvironment between tissue samples. These marked differences of co-expressed targets on tumor infiltrating lymphocytes were scrutinized through quantitative image analysis to further reveal both the diversity and degree of individuality between tissue samples. Quantitatively measuring the expression of multiple targets in single cells within intact tissues exposed the distinct milieu of targetable therapeutic molecules, leading to the potential identification of responsive tumors which could help guide in stratifying patients for different combinatorial approaches.
Citation Format: Jeffrey Kim, Nan Su, Xiao-Jun Ma, Emily Park. Single cell co-expression profiles of immunotherapy targets in the tumor microenvironment of NSCLC samples [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 1990. doi:10.1158/1538-7445.AM2017-1990