bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 969: Tunneling nanotubes, a novel mode of tumor cell-macrophage communication in tumor cell invasion
Authors: Hanna Samer , McCoy-Simandle Kessler , Leung Edison , Condeelis John , Cox Dianne 
Published: August 2018

Abstract
The interaction between tumor cells and macrophages is crucial in promoting tumor invasion and metastasis. These two cell types are engaged in a mutual interaction in which tumor-associated macrophages produce epidermal growth factor (EGF) to activate tumor cells. In turn, tumor cells produce colony-stimulating factor-1 (CSF-1) that stimulates macrophages. The tumor cell - macrophage pairs formed in response to this paracrine signaling are then attracted toward blood vessels under an endothelial cell produced HGF gradient. This mutual signaling interaction leads to the co-migration and invasion of both cell types as imaged both in vitro and in vivo. . Recent studies have revealed an additional novel mechanism of intercellular communication between macrophages that can transmit signals over long distances through membranous actin-based tunneling nanotubes (TNTs). Our data demonstrates that heterotypic TNTs form between macrophages and tumor cells in co-culture. This novel interaction induced changes in tumor cell morphology consistent with a more invasive phenotype which was dependent on EGF-EGFR signaling. Moreover, the presence of these heterotypic TNTs was important for tumor cell invasion in an in vitro 3D invasion assay. Furthermore, reduction of M-Sec (TNFAIP2) in macrophages, a protein involved in TNT formation, inhibited tumor cell elongation and blocked the ability of tumor cells to invade. Using a modified 1D assay that mimics macrophage-dependent tumor cell streaming observed in vivo, we show a significant increase in long distance directional migration of tumor cells towards an endothelial-coated bead in a TNT dependent manner. We also employed an in vivo zebrafish model that recreates macrophage mediated tumor cell invasion in a more physiological fashion. The presence of macrophages increased tumor spread from the injection site, number of metastatic foci, and the distance of metastatic spread in a macrophage TNT-dependent manner. Overall, our studies support a role for TNTs as a novel means of interaction between tumor cells and macrophages that may lead to tumor progression and metastasis.
Citation Format: Samer Hanna, Kessler McCoy-Simandle, Edison Leung, John Condeelis, Dianne Cox. Tunneling nanotubes, a novel mode of tumor cell-macrophage communication in tumor cell 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 969.
Abstract 971: Three-dimensional gene regulatory landscapes in normal and cancer cells
Authors: Abraham Brian J. , Guo Yang Eric , Hnisz Denes , Li Charles H. , Weintraub Abraham S. , Day Daniel S. , Schuijers Jurian , Lee Tong Ihn , Young Richard A. 
Published: August 2018

Abstract
Key oncogenes can be misregulated in tumor cells by the acquisition of tumor-specific enhancers that direct gene expression through physical contacts (1,2). Identifying the full complement of enhancers regulating each oncogene could identify additional vulnerabilities in tumor expression programs, but remains challenging, because a given enhancer can regulate multiple genes and each of its targets may be genomically distant. Here we use DNA interaction data to construct gene regulatory landscapes for all expressed genes in a tumor cell and demonstrate that sets of enhancers can be assigned to these oncogenes using direct looping and insulated neighborhood data. A subset of these landscapes contains an exceptional amount of transcriptional apparatus, reminiscent of SEs (3), so we term this subset 3D-SEs. Well-characterized oncogenes, including c-Myc, acquire 3D-SEs in tumor cells where a c-Myc¬-associated linear SE was not identified, suggesting SE acquisition by c-Myc and other oncogenes has been underestimated. Each gene's regulatory network can also surprisingly extend beyond the confines of insulated neighborhoods and incorporate additional distal enhancers. Visualizing instances of 3D-SEs with microscopy demonstrates that they are components of liquid-liquid phase-separated bodies in cells, suggesting gene regulatory landscapes underpin these transcriptional condensates. The interactions comprising gene regulatory networks and their target genes thus extend previous interpretations of the targets of enhancers, signaling pathways, and disease-associated enhancer variants.
References: 1. Hnisz, Abraham, Lee, et al. and Young, Cell 2013. 2. Mansour, Abraham, et al. and Young and Look, Science 2014. 3. Whyte, Orlando, Hnisz, Abraham, et al. and Young, Cell 2013.
Citation Format: Brian J. Abraham, Yang Eric Guo, Denes Hnisz, Charles H. Li, Abraham S. Weintraub, Daniel S. Day, Jurian Schuijers, Tong Ihn Lee, Richard A. Young. Three-dimensional gene regulatory landscapes in normal and cancer cells [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 971.
Abstract 993: Wnt-er is coming: WNT5A promotes a slow cycling phenotype via p53 in conditions of stress
Authors: Webster Marie R. , Fane Mitchell , Kaur Amanpreet , Alicea Gretchen , Ecker Brett L. , Ndoye Abibatou , Kugel Curtis , Basu Subhasree , Valiga Alexander , Appleton Jessica L. , Murphy Maureen E. , Weeraratna Ashani 
Published: August 2018

Abstract
Resistance to targeted therapy and chemotherapy increases with age. Previously, we found that aged skin fibroblasts secrete sFRP2, which decreases ß-catenin, MITF, and APE1 in melanoma cells, and promotes invasion. Loss of APE1, a key redox effector, increased DNA damage in melanoma cells and caused the cells to become resistant to targeted therapy. Here we show that the aging tumor microenvironment drives a slow cycling phenotype in melanoma cells via WNT5A and p53. We found WNT5A expression in melanoma cells correlates with p53 expression and a higher percent of slow cycling cells. Knocking down WNT5A decreases both p53 expression and the percent of slow cycling cells. When we isolated slow cycling cells by flow cytometry, we found that they have increased WNT5A, p53, and p21 expression. Analysis of patient tumors in the TCGA data base revealed that patients with higher than average p53 expression, also express WNT5A. To determine if WNT5A and p53 may be promoting the survival of metastatic melanoma in an aged microenvironment, we examined tumors from young and aged C57/BL6 mice generated using Yumm1.7 cells. We found that tumors in aged mice have a higher percentage of cells expressing p53 and increased WNT5A expression compared to tumors in young mice. Treatment of human melanoma cells with conditioned media from aged dermal fibroblasts decreases proliferation and increases the percent of slow cycling. Inhibition of p53 re-sensitizes human melanoma cells in conditioned media from aged fibroblasts to combination BRAFi/MEKi. These data suggest, it may be these slow cycling cells driven by WNT5A and p53, which are enriched in an aging microenvironment, that are driving resistance to targeted therapy in aged patients.
Citation Format: Marie R. Webster, Mitchell Fane, Amanpreet Kaur, Gretchen Alicea, Brett L. Ecker, Abibatou Ndoye, Curtis Kugel, Subhasree Basu, Alexander Valiga, Jessica L. Appleton, Maureen E. Murphy, Ashani Weeraratna. Wnt-er is coming: WNT5A promotes a slow cycling phenotype via p53 in conditions of stress [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 993.
Abstract 994: Cancer cells induce a protumorigenic senescent phenotype in fibroblasts through MMP1 but not autophagy in large cell carcinoma of the lung
Authors: Alcaraz Jordi , Gabasa Marta , Ikemori Rafael , Reguart Noemí , Radisky Evette , Radisky Derek 
Published: August 2018

Abstract
Large cell carcinoma (LCC) is among the most aggressive histologic subtypes of non-small cell lung cancer, but the mechanisms underlying such aggressive nature remain unknown. We recently showed that fibroblasts from LCC patients exhibit premature senescence in vitro, and that co-culturing LCC cells (but not cancer cells from other lung cancer subtypes) with normal fibroblasts in transwells is sufficient to induce senescence in the latter in an oxidative stress-dependent manner, supporting that fibroblast senescence is induced by a secreted factor(s) from LCC cells. Remarkably, we also found that senescent fibroblasts secrete factors that stimulate the growth and invasion of LCC cells beyond the stimulation elicited by nonsenescent fibroblasts, revealing that fibroblast senescence may contribute to the aggressive nature of LCC. Whole-genome transcriptional profiling of a panel of lung cancer cell lines identified MMP1 among the genes with larger expression in LCC compared to other lung cancer subtypes. Since MMPs can induce oxidative stress, we examined whether the excessive MMP1 expression in LCC cells was involved in the induction of fibroblast senescence in co-cultures. Knocking down MMP1 in LCC cells was sufficient to abrogate fibroblast senescence in co-cultures as well as the growth and invasion enhancement elicited by the conditioned medium of fibroblasts in LCC cells. In contrast, autophagy, which has been previously associated with fibroblast senescence in breast cancer, was not upregulated in fibroblasts upon co-culture with LCC cells. These results support that the selective aberrant expression of MMP1 in LCC cells plays a major role in their ability to induce a protumorigenic senescent phenotype in adjacent fibroblasts through a mechanism that is independent of autophagy. Moreover, our observations identify MMP1 as a potential therapeutic target against the aberrant cancer cell-fibroblast crosstalk in LCC.
Citation Format: Jordi Alcaraz, Marta Gabasa, Rafael Ikemori, Noemí Reguart, Evette Radisky, Derek Radisky. Cancer cells induce a protumorigenic senescent phenotype in fibroblasts through MMP1 but not autophagy in large cell carcinoma of the lung [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 994.
Abstract CT017: Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients
Authors: Rodriguez-Ruiz Maria E. , Perez-Gracia Jose L. , Rodriguez Inmaculada , Alfaro Carlos , Gil-Bazo Ignacio , Gurpide Alfonso , Salazar Andres , Melero Ignacio 
Published: August 2018

Abstract
BACKGROUND: Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local injections of dsRNA analogues (mimicking viral RNA) and repeated vaccinations with tumor-lysate loaded dendritic cells shows efficacy against colon cancer mouse models. In the context of immunotherapy, radiotherapy can exert beneficial abscopal effects on distant non-irradiated lesions.
PATIENTS AND METHODS: In this pilot phase I study, 15 advanced cancer patients received two 4-week cycles of four intradermal daily doses of monocyte-derived dendritic cells preloaded with autologous tumor lysate and matured for 24h with poly-ICLC (Hiltonol), TNF-α and IFN-α. On days +8 and +10 of each cycle, patients received intratumoral image-guided 0.25 mg injections of the dsRNA-analogue Hiltonol. Cyclophosphamide 600 mg/m2 was administered one week before each cycle. Six patients received stereotactic ablative radiotherapy (SABR) on selected tumor lesions, including those injected with Hiltonol. Expression of 25 immune-relevant genes was sequentially monitored by RT-PCR on circulating PBMCs and serum concentrations of a cytokine panel were sequentially determined before and during treatment.
RESULTS: Combined treatment was feasible, safe and well tolerated, without grade 3-4 adverse events. One heavily pretreated castration-resistant prostate cancer patient experienced a remarkable mixed abscopal response to SABR and combined treatment. No objective responses were observed, while nine patients (Disease control rate=71%) presented stable disease (five in the six-patient radiotherapy cohort). Intratumoral Hiltonol increased IFN-β and IFN-α mRNA in circulating PBMC. Dendritic-cell vaccination increased serum IL-12 and IL-1β concentrations, especially in patients presenting stable disease.
CONCLUSIONS: This radio-immunotherapy combination strategy, aimed at resembling viral infection in tumor tissue in combination with a dendritic-cell vaccine and SABR, is safe and provides evidence of immune-associated activity and signs of preliminary clinical efficacy.
Citation Format: Maria E. Rodriguez-Ruiz, Jose L. Perez-Gracia, Inmaculada Rodriguez, Carlos Alfaro, Ignacio Gil-Bazo, Alfonso Gurpide, Andres Salazar, Ignacio Melero. Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients [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 CT017.
Abstract CT039: Cyclin E1 (CCNE1) expression associates with benefit from palbociclib in metastatic breast cancer (MBC) in the PALOMA3 trial
Authors: Turner Nicholas C. , Liu Yuan , Zhu Zhou , Loi Sherene , Colleoni Marco , Loibl Sibylle , DeMichele Angela , Harbeck Nadia , André Fabrice , Zhang Zhe , Giorgetti Carla , Bartlett Cynthia Huang , Cristofanilli Massimo 
Published: August 2018

Abstract
BACKGROUND: The CDK4/6 inhibitor palbociclib in combination with fulvestrant (F) improved progression-free survival (PFS) vs F alone in previously-treated MBC. Prior pre-clinical research, and the NeoPalAna window study, identified high CCNE1 expression as a potential palbociclib resistance marker. We conducted large panel gene expression analysis of baseline tumor tissue to identify biomarkers (BMs) that predicted the relative benefit of palbociclib.
METHODS: The PALOMA3 trial randomized 521 patients (pts) with endocrine-pretreated MBC to receive palbociclib + F or placebo (PBO) + F. All pts, except bone only or early relapse, provided FFPE tissue taken from recurrent disease. EdgeSeq Oncology BM Panel (HTG Molecular Diagnostics) was used for mRNA profiling, assessing 2534 cancer related genes. Primary objective was to evaluate the association of cell cycle pathway with palbociclib + F vs F alone treatment effect by using gene expression as a continuous variable or dichotomization by median level with Cox regression analysis.
RESULTS: 302 pts had tumor tissue analyzed (194/347 [56%] palbociclib + F; 108/174 [62%] PBO+F). The BM and overall populations had similar treatment effect. Benefit from palbociclib was greater in patients with low tumor CCNE1 expression (median PFS: palbociclib + F 14.1 mo vs PBO+F 4.8 mo, HR 0.32) than high tumor CCNE1 expression (palbociclib + F 7.6 mo vs PBO+F 4.0 mo; HR 0.85) (interaction p=0.0024). Similar results were observed with CCNE1 as a continuous variable (interaction p=0.0008). Expression levels of CDK4, CDK6, cyclin D1 and RB1 did not associate with benefit from palbociclib, and both luminal A and B tumors derived benefit from palbociclib. In exploratory analysis, high E2F-regulon expression predicted for relative resistance to palbociclib.
CONCLUSION: Higher expression of CCNE1 was associated with relative resistance to palbociclib, although all biomarker groups derived benefit from treatment. This data supports CDK2 as the key bypass kinase of CDK4/6 inhibition, and potential to target CDK2 to subvert resistance. Sponsor: Pfizer
Citation Format: Nicholas C. Turner, Yuan Liu, Zhou Zhu, Sherene Loi, Marco Colleoni, Sibylle Loibl, Angela DeMichele, Nadia Harbeck, Fabrice André, Zhe Zhang, Carla Giorgetti, Cynthia Huang Bartlett, Massimo Cristofanilli. Cyclin E1 (CCNE1) expression associates with benefit from palbociclib in metastatic breast cancer (MBC) in the PALOMA3 trial [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 CT039.
Abstract CT084: HEPANOVA: A phase II trial of tumor treating fields concomitant with sorafenib for advanced hepatocellular carcinoma
Authors: Grosu Anca-Ligia , Strouthos Josif , Brunner Thomas , Weinberg Uri 
Published: August 2018

Abstract
Tumor Treating Fields (TTFields) are a non-invasive, regional antimitotic treatment modality, which has been approved for the treatment of glioblastoma by the FDA. TTFields predominantly act by disrupting the formation of the mitotic spindle during metaphase. TTFields were effective in multiple preclinical models of hepatocellular carcinoma (HCC), leading to a significant increase in cell death. The Phase 2 HEPANOVA study is the first trial testing TTFields in HCC patients, and is designed to test the safety and efficacy of adding TTFields to sorafenib in advanced HCC.
Trial Design: Patients (N=25) with unresectable HCC who are not amenable to any local treatment will be enrolled in this prospective, single-arm study. The study enrolls patients with ECOG score of 0-2 and Barcelona clinic liver cancer (BCLC) stage 0-C. Patients must have a measurable disease per RECIST Criteria. Having implanted electronic devices in the torso is exclusionary. Sorafenib will be administered at standard dose (400 mg daily). TTFields (150kHz) will be deilvered for 18 hours/day until local disease progression per RECIST Criteria. Clinical follow up will be performed q4w, and a CT/MRI scan q12w. Following disease progression in the liver, patients will discontinue TTFields and be followed monthly for survival. Overall response rate will be the primary endpoint and in-field control rate, progression-free survival rate at 12 month (PFS12), OS rate at 1 year and toxicity will all be secondary endpoints. Sample size was calculated using an Exact test for proportions considering the weighted average of ORR of patients who had either complete or partial response per RECIST criteria in historical studies with sorafenib is 4.5%. A sample size of 25 patients was required to achieve a power of approximately 80% at a one-sided alpha level of 0.05 using a single sample Exact test for proportions.
Citation Format: Anca-Ligia Grosu, Josif Strouthos, Thomas Brunner, Uri Weinberg. HEPANOVA: A phase II trial of tumor treating fields concomitant with sorafenib for advanced hepatocellular carcinoma [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 CT084.
Abstract CT108: Tumor treating fields (TTFields) in combination with Lomustine (CCNU) in the EF-14 phase III clinical study: A safety analysis
Authors: Kinzel Adrian , Lavy-Shahaf Gitit , Kirson Eilon D 
Published: August 2018

Abstract
Introduction:
TTFields are low intensity (1-3V/cm), intermediate frequency (100-300 KHz) alternating electrical fields for the treatment of solid tumors. In the EF-14 phase 3 study, TTFields showed a significant overall and progression-free survival benefit for patients with newly diagnosed glioblastoma (GBM), in combination with Temozolomide (TMZ) (OS from randomization 20.9 vs. 16.0 months, p-value&lt;0.001). The OS and PFS benefit of TTFields was seen in all patient subgroups, and was independent of MGMT promotor methylation-status, age, performance status and gender. TTFields were not associated with additional systemic toxicity. At recurrence, patients were allowed to continue TTFields with second line therapies. Here, we analyzed the safety data of TTFields + lomustine (CCNU) to evaluate the safety and feasibility of this combination.
Methods:
Patients in the EF-14 trial received TTFields until second progression, or for 24 months. Change in chemotherapy regimen was allowed in both groups after tumor progression. We compared the patients who received lomustine as second-line chemotherapy in combination with TTFields (n=134) to the patients who received lomustine as monotherapy after first progression (n=39). We compared baseline characteristics and the adverse event profile between the two groups.
Results:
Baseline characteristics were well balanced between both groups except for less female patients in the lomustine only group (7.7% vs. 22.4%). Median age in the TTFields/lomustine group was 55.5 years (29-83) compared to 50.0 years (19-71) for lomustine alone. The addition of TTFields to lomustine therapy was not associated with any significant increase in rates of systemic adverse events compared to lomustine therapy alone (number of patients with &gt; 1 SAE 30 % vs. 31 %) and the distribution, severity and overall incidence of adverse events were not statistically different in patients in the two treatment groups.
Discussion:
The data show that the combination of TTFields and lomustine is a safe and feasible combination. This analysis emphasizes again the strong safety profile of TTFields and the high potential of combining TTFields with other therapy modalities. This data is especially important in light of the recently presented promising data from a small randomized trial that tested the combination of lomustine + TMZ in newly diagnosed (MGMT promotor-methylated only) GBM patients.
Citation Format: Adrian Kinzel, Gitit Lavy-Shahaf, Eilon D Kirson. Tumor treating fields (TTFields) in combination with Lomustine (CCNU) in the EF-14 phase III clinical study: A safety analysis [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 CT108.