bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4834: Circulating microRNA-762 promotes colorectal cancer proliferation and invasion by upregulating the Wnt-1/β-catenin pathway
Authors: Chen Ying-Yin , Lai Peng-Sheng , Chen Chung-Yu , Liao Hui-Fen 
Published: September 2020

Abstract
Background: A number of microRNAs (miRNAs) have been demonstrated to be associated with the diagnosis, progression and prognosis of colorectal cancer (CRC). However, the function of miRNA-762 (miR-762) in CRC remains unclear, and the molecular mechanisms underlying the effects of miR-762 in CRC require further investigation.
Methods: The circulating miRNAs from BALB/c mice with CRC CT26 cell implantation were assayed by microarray. Then, miR-762 mimic and inhibitor were transfected to CT26 cells for analysis of cell viability, invasion, and epithelial-mesenchymal transition (EMT), cell cycle, and regulatory molecule expression. Human subjects were included for comparison the circulating miR-762 levels in CRC patients and control donors, as well as the patients with and without distant metastasis.
Results: The screening for miRNA levels in mice with CRC cell implantation indicated that plasma miR-762 was upregulated. Transfection of miR-762 mimic to CT26 cells increased cell viability, invasion, and EMT, whereas transfection of miR-762 inhibitor decreased the above abilities. Western blot analysis showed that miR-762 mimic transfection upregulated the expression of Wnt-1 and β-catenin, as well as increased the nuclear translocation of β-catenin. Further analysis showed that serum miR-762 levels in CRC patients were higher than in control donors. Among the CRC patients (n = 20), six patients with distant metastasis showed higher serum miR-762 levels than the patients without distant metastasis.
Conclusions: Circulating miR-762 could promote CRC disease development and progression through the Wnt/β-catenin signaling. miR-762 might be used as a biomarker for CRC diagnosis and targeted therapy.
Citation Format: Ying-Yin Chen, Peng-Sheng Lai, Chung-Yu Chen, Hui-Fen Liao. Circulating microRNA-762 promotes colorectal cancer proliferation and invasion by upregulating the Wnt-1/β-catenin pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4834.
Abstract 4841: Functional genome-wide screening identifies triple-negative breast cancer cell cycle-dependent vulnerability driven by genomic gain of death effector domain-containing protein
Authors: Ni Yingjia , Schmidt Keon R. , Werner Barnes A. , Koenig Jenna K. , Guldner Ian H. , Schnepp Patricia M. , Tan Xuejuan , Jiang Lan , Host Misha , Sun Longhua , Howe Erin N. , Wu Junmin , Littlepage Laurie E. , Nakshatri Harikrishna , Zhang Siyuan 
Published: September 2020

Abstract
Triple-negative breast cancer (TNBC) persists as a clinical challenge, with targeted therapeutic options remaining limited for the subtype due to few targetable tumor-specific vulnerabilities. While basal-like TNBC tumors express epidermal growth factor receptor (EGFR), the target of multiple clinically efficacious therapies, TNBC showed little to no response to anti-EGFR therapy in clinical trials. Using a genome-wide synthetic lethal pooled barcoded shRNA screen, we identified Death Effector Domain-containing protein (DEDD), upregulated in over 60% of TNBC tumors, as a driver of mitogen-independent G1/S cell cycle transition in TNBC under EGFR inhibition. This cell cycle role of DEDD depends on cytoplasmic localization and is independent of nuclear DEDD, which maintains roles in apoptosis. Cytosolic DEDD promotes G1/S transition through direct interaction with Rb family proteins, encouraging their degradation. Further, DEDD interacts with heat shock 71kDa protein 8 (HSC70) to augment cyclin D1 expression and drive transition to S phase. These interactions of overexpressed cytosolic DEDD with the G1/S checkpoint mechanism present a vulnerability of TNBC to cell cycle inhibition. Frequent Rb-loss in TNBC has prevented clinical testing of CDK4/6 inhibitors in TNBC, however. Yet, we found TNBC with DEDD overexpression to be sensitive to a combination of CDK4/6 inhibitor and EGFR inhibitor in vitro and in vivo, independent of Rb status. This novel vulnerability presented by DEDD overexpression in TNBC suggests promising therapeutic potential for CDK4/6 inhibitor use in combinatorial regimens.
Citation Format: Yingjia Ni, Keon R. Schmidt, Barnes A. Werner, Jenna K. Koenig, Ian H. Guldner, Patricia M. Schnepp, Xuejuan Tan, Lan Jiang, Misha Host, Longhua Sun, Erin N. Howe, Junmin Wu, Laurie E. Littlepage, Harikrishna Nakshatri, Siyuan Zhang. Functional genome-wide screening identifies triple-negative breast cancer cell cycle-dependent vulnerability driven by genomic gain of death effector domain-containing protein [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4841.
Abstract 4858: Oncogenic HIPPO-YAP1: in vivo target validation of YAP1 in malignant mesothelioma
Authors: Calvet Loreley , Santos Odette Dos , Jean-Baptiste Véronique , Spanakis Emmanuel , Ruffin Yvette , Sanchez Isabelle , Mestadier Jessica , Soubigou Stéphane , Feteanu Sylvie , Picard Pascale , Boumaya Chagri , Pollard Jack , Dib Colette , Sidhu Sukhvinder , Debussche Laurent , Valtingojer Iris 
Published: September 2020

Abstract
Yes associated protein YAP1 (YAP1) is a cofactor of gene transcription and exerts its action through association with transcription factors from the TEAD family. Activity of YAP1-TEAD is tightly regulated by the HIPPO pathway and upon activation the expression of pro-survival and anti-apoptotic genes is induced. The HIPPO pathway consists of a series of Ser/Thr kinases, which lead to the phosphorylation of YAP1, and hence to its inactivation by either sequestration in the cytoplasm, or degradation. HIPPO pathway deletions and YAP1 activation are particularly prevalent (&gt; 60 %) in patients with malignant pleural mesothelioma. We use a malignant mesothelioma tumor cell line with a HIPPO deleted genetic background (MSTO-211H, LATS1 loss) to demonstrate, that downregulation of YAP1 leads to the inhibition of YAP1-dependent gene expression, the induction of apoptosis and the inhibition of cell growth in vitro. When these cell lines are grown as an in vivo subcutaneous xenograft in mice, downregulation of YAP1 leads to the inhibition of YAP1-dependent gene expression and eventually results in the regression of established tumors. This effect is specific to YAP1 activated mesothelioma models and is not observed in the HIPPO pathway independent HCT116 colon cancer model. We show here, that YAP1 activity alone is required for tumor maintenance in vivo in the context of HIPPO pathway genetic alterations, and thus confirm the relevance of this target for a drug discovery approach.
Citation Format: Loreley Calvet, Odette Dos Santos, Véronique Jean-Baptiste, Emmanuel Spanakis, Yvette Ruffin, Isabelle Sanchez, Jessica Mestadier, Stéphane Soubigou, Sylvie Feteanu, Pascale Picard, Chagri Boumaya, Jack Pollard, Colette Dib, Sukhvinder Sidhu, Laurent Debussche, Iris Valtingojer. Oncogenic HIPPO-YAP1: in vivo target validation of YAP1 in malignant mesothelioma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4858.
Abstract 4934: DCBLD2 mediated cisplatin-induced epithelial-to-mesenchymal transition and metastasis in non-small cell lung cancer
Authors: Chen Xiaosu , Lv Yajing , Huang Chongbiao , Xiang Rong 
Published: September 2020

Abstract
In clinical practice, we observed that many patients with solid tumors were diagnosed with early metastasis after chemotherapy, consistent with a large number of preclinical and clinical repots. However, the mechanism how chemotherapy induced tumor metastasis was seldomly reported. In this work, we found that cisplatin promoted epithelial-to-mesenchymal transition (EMT), cell motility and metastasis in non-small cell lung cancer (NSCLC). Moreover, we validated DCBLD2 was a key mediator in cisplatin-induced metastasis in NSCLC through an in vivo, genome-scale CRISPR/Cas9 activation screening. DCBLD2 was abnormally high-expressed in patients with NSCLC, in accordance with the analysis of TCGA database. The expression level of DCBLD2 was negatively correlated with the prognosis of NSCLC patients. Mechanically, DCBLD2 promoted EMT, cell migration in NSCLC cells and metastasis in a mouse xenograft models by binding to cytoskeletal proteins. In addition, we found that cisplatin played an essential role in promoting DCBLD2 expression. The ERK signaling pathway could be activated by cisplatin with phosphorylated, leading to the transcription factor FOS binding to the promoter region of DCBLD2, upregulating the expression of DCBLD2. In conclude, DCBLD2 was a contextual determinant of chemotherapy and metastatic in NSCLC and a potential target for anti-metastasis drugs.
Citation Format: Xiaosu Chen, Yajing Lv, Chongbiao Huang, Rong Xiang. DCBLD2 mediated cisplatin-induced epithelial-to-mesenchymal transition and metastasis in non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4934.
Abstract 4959: Targeting of the eukaryotic translation initiation factor 4A against breast cancer stemness
Authors: Sridharan Sangita , Robeson Megan , Bastihalli Diwakar Tukaramrao , Howard Cory , Subramaniyan Boopathi , Tilley Augustus , Raman Dayanidhi 
Published: September 2020

Abstract
Chemoresistance is a clinically significant issue in triple-negative breast cancer (TNBC) patients, leading to minimal residual disease. The surviving breast cancer stem cells (BCSCs) undergo multilineage differentiation and repopulate a more aggressive primary tumor leading to metastasis and subsequent mortality. Not only are BCSCs innately chemo/radioresistant but also contribute to therapy failure through interconversion between BCSCs and bulk tumor cells. Therefore, it is imperative to co-target BCSCs and bulk tumor cells simultaneously. Identifying novel molecular targets is key to eliminate both bulk tumor cells and BCSCs. The eukaryotic protein translation initiation machinery, the eIF4F complex, is a convergence point for many oncogenic signaling pathways. This complex plays a vital role in translation of many oncogenic mRNAs implicated in cell cycle, tumor progression, chemoresistance and metastasis. We have previously demonstrated that the mRNA helicase eIF4A1, of the eIF4F complex, might serve as a vulnerable node to kill TNBC cells. In the current study, we hypothesized that targeting of eIF4A1 would reduce/eliminate both bulk tumor cells and BCSCs and overcome chemoresistance. In order to evaluate the effects of targeting eIF4A1 in BCSCs, we isolated BCSCs based on aldehyde dehydrogenase activity and CD44 expression by Fluorescence Activated Cell Sorting and characterized for stemness. Through pharmacological targeting (Rocaglamide A) and genetic ablation (CRISPR-Cas9) of eIF4A1, we demonstrated that there was a statistically significant reduction in the self-renewal ability indicated by the reduction in primary and secondary mammosphere formation efficiency (MFE) of BCSCs, levels of the pluripotency transcription factors (SOX2, OCT4 and NANOG), expression of drug transporters (ABCG2, ABCB1 and ABCC1) and increased induction of apoptotic cell death. Overall, we demonstrated that targeting eIF4A1 is effective in eliminating BCSCs through reduction in the levels of stemness factors and drug transporters. This sets up a stage to employ small molecule inhibitors against eIF4A1 in co-targeting strategic therapies.
Citation Format: Sangita Sridharan, Megan Robeson, Diwakar Tukaramrao Bastihalli, Cory Howard, Boopathi Subramaniyan, Augustus Tilley, Dayanidhi Raman. Targeting of the eukaryotic translation initiation factor 4A against breast cancer stemness [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4959.
Abstract 5017: EphA2 is a clinically relevant target for breast cancer bone metastatic disease
Authors: Brantley-Sieders Dana M. 
Published: September 2020

Abstract
While advances in molecular targeted therapies have increased survival for breast cancer patients, outcomes for patients with metastatic disease remain poor. EphA2 receptor tyrosine kinase (RTK) is highly expressed in breast tumor cells across multiple molecular subtypes and correlates with poor patient prognosis. As metastasis of breast cancer to bone is a major cause of morbidity and mortality in patients, we investigated the role of EphA2 in this clinically relevant phenomenon. Analysis of human patient gene expression datasets and human breast-to-bone metastasis samples revealed high level ephA2 expression in bone lesions relative to other sites of metastatic dissemination, and EphA2 positive staining on breast tumor cells in bone metastatic lesions, respectively. EphA2 loss of function in tumor cells reduced tumor-induced osteolysis in two independent intratibial tumor engraftment models (4T1 and MDA-MB-231) as well as in an intracardiac experimental metastasis model (MDA-MB-231) in vivo. We observed a significant reduction in osteoclasts in animals harboring EphA2 loss of function tumors relative to control tumors. Further in vitro analyses revealed that blocking EphA2 function resulted in defective precursor maturation into functional osteoclasts through an interleukin-6 (IL-6) dependent mechanism. Pharmacologic inhibition of EphA2 decreased breast tumor induced osteolytic disease severity in vivo. Together, these data provide pre-clinical validation of EphA2 as a clinically relevant molecular target for breast cancer bone metastatic, osteolytic disease, warranting further investigation of molecular mechanisms that link EphA2 to tumor-induced osteolysis and eventual clinical development.
Citation Format: Dana M. Brantley-Sieders. EphA2 is a clinically relevant target for breast cancer bone metastatic disease [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5017.
Abstract 5038: Limited inhibition of multiple nodes in a driver network blocks metastasis
Authors: Yesilkanal Ali Ekrem , Yang Dongbo , Tiwari Payal , Sabino Alan U. , Lee Jiyoung , Xie Xiao-He , Sun Siqi , Dann Christopher , Steinberg Ethan , Stuhlmiller Timothy , Frankenberger Casey , Goldsmith Elizabeth , Johnson Gary L. , Ramos Alexandre F. , Rosner Marsha 
Published: September 2020

Abstract
High-dose, single-drug treatment is unsuccessful at suppressing metastasis due to cellular heterogeneity and feedback activation. Here we demonstrate that targeting driver network signaling capacity by limited inhibition at multiple nodes is a more effective anti-metastatic strategy. A physiological metastasis suppressor, Raf Kinase Inhibitory Protein, decreases the activity of multiple kinases in the stress-regulated MAP kinase (MAPK) network and reduces the output to metastatic transcription factor BACH1 that upregulates motility-related genes. This effect is mimicked by a low-dose four-drug cocktail (4D-MAPKi) that blocks metastatic colonization in mouse breast cancer models and increases survival. Drug treatment and network modeling show that 1) multi-kinase inhibition is required to suppress signaling output across cells with different MAPK network topologies, and 2) restricting inhibition of individual kinases prevents threshold activation of other compensatory kinase networks. This low-dose multi-drug approach to decrease signaling capacity of a driver network represents a transformative, clinically-relevant strategy for anti-metastatic treatment.
Citation Format: Ali Ekrem Yesilkanal, Dongbo Yang, Payal Tiwari, Alan U. Sabino, Jiyoung Lee, Xiao-He Xie, Siqi Sun, Christopher Dann, Ethan Steinberg, Timothy Stuhlmiller, Casey Frankenberger, Elizabeth Goldsmith, Gary L. Johnson, Alexandre F. Ramos, Marsha Rosner. Limited inhibition of multiple nodes in a driver network blocks metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5038.
Abstract 5041: Inhibition of RUNX-CBFβ binding reduces RSPO3 expression and EMT features in breast cancer cells
Authors: Felcher Carla M. , Tocci Johanna M. , Sola Martin E. Garcia , Bushweller John H. , Castilla Lucio H. , Kordon Edith C. 
Published: September 2020

Abstract
We have recently identified R-spondin3 (RSPO3) as a novel key modulator of breast cancer development that may become a potential target for treatment of the basal subtype, which lacks efficient therapeutic options to date. RSPO3 is expressed in the basal stem cell-enriched compartment of mouse mammary glands whereas it is absent in the mature luminal cells. RSPO3 knockdown in mouse mammary tumor cells reduces canonical Wnt signaling pathway, epithelial-to-mesenchymal transition (EMT)-like features, migration capacity, and tumor formation in vivo. To evaluate the relevance of RSPO3 in human breast cancer, we analyzed samples from 75 patients with ductal infiltrating breast carcinomas, where we found a high prevalence of positive immunoreactivity for RSPO3 (70%). Expression data of The Cancer Genome Atlas Network from 1985 human breast carcinoma samples showed that RSPO3 is primarily expressed in Claudin-low breast cancer subtype, which is characterized for having stem cells features. In culture assays revealed that knockdown of RSPO3 expression reduced SOX2 expression and impaired mammary tumor cell ability to form mammospheres. Previous reports suggested the potential involvement of RUNX1-CBFβ on RSPO3 transcription in mammary tumor cells. Therefore, we evaluated if pharmacologic inhibition of RUNX1 activity would reduce RSPO3 expression and activity in the cancer stem cell compartment. Treatment of breast cancer cells with AI-10-104, a small molecule that inhibits CBFβ-RUNX interaction, reduced RSPO3 mRNA and protein levels, and reduced the migration ability of MDA-MB231 breast cancer cells, ability that was recovered upon treatment with recombinant RSPO3. In addition, AI-10-104 inhibited the expression of canonical Wnt pathway targets, EMT and stem-cell markers. Therefore, our results demonstrate that inhibition of RUNX-CBFβ transcriptional activity leads to a down-regulation of RSPO3 expression, constituting a new molecular target for therapeutic modulation in breast cancer treatment.
Citation Format: Carla M. Felcher, Johanna M. Tocci, Martin E. Garcia Sola, John H. Bushweller, Lucio H. Castilla, Edith C. Kordon. Inhibition of RUNX-CBFβ binding reduces RSPO3 expression and EMT features in breast cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5041.
Abstract 5059: Breast cancer patient-derived xenograft models for pre- and co-clinical investigation of immune based therapies
Authors: Wulf-Goldenberg Annika , Kiver Verena , Stecklum Maria , Brzezicha Bernadette , Jurmeister Philipp , Schweiger Caroline , Blohmer Jens-Uwe , Keilholz Ulrich , Hoffmann Jens 
Published: September 2020

Abstract
Breast cancer is a highly heterogeneous disease, with a heterogeneous prognosis. Patient-derived xenograft models (PDX) can reflect this heterogeneity and can be used to support the development of novel therapeutic strategies against breast cancer. Preclinical experiments with larger cohorts of breast cancer PDX can be used to model a clinical phase II study with new drugs or drug combinations. The predictive value of these preclinical trials is currently evaluated in co-clinical trials, where treatment effects are compared between patients and their corresponding PDX. We present results from our translational pre- and co-clinical studies in breast cancer immune therapy.
As part of the EFRE-POP Project, we established PDX by collecting breast cancer tissue samples from surgery and engrafting them on immunodeficient mice. The tissues were obtained from patients with disease progression after chemotherapy with three to four drugs. PDXs have been successfully engrafted, phenotypically characterized and drug-screened. The PDXs were tested for response to the standard of care therapies. The staining for estrogen/progesterone/androgen/Her2 receptors, Ki-67, and CK5/6 of the original tumor and the PDX were comparable. The patient tumors and the breast cancer PDX models were further analyzed for the expression of PD-L1. We identified four patients that had received PD-1 or PD-L1 antibodies after a sample (used to establish a corresponding PDX) was obtained.
To evaluate the response of our preclinical PDX models to immune checkpoint inhibitors, we engrafted mice with a human immune system either by transplanting allogeneic hematopoietic stem cells (HSC) or allogenic PBMC's from healthy donors. Besides, we were able to obtain PBMC's from the patients to set up an autologous model. The patient-derived tumors were transplanted to these humanized mice and after successful engraftment treated with the PD-1 or PD-L1 antibodies corresponding with the clinical treatment of the patient.
In summary, humanized PDX of refractory tumors have been established and the first pre-clinical evaluation of response to immune therapy provides evidence that xenografts respond in a qualitatively similar manner as the patient. This suggests a translational relevance of the described pre-clinical models.
Citation Format: Annika Wulf-Goldenberg, Verena Kiver, Maria Stecklum, Bernadette Brzezicha, Philipp Jurmeister, Caroline Schweiger, Jens-Uwe Blohmer, Ulrich Keilholz, Jens Hoffmann. Breast cancer patient-derived xenograft models for pre- and co-clinical investigation of immune based therapies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5059.