bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A59: A novel bispecific FAP-DR5 antibody inducing potent and tumor-specific death receptor 5 (DR5) activation by fibroblast activation protein (FAP) dependent crosslinking
Authors: Wartha Katharina , Weiser Barbara , Friess Thomas , Majety Meher , Runza Valeria , Herting Frank , Weber Thomas , Scheuer Werner , Harring Suzana Vega , Sade Hadassah , Niu Huifeng 
Published: May 2015

Abstract
Background: Activation of the extrinsic apoptosis pathway in tumor cells through agonistic death receptor 5 (DR5) antibodies has been evaluated in the clinic with limited success so far. In this context, several reports show that DR5 activation is strongly dependent on receptor hyperclustering on the cell surface. Therefore a therapeutic principle that induces DR5 hyperclustering specifically at the tumor site may provide superior efficacy, potency and safety compared to conventional DR5 agonistic antibodies. Fibroblast activation protein (FAP) is a marker for activated fibroblasts and abundantly expressed in cancer associated fibroblasts of various epithelial tumor indications and as a tumor antigen on tumors of mesenchymal origin. Due to its relative absence from normal tissues, FAP can be used as a tumor targeting antigen. Here, we are using the broad expression of FAP in tumor stroma for crosslinking of DR5 by a bispecific antibody.
Aim: In order to achieve superior tumor targeting and tumor located DR5 hyperclustering we have generated a bispecific antibody, RG7386, comprised of an agonistic DR5 binder and a FAP targeting moiety.
Results: RG7386 shows potent and selective binding to FAP and DR5 and can simultaneously bind to both targets. In in vitro co-culture assays, using human DLD1 colon tumor cells and FAP expressing fibroblasts, RG7386 induces potent, FAP dependent DR5 hyperclustering and apoptosis induction in DR5 positive tumor cells (IC50: 0.05 nM). In preclinical in vivo models with co-injection of DLD-1 tumor cells and fibroblasts as well as patient-derived colorectal cancer models, RG7386 shows FAP dependent efficacy and apoptosis induction superior to conventional DR5 antibodies. Furthermore the superior induction of apoptosis could be confirmed by in vivo and ex vivo analysis of cleaved Caspase-3 with imaging, Luminex and histopathology.
Conclusion: RG7386 is a promising novel therapeutic entity for the treatment of solid tumors with FAP positive tumor stroma inducing DR5 activation by FAP dependent DR5 hypercrosslinking which results in potent anti-tumor activity.
Citation Format: Katharina Wartha, Barbara Weiser, Thomas Friess, Meher Majety, Valeria Runza, Frank Herting, Thomas Weber, Werner Scheuer, Suzana Vega Harring, Hadassah Sade, Huifeng Niu. A novel bispecific FAP-DR5 antibody inducing potent and tumor-specific death receptor 5 (DR5) activation by fibroblast activation protein (FAP) dependent crosslinking. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A59. doi:10.1158/1538-7445.CHTME14-A59
Abstract A62: TGF-β regulates CXCL1 expression in mammary carcinoma associated fibroblasts through novel Smad2/3- and HGF/c-Met-dependent mechanisms.
Authors: Zou An , Lambert Diana , Yeh Henry , Fang Wei Bin , Cheng Nikki 
Published: May 2015

Abstract
CXCL1 is a chemokine secreted by macrophages, neutrophils, epithelial cells and fibroblasts, and plays a role in inflammation and wound healing. Enhanced expression of CXCL1 in tumor epithelium is associated with cell invasion, angiogenesis in melanoma, bladder, ovarian and breast cancer. However, little is known about CXCL1 expression in tumor stroma. Through analysis of gene expression data, our studies reveal that high RNA levels of CXCL1 in breast tumor stroma is associated with increased rate of recurrence and shorter relapse-free survival. We noticed decreased secretion levels of TGF-β and increased secretion of CXCL1 in tumor derived fibroblasts. Increased CXCL1 expression was also observed in mammary fibroblasts in which the TGF-β type II receptor was knocked out. By immunohistochemistry analysis we found that expression of CXCL1 inversely correlated with expression of TGF-β, phosphorylated-Smad2 and phosphorylated-Smad3 in breast tumor stroma. We hypothesized that TGF-β suppresses CXCL1 expression in breast fibroblasts. Our goal for this project was to determine the molecular mechanisms through which TGF-β suppresses CXCL1 expression using mammary fibroblasts derived from MMTV-PyVmT mammary tumor model. Treatment of fibroblasts with recombinant TGF-β decreased CXCL1 transcription and secretion by up to 85% over time, as determined by RT-PCR and ELISA. SiRNA silencing of TGF-β signaling transducers, Smad2 and Smad3, increased CXCL1 transcription and secretion in mammary fibroblasts. In addition, TGF-β suppressed expression of HGF, a factor that enhanced CXCL1 expression in mammary fibroblasts. Knockdown of HGF or treatment of fibroblasts with c-Met inhibitors reduced CXCL1 expression. These data indicate TGF-β suppresses CXCL1 expression through Smad2/3-dependent mechanisms. As a secondary mechanism, TGF-β suppresses CXCL1 expression through down-regulation of HGF/c-Met signaling. This is the first report to characterize the mechanisms of CXCL1 expression in mammary fibroblasts and demonstrate a clinical relevance for CXCL1 expression in breast cancer stroma.
Citation Format: An Zou, Diana Lambert, Henry Yeh, Wei Bin Fang, Nikki Cheng. TGF-β regulates CXCL1 expression in mammary carcinoma associated fibroblasts through novel Smad2/3- and HGF/c-Met-dependent mechanisms.. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A62. doi:10.1158/1538-7445.CHTME14-A62
Abstract A73: AMPK activation mediates dasatinib-induced EGFR degradation and apoptosis in head and neck cancer
Authors: Lin Yu-Chin Lin , Wu Meng-Hsuan , Wei Tzu-Tang , Lin Yun-Chieh , Chen Ching-Chow 
Published: May 2015

Abstract
Head and neck squamous cell carcinoma (HNSCC) is a worldwide disease with aggressive course and dismal outcome. Dasatinib, a Bcr-abl and Src in hibitor, has been approved clinically for CML and shown activities against solid tumors in vitro. In our recent work, degradation of epidermal growth factor receptor (EGFR) plays a role in dasatinib-induced apoptosis in HNSCC cells. We further explored the mechanism of this event. ER stress was induced by dasatinib and played a role in dasatinib-EGFR degradation. C-cbl activation was induced by ER stress and shown to mediate ER-stress induced EGFR degradation. In addition, AMPK activation was induced by dasatinib, which was proved to be involved in dasatinib-induced ER stress and EGFR degradation. Activation of AMPK with metformin not only enhanced dasatinib-induced growth inhibition and apoptosis but also sensitized dasatinib-resistant cells. Furthermore, xenograft model showed that metformin potentiated anti-cancer effect of dasatinib through activation of AMPK and ER stress. Our results disclose that AMPK-dependent ER stress plays a crucial role in the anti-cancer effect of dasatinib in HNSCC and further activation of AMPK by metformin might enhance dasatinib efficacy.
Citation Format: Yu-Chin Lin Lin, Meng-Hsuan Wu, Tzu-Tang Wei, Yun-Chieh Lin, Ching-Chow Chen. AMPK activation mediates dasatinib-induced EGFR degradation and apoptosis in head and neck cancer. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A73. doi:10.1158/1538-7445.CHTME14-A73
Abstract B09: Sphingosine kinase 1 (SPHK1) is a novel mediator of tumor-stroma interaction in ovarian cancer
Authors: Beach Jessica A. , Aspuria Paul-Joseph , Cheon Dong-Joo , Gozo Maricel C. , Karlan Beth Y. , Orsulic Sandra 
Published: May 2015

Abstract
Sphingosine kinase-1 (SPHK1) is an enzyme that catalyzes the formation of the prosurvival second messenger sphingosine-1-phosphate (S1P) from the proapoptotic lipid sphingosine. The balance between sphingosine and S1P forms a sphingolipid rheostat that is primed for cell death when the balance shifts towards sphingosine/ceramide or to cell survival when S1P levels are increased. Elevated levels of S1P have been observed in several cancers, including ovarian cancer where it is elevated in both the ascites and serum of patients. Correspondingly, high expression of SPHK1 has also been described in multiple cancer types and has been linked to disease progression. Here we report that SPHK1 is overexpressed in a subset of epithelial ovarian cancers (EOC) and correlates with poor progression-free survival. Overexpression and knockdown of SPHK1 in multiple human EOC cell lines modulates in vitro cell proliferation, anchorage-independent growth, and chemosensitivity. In mouse xenograft studies, intraperitoneal administration of a SPHK1-specific inhibitor (SKI-5c) decreases tumor size, indicating that SPHK1 may be a potential therapeutic target in EOC. S1P is a secreted factor that has been shown to influence the tumor microenvironment of other cancers; however its role in EOC has not been fully established. Using a co-culture model, we show that overexpression of SPHK1 in EOC cells stimulates the transition of normal ovarian stromal fibroblasts to myofibroblasts, and enhances stromal SPHK1 expression. In a reciprocal manner, overexpression of SPHK1 in stromal fibroblast results in increased expression of MMP2 and MMP9 in EOC cells, which may contribute to a more invasive phenotype. Interestingly, stromal SPHK1 expression also enhanced expression of SPHK1 and the S1P receptor (S1PR1) in the EOC cells. Biostatistical analysis suggests a significant correlation between SPHK1 expression in EOC cells and the expression of several extracellular matrix genes (FN1, POSTN, VCAN), which have been shown to have role in the EOC tumor microenvironment. Overall, these results suggest that SPHK1 is a critical regulator of ovarian tumor cell proliferation and survival, and a mediator of tumor-stroma interaction.
Citation Format: Jessica A. Beach, Paul-Joseph Aspuria, Dong-Joo Cheon, Maricel C. Gozo, Beth Y. Karlan, Sandra Orsulic. Sphingosine kinase 1 (SPHK1) is a novel mediator of tumor-stroma interaction in ovarian cancer. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B09. doi:10.1158/1538-7445.CHTME14-B09
Abstract B14: Activin A regulates cell interactions in the microenvironment of oral squamous cell carcinomas
Authors: Coletta Ricardo D. , Bufalino Andreia , Sobral Lays M. , Rodrigues Priscila C. , Graner Edgard , Kowalski Luis P. , Salo Tuula 
Published: May 2015

Abstract
Although the molecular mechanisms by which carcinoma-associated fibroblasts (CAFs) influence oral squamous cell carcinomas (OSCC) remain largely unknown, previous studies demonstrated that presence of CAFs in the stroma of OSCCs is an important risk factor of patient's shortened survival. Here we showed that activin A is produced in higher levels by CAFs compared to normal oral fibroblasts, and that activin A released by CAFs significantly increases OSCC cell proliferation and xenograft tumor volume, whereas down-regulation of activin A decreases OSCC proliferation. Furthermore, activin A reduced OSCC cell death even when challenged by staurosporine, and promoted migration, invasion and the expression of epithelial-mesenchymal transition (EMT) markers (decreases E-cadherin and increases vimentin and N-cadherin) of OSCC cells. Immunohistochemical analysis of 115 OSCC samples revealed that increased activin A expression is significantly correlated with presence of regional metastasis (N stage, p=0.034), poorly differentiated tumors (p=0.013) and shown to be predictive of a shortened disease-free survival (HR: 1.74, 95% CI: 1.39-2.97, p=0.016). Importantly, immunohistochemical expression of activin A was significantly associated with presence of occult lymph node metastasis (p=0.006), which has an important impact on clinical management and prognostication of patients with OSCCs. In conclusion, our data demonstrate that activin A is an important molecule for OSCCs, and its pleiotropic effects on proliferation and invasion are important on control of the aggressiveness of OSCCs.
Citation Format: Ricardo D. Coletta, Andreia Bufalino, Lays M. Sobral, Priscila C. Rodrigues, Edgard Graner, Luis P. Kowalski, Tuula Salo. Activin A regulates cell interactions in the microenvironment of oral squamous cell carcinomas. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B14. doi:10.1158/1538-7445.CHTME14-B14
Abstract B15: Bone marrow stromal cell-secreted inflammatory cytokines promote treatment resistance and survival of prostate cancer cells
Authors: Chang Megan , Morgado Micaela , Patel Viral , Gwede Michael , Farach-Carson Mary Cindy , Delk Nikki 
Published: May 2015

Abstract
It is well established that prostate cancer (PCa) cells hone to, adapt, and thrive in the bone. Importantly, bone metastases are found in over 80% of PCa deaths. Therefore, it is imperative to elucidate and characterize the molecular mechanisms that enable PCa cells to thrive in the bone and resist conventional PCa therapies, such as hormone ablation or anti-androgens. We found that the HS-5 bone marrow stromal cell (BMSC) line, a secretory BMSC line that can support hematopoietic stem cell growth, secretes paracrine factors that induce apoptosis in PCa cells. However a subpopulation of the PCa cells can survive the BMSC-induced death. The surviving PCa subpopulation differentiates into a neuronal morphology and looses androgen receptor (AR) expression, reminiscent of treatment-resistant neuroendocrine PCa. Ideally, the loss of AR would induce PCa cell death; however we observe a concomitant increase in the autophagy-related cell survival protein, p62/SQSTM1, and induction of cytoprotective autophagy. Furthermore, we find that interleukin-1 beta (IL-1β) and IL-6, inflammatory cytokine secreted by HS-5 BMSCs, are sufficient to promote PCa neuronal morphology, reduce AR accumulation, upregulate p62/SQSTM1 levels, and induce autophagy. In addition, genetic silencing of p62/SQSTM1 causes PCa cell death and pharmacological inhibition of cytokine or autophagy signaling attenuates PCa neuroendocrine differentiation. Thus, our PCa-bone marrow stromal cell model suggests that PCa cells can co-opt the immune system in the bone microenvironment leading to PCa androgen independence, treatment resistance, and survival in the bone. Furthermore, our data suggests that inhibiting inflammatory cytokine signaling and/or the autophagy process are rational strategies to combat PCa bone metastasis.
Citation Format: Megan Chang, Micaela Morgado, Viral Patel, Michael Gwede, Mary Cindy Farach-Carson, Nikki Delk. Bone marrow stromal cell-secreted inflammatory cytokines promote treatment resistance and survival of prostate cancer cells. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B15. doi:10.1158/1538-7445.CHTME14-B15
Abstract B17: Exploiting evolution to develop better personalized therapeutic strategies
Authors: Gallaher Jill A. , Anderson Alexander R. A. 
Published: May 2015

Abstract
Targeted drugs have been emerging as the future direction for personalized medicine. These drugs focus on blocking specific pathways identified by genetic alterations, but often a single biopsy reveals only a portion of the genetic heterogeneity. Even upon complete characterization of a particular tumor, successful treatment relies on targeting all of the major driver mutations, which furthermore have a possibility to fail due to resistance. With a very heterogeneous disease, this is a point-and-shoot approach with many moving targets.
While the genotypes become more heterogeneous over time, the phenotypes tend to converge as the environment selects for the most fit subtypes of cells. And while genetic mutation happens by chance, phenotypic adaptation in response to environmental changes are more predictable. By focusing on phenotypic traits, we are targeting the highest level of functional cell behavior. But even at this scale there is complexity. For example, how should a phenotype propagate - do all clones share the same phenotype, or is there some plasticity? The answer affects how the right timing and sequencing of drugs could shape the population into a more targetable one instead of into a mutationally resistant one.
To explore this tangled web of genotypic and phenotypic progression and selection, we build an agent based model. This approach allows us to investigate interactions of single cells and evolution of the collective population in an environment with spatial competition. Utilizing this agent based approach we investigate how both sequence and timing of different therapeutic methods alter the intratumor heterogeneity both at the genotypic and phenotypic scales.
Citation Format: Jill A. Gallaher, Alexander R. A. Anderson. Exploiting evolution to develop better personalized therapeutic strategies. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B17. doi:10.1158/1538-7445.CHTME14-B17
Abstract B26: Reelin signaling in tumor microenvironment is required for metastasis of mammary carcinoma cells.
Authors: Khialeeva Elvira , Chou Joan W. , Carpenter Ellen M. 
Published: May 2015

Abstract
We have investigated the role of reelin signaling in the microenvironment of breast cancer and found that reelin is essential for progression of mammary tumors to metastasis. Reelin signaling serves to position neurons in the developing central nervous system, but functions of this signaling pathway in other tissues have not been studied until recently. Our laboratory discovered that the reelin pathway is an important regulator of mammary gland development. We showed that reelin and Dab1, the intracellular adaptor protein for reelin, are required for timely development and proper morphology of the mammary gland. We also found that normal mammary epithelial cells (MECs) can respond to exogenous reelin by slowing their migration rate, while mouse mammary carcinoma 4T1 cells lose this response, likely through downregulation of Dab1 mRNA. Orthotopic injections of 4T1 cells into wild type Balb/C mice resulted in aggressive tumors that produced numerous metastases in the lungs by 4 weeks post-injection. However, when these cells were injected into mice that lack reelin or Dab1 (reeler and Dab1 mutant mice), we saw a dramatic reduction in lung metastases despite the presence of primary tumors comparable in size to the tumors formed in wild type mice. We show that this phenotype is dependent upon loss of reelin in the host environment, since tumor cells isolated from reeler mutant mice produce primary tumors and lung metastases when injected into Balb/C mice. Using soft agar colony assays and Western blotting, we show that the inability of 4T1 cells to metastasize in mutant animals might be due to a reduced capacity of mammary carcinoma cells to undergo epithelial to mesenchymal transition (EMT) in an environment deficient for reelin signaling. In addition, tumors from reeler and Dab1 mutant mice appear to have more differentiated cells as shown by anti-α smooth muscle Actin and anti-K14 immunostaining. Ki-67 staining showed no differences in proliferation between tumors from wild type, reeler or Dab1 mutant mice. Finally, tail vein injections of 4T1 cells into reeler mutant mice also fail to produce metastases, indicating that reelin signaling in the host environment might have important functions at several steps of the metastatic process. Our results implicate reelin signaling as an essential component of transition from the primary tumor to a metastatic carcinoma.
Citation Format: Elvira Khialeeva, Joan W. Chou, Ellen M. Carpenter. Reelin signaling in tumor microenvironment is required for metastasis of mammary carcinoma cells.. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B26. doi:10.1158/1538-7445.CHTME14-B26
Abstract B35: The role of tumor associated macrophages (TAMs) in triple-negative breast cancer (TNBC) invasion revealed by species-specific RNA sequencing
Authors: Rabe Daniel C. , Frankenberger Casey A. , Bainer Russell , Sankarasharma Devipriya , Chada Kiran , Krausz Thomas , Gilad Yoav , Rosner Marsha Rich 
Published: May 2015

Abstract
Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer. While five-year survival rates have reached 98% in patients treated with anti-ER or anti-HER2 therapies, patients with TNBC have a five-year survival rate of only 24%. Currently, the only form of therapy for these patients is surgery and platinum based chemotherapy. However, patient outcome is generally poor. Additionally, this disease disproportionately affects African-American women and lower income women, with rates seen approximately three times higher in African-American women compared to the rest of the population. An alternative strategy for treating TNBC patients involves targeting the tumor stroma. To better understand interaction between the tumor and stroma necessary for metastasis and invasion, we employed a triple-negative breast cancer (TNBC) model in which the metastasis suppressor Raf Kinase Inhibitory Protein (RKIP) controls primary tumor invasiveness. RKIP expression, which converts invasive tumors to non-invasive tumors, dramatically inhibits macrophage infiltration. The mechanism, which is dependent on Let-7 suppression of HMGA2, involves decreased expression of the chemokine CCL5. Furthermore, overexpression of CCL5 partially rescued the infiltration of macrophages into the tumor and intravasation of tumor cells into the blood stream. The relationships of the genes in the RKIP, HMGA2, CCL5, and macrophage pathways were observed in multiple sets of expression array data from breast cancer patients. Regulation of macrophage infiltration was observed in tumors from an HMGA2 knockout mouse model. These results show that RKIP regulates macrophage recruitment by tumors and demonstrate for the first time that metastasis suppressor genes can regulate the tumor microenvironment.
Citation Format: Daniel C. Rabe, Casey A. Frankenberger, Russell Bainer, Devipriya Sankarasharma, Kiran Chada, Thomas Krausz, Yoav Gilad, Marsha Rich Rosner. The role of tumor associated macrophages (TAMs) in triple-negative breast cancer (TNBC) invasion revealed by species-specific RNA sequencing. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B35. doi:10.1158/1538-7445.CHTME14-B35