bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4096: Identification of EMT inhibitors using novel zebrafish reporter lines
Authors: Jimenez Laura , Wang Jindong , Jette Cicely , Warner Steven L. , Bearss David , Stewart Rodney 
Published: August 2015

Abstract
The Epithelial to Mesenchymal Transition (EMT) plays a crucial role during development and aberrant reactivation of EMT in tumor cells promotes metastasis and drug resistance. Mechanisms that control EMT remain incompletely understood, hampering efforts to target EMT in cancer patients. To identify upstream inducers and downstream effectors of EMT we have developed a novel zebrafish neural crest (NC) EMT reporter line, Tg(snail1b:GFP), for in vivo screening of EMT and cell migration inhibitors. After screening a number of candidate kinase inhibitors for their ability to block NC migration in live Tg(snail1b:GFP) embryos, we found that the AXL receptor tyrosine kinase inhibitor, TP-0903 (HCI-2084), potently blocks hindbrain morphogenesis and cranial NC cell migration. Treatment of embryos at the 3-somite stage with TP-0903 significantly decreases twist1a expression, a key regulator of EMT, blocks differentiation of dlx2a-expressing chondrogenic precursors, and instead promotes the differentiation of mitfa-expressing melanophore precursors that form adjacent to the neural tube. RNA-Seq analysis revealed that TP-0903 treated embryos have a significant upregulation of retinoic acid (RA) signaling. Co-treatment of TP-0903 with DEAB, an RA inhibitor, rescues the hindbrain and NC migration and differentiation defects caused by TP-0903 treatment. We are currently investigating the potential role of AXL in NC cell migration and differentiation, and evaluating TP-0903 as a possible therapy for neuroblastoma, by using the zebrafish neuroblastoma pre-clinical model and human neuroblastoma cells in vitro.
Citation Format: Laura Jimenez, Jindong Wang, Cicely Jette, Steven L. Warner, David Bearss, Rodney Stewart. Identification of EMT inhibitors using novel zebrafish reporter lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4096. doi:10.1158/1538-7445.AM2015-4096
Abstract 4099: IGF1R signaling connects DNp73-mediated EMT with the acquisition of cancer stem cell properties
Authors: Meier Claudia , Steder Marc , Hardtstock Philip , Alla Vijay , Pützer Brigitte M. 
Published: August 2015

Abstract
Metastatic spread is the major cause of cancer-associated mortality and induced in primary tumor cells by the acquisition of mesenchymal features. Emerging evidence suggests that metastasis-initiating cancer cells undergoing epithelial-mesenchymal transition (EMT) possess stem cell-like traits. In this study, we demonstrate that oncogenic DNp73, an inhibitor of p53 tumor suppressor family members, has a fundamental role in driving both, transition into a mesenchymal state and providing cancer cells with stem cell-like properties through constitutive activation of IGF1R signaling. In patient melanoma tissues, DNp73 expression correlates with increased Breslow depth and is enriched in skin cancer metastases. Knockdown of endogenous DNp73 in highly metastatic cell lines abolishes the aggressive phenotype, whereas tumor xenografts overexpressing DNp73 possess significantly greater capacity to invade the surrounding tissue and form metastatic lesions. Transition from an epithelial to a motile mesenchymal phenotype is accompanied by a drastic reorganization of the cytoskeleton and modulation of cell-cell adhesion molecules. Importantly, regulation of EMT by DNp73 is induced through activation of IGF1R-AKT signaling followed by an increase of Slug and loss of E-cadherin. Additionally, we identified a novel interplay between DNp73 and IGF1R in the development of cancer stemness. Tumor spheres derived from metastatic melanoma cells with endogenously high DNp73 display a strong capacity for self-renewal and tumor growth after subcutaneous injection in mice compared to DNp73-depleted cancer stem cells. Our results clearly demonstrate that DNp73-driven stemness involves IGF1R activation. Selective inhibition of IGF1R blocks DNp73-mediated upregulation of Nanog, Oct4 and CD133, which is accompanied by a decrease in spheroid formation and tumor invasiveness. Taken together, our findings show for the first time that DNp73 is crucial to endow cancer cells with mesenchymal properties and the ability to self-renew, which is responsible for malignant progression and tumor dissemination. Moreover, we establish IGF1R as driving force for a DNp73-induced aggressive cancer phenotype, highlighting the DNp73-IGF1R cascade as promising therapeutic target to selectively prevent metastasis initiation.
Citation Format: Claudia Meier, Marc Steder, Philip Hardtstock, Vijay Alla, Brigitte M. Pützer. IGF1R signaling connects DNp73-mediated EMT with the acquisition of cancer stem cell properties. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4099. doi:10.1158/1538-7445.AM2015-4099
Abstract 4103: Knockdown of Notch1 inhibits tumor cell proliferation, migration, and invasion and reverses epithelial-mesenchymal transition (EMT) in nasopharyngeal carcinoma
Authors: Guo Huajiao , Lu Yi , Qian Chaonan , Zhang Jian 
Published: August 2015

Abstract
Despite a large bodies of evidences support an oncogenic role of Notch signaling in several human solid cancers, however, the pleiotropic effects and molecular mechanisms of blockage of Notch signaling on nasopharyngeal carcinoma (NPC) remain unclear. In this study, Real-time RT-PCR and western blotting were firstly used to examine the expression of Notch1 receptor in a panel of NPC cell lines. CNE1 and CNE2 cells expressed a higher level of Notch1 compared to HONE1, SUNE1 and HK cells. Then Notch1 expression was specifically knocked down in CNE1 and CNE2 cells by Notch1 short hairpin RNA (shRNA). This resulted in a significant inhibition of cell proliferation, migration, and invasion; and interestingly, epithelial-mesenchymal transition (EMT) was reversed in these Notch1-transfected cells along with demonstration of epithelialioid-like morphology change and increase of E-cadherin and decrease of Vimentin expressions. In addition, targeted knockdown of Notch1 dramatically inhibited expression of urokinase plasminogen activator (uPA) and its receptor uPAR, chemokine CCL2 and CXCL16 indicating that these factors are downstream targets of Notch1. Finally, knockdown of Notch1 significantly diminished CNE1 cell growth in a murine model concomitant with inhibition of cell proliferation and induction of apoptosis. Taken together, these results suggest Notch1 may become a therapeutic target in nasopharyngeal carcinoma.
Note: This abstract was not presented at the meeting.
Citation Format: Huajiao Guo, Yi Lu, Chaonan Qian, Jian Zhang. Knockdown of Notch1 inhibits tumor cell proliferation, migration, and invasion and reverses epithelial-mesenchymal transition (EMT) in nasopharyngeal carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4103. doi:10.1158/1538-7445.AM2015-4103
Abstract 4110: Inhibition of angiopoietin 1/2 and c-MET impairs metastatic potential in a patient derived xenograft of renal carcinoma
Authors: Orillion Ashley , Adelaiye-Ogala Remi , Shen Li , Ciamporcero Eric , Ku Sheng Yu , Ramakrishnan Swathi , Elbanna May , Chintala Sreenivasulu , Pili Roberto 
Published: August 2015

Abstract
Background: Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer and diagnoses have been on the rise since the 1990s. While patients with early stage ccRCC have more than a 50% survival rate over four years, those with advanced stage disease have a less than 10% chance of 5 year survival. In our current study, we utilized an angiopoietin 1/2 inhibitor (Amgen 386) and a novel c-MET inhibitor in murine models grafted with human derived xenografts (PDX) with a high metastatic penetrance. Our goal was to assess the ability of these compounds to prolong survival via metastatic inhibition. Methods: Seven week old SCID mice were implanted either subcutaneously or orthotopically with human ccRCC PDX RP-R-02LM. Approximately one month post implantation, mice were started on treatment with Angiopoietin 1/2 inhibitor (Amgen 386), c-met inhibitor (compound A) or a combination of the two. Amgen 386 was administered twice a week subcutaneously at 5.6mg/kg. Compound A was given daily via oral gavage at 30mg/kg. As a survival study, treatment was continued until the mice reached a point where they needed to be euthanized or they were found dead. Results: In our metastatic PDX model, RP-R-02LM, Amgen386 single agent treatment and combination c-MET inhibitor and Amgen386 treatment significantly reduced metastases significantly, p = 0.0075 and p = 0.0001 respectively. Further, an ongoing survival study has shown that at four and a half months post implantation both single agent and combination treatments prolong the survival of mice implanted with RP-R-02LM, a highly metastatic PDX. Conclusions: Our preliminary results suggest that Amgen386 in combination with a novel c-MET inhibitor are significantly inhibiting the spread of metastases and prolonging survival. This indicates a potential use for combination therapy in treating patients with ccRCC in advanced stages of the disease.
Citation Format: Ashley Orillion, Remi Adelaiye-Ogala, Li Shen, Eric Ciamporcero, Sheng Yu Ku, Swathi Ramakrishnan, May Elbanna, Sreenivasulu Chintala, Roberto Pili. Inhibition of angiopoietin 1/2 and c-MET impairs metastatic potential in a patient derived xenograft of renal carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4110. doi:10.1158/1538-7445.AM2015-4110
Abstract 4119: Tyrosine phosphorylation of MACC1 is essential and druggable for colorectal cancer metastasis restriction
Authors: Kobelt Dennis , Dittmar Gunnar , Fleuter Claudia , Smith Janice , Dahlmann Mathias , Migotti Rebekka , Schlag Peter M. , Stein Ulrike S. 
Published: August 2015

Abstract
We identified the previously undescribed gene Metastasis Associated in Colon Cancer 1 (MACC1). MACC1 is a metastasis inducer and prognostic biomarker for colorectal cancer (CRC). MACC1 has meanwhile been confirmed as decisive driver for tumorigenesis and metastasis for a broad variety of solid cancers. Here we aim to identify the impact of defined tyrosine phosphorylations on the function of the metastasis inducer MACC1.
In silico identified MACC1 tyrosine phosphorylation (pY) sites were ranked and most promising positions were site-directed mutated in wildtype (wt) MACC1 constructs. Human CRC cells were transduced with these constructs. Tyrosine phosphorylation was quantified by selected reaction monitoring (SRM)-mass spectrometry. Effects of pY-MACC1 mutants on cell migration, proliferation, dissemination and colony formation were assessed in cell culture as well as on liver metastasis formation in human CRC-xenografted mice. To identify MACC1-phosphorylating kinases the MACC1 interactome was identified using mass spectrometry. Most promising binding partners were validated by immunoprecipitation. Impact of inhibitors targeting kinases phosphorylating MACC1 was assessed on MACC1-induced tumor growth and liver metastasis in human CRC-xenografted mice by in vivo imaging.
We report that tyrosine phosphorylation of MACC1 is hierarchical and essential for motility and proliferation in cell culture, as well as for tumor growth and metastasis in mice. We identified kinases for MACC1 phosphorylation. Targeting these kinases using inhibitors employed in clinical trials restricts MACC1-induced tumor growth and metastasis in mice.
MACC1 tyrosine phosphorylation is crucial for metastasis and is druggable by small molecule inhibitors. This fundamental finding opens new therapeutic options for inhibition of MACC1-induced cancer metastasis.
Citation Format: Dennis Kobelt, Gunnar Dittmar, Claudia Fleuter, Janice Smith, Mathias Dahlmann, Rebekka Migotti, Peter M. Schlag, Ulrike S. Stein. Tyrosine phosphorylation of MACC1 is essential and druggable for colorectal cancer metastasis restriction. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4119. doi:10.1158/1538-7445.AM2015-4119
Abstract 4122: C-Met inhibition sensitivity in vitro: Autocrine vs. paracrine activation of the c-Met pathway
Authors: Hughes Veronica , Siemann Dietmar W. 
Published: August 2015

Abstract
Tumor cells frequently harbor abnormalities in signaling pathways, leading to increased migration, invasion, survival, angiogenesis, and proliferation. C-Met is one such commonly aberrant pathway. C-Met is a receptor tyrosine kinase critical for embryogenesis and liver repair, and protein levels are often elevated in a large variety of tumors. C-Met is activated by the endogenous ligand Hepatocyte Growth Factor (HGF). HGF is produced by mesenchymal cells and stimulates the c-Met protein, leading to a variety of downstream signaling pathways that result in increased migration, proliferation, survival, and angiogenesis.
While many tumor cells express the c-Met receptor, a number of tumor types, including glioblastoma and osteosarcoma, have been observed to co-express both HGF and c-Met, and activate the pathway in an autocrine manner. The purpose of the current study was to determine whether tumor cells utilizing autocrine c-Met signaling would more sensitive to c-Met inhibition than those relying on the paracrine pathway. Experimental procedures include ELISA, western, migration, invasion, and clonogenic cell survival. Cell lines investigated include: two glioblastoma cell lines (U87 and U118), two osteosarcoma cell lines (OS156 and OS521), two fibrosarcoma cell lines (KHT and RIF), a breast (MDA-MB-231) and a prostate cancer cell line (PC-3). The small molecule c-Met inhibitor BMS-777607 and an HGF-neutralizing antibody were used to compare the effects interrupting the c-Met axis in these tumor cell lines.
Data obtained using ELISA of conditioned media show that the glioblastoma (U87 and U118) and fibrosarcoma (KHT) cells secrete HGF, while the breast and prostate cells (MDA-MB-231; PC-3) do not. Furthermore western blot analysis showed higher basal levels of phospho-c-Met among the HGF-secreting cell lines in comparison to the non-HGF secreting cell lines, indicating that the KHT, U87, and U118 models activate c-Met in an autocrine manner, while the MDA-MB-231 and PC-3 lines activate c-Met in a paracrine manner. Importantly preliminary assessments indicate the autocrine glioblastoma and fibrosarcoma cell lines to be more sensitive to small molecule c-Met inhibition than the paracrine breast and prostate cancer cell lines. Investigations of additional cancer models are ongoing but our findings to date support the notion that cancer cells that autocrine activate the c-Met pathway may more susceptible to c-Met inhibition than those utilizing primarily paracrine activation of this pathway.
Citation Format: Veronica Hughes, Dietmar W. Siemann. C-Met inhibition sensitivity in vitro: Autocrine vs. paracrine activation of the c-Met pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4122. doi:10.1158/1538-7445.AM2015-4122
Abstract 4125: SSA, a novel sulindac derivative, inhibits breast cancer cell invasion and migration
Authors: Yi Bin , Feng Xingling , Ma Ruixia , Zhang Xiaoguo , Chang Hong , Zhao Hongyou , Liang Ziping , Chen Xi , Hu Xiuhua , Piazza Gary , Xi Yaguang 
Published: August 2015

Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs), such as sulindac, have been reported for striking chemopreventive activity in various types of human cancer, including breast cancer. However, few studies have reported that sulindac is able to prevent tumor metastasis. In this study, we aim to study anti-metastatic activity of sulindac in breast cancer and explore the mechanistic basis responsible for this activity, which we hypothesize may involve a cyclooxygenase (COX) independent mechanism. Numerous studies have reported that the anticancer properties of sulindac might involve, at least partially, a non-COX mediated mechanism, which provides an insight into development of safer and more efficacious new derivatives. We have previously described a chemical derivative of sulindac, referred to as sulindac sulfide amide (SSA), which lacks inhibitory effect on COX-1 or -2, yet shows greater potency to inhibit tumor cell growth compared with sulindac sulfide (SS). Our results showed that SSA treatment at a sub-cytotoxic concentration (4μM) for 36 h significantly inhibits both migration and invasion of highly aggressive MDA-MB-231, BT-20 and SK-BR-3 breast tumor cells. When treating non-invasive breast MCF-7 cells with TGF-β1 to induce their motility, we found that SSA could significantly counteract the induced motility of these cells. These results indicate that SSA can suppress breast tumor cell invasion by modulation of TGF-β1 signaling. We further studied Smad-2/3 that are important downstream components in the TGF-β1 signaling pathway and found that SSA could inhibit Smad-2/3 phosphorylation and reduce their translocation to the nucleus. In addition, Smad-2/3 knockdown could mimic the anti-invasive effect of SSA in MDA-MB-231 cells, regardless of the presence of TGF-β1. In summary, we demonstrate that the non-COX inhibitory derivative, SSA can suppress breast cancer cell invasion and migration. These observations suggest that inhibition of TGF-β1/Smad signaling is responsible for the inhibitory effect of SSA on breast tumor cell invasion and migration.
Citation Format: Bin Yi, Xingling Feng, Ruixia Ma, Xiaoguo Zhang, Hong Chang, Hongyou Zhao, Ziping Liang, Xi Chen, Xiuhua Hu, Gary Piazza, Yaguang Xi. SSA, a novel sulindac derivative, inhibits breast cancer cell invasion and migration. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4125. doi:10.1158/1538-7445.AM2015-4125
Abstract 4127: Bolus high-dose neoadjuvant sunitinib treatment overcomes potential for rebound growth during pre-surgical treatment breaks
Authors: Mastri Michalis , Tracz Amanda , Shen Li , Pili Roberto , Ebos John M.L. 
Published: August 2015

Abstract
Preclinical and clinical studies have suggested that stopping antiangiogenic therapy may lead to rapid revascularization and rebound tumor growth in certain instances. However, the implications for these findings remain unclear. It is possible that treatment rebounds may impact disease progression following neoadjuvant therapy, where drugs are administered for short periods and then halted prior to surgical removal of a primary tumor. Indeed, recent retrospective clinical studies have suggested that neoadjuvant antiangiogenic treatment discontinuation increases vascular proliferation and, in turn, might increase post-surgical disease progression and metastasis. However, this hypothesis has not been studied experimentally in clinically relevant mouse models of metastatic disease.
We examined the effect of treatment discontinuation in the neoadjuvant setting using approved vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) such as sunitinib. Our studies utilized models of spontaneous metastatic breast, melanoma, and kidney cancer following surgical removal of orthotopically grown primary tumors. Neoadjuvant sunitinib treatment periods were 14 days in duration (60 mg/kg) with treatment breaks of 0, 3, 7, and 11 days compared. Pre-surgical molecular and cellular biomarkers were investigated as potential surrogates for post-surgical metastatic disease progression. These included tumor and vascular cell Ki67 and CD31 expression, as well as circulating tumor cells (CTCs) and myeloid derived suppressor cells (MDSCs).
Our results show that VEGF RTKI neoadjuvant treatment benefits observed pre-surgically (such as reduction in primary tumor growth) did not consistently correlate with post-surgical survival and reduced metastatic recurrence. The addition of treatment breaks prior to surgery had positive or negative impact on post-surgical survival depending on the tumor model used. Interestingly, high-dose bolus (3 day) neoadjuvant sunitinib (120 mg/kg) treatment consistently improved post-surgical benefits when compared to sustained treatments, despite gaps in therapy. Finally, our results show that tumoral CD31+/Ki67+ cells, CTCs, and MDSCs may serve as surrogate markers of metastatic potential and predict the impact of treatment cessation on disease recurrence.
Citation Format: Michalis Mastri, Amanda Tracz, Li Shen, Roberto Pili, John M.L. Ebos. Bolus high-dose neoadjuvant sunitinib treatment overcomes potential for rebound growth during pre-surgical treatment breaks. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4127. doi:10.1158/1538-7445.AM2015-4127