bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A112: Eradication of cancer stem-like cells in PDAC
Authors: Arumugam Thiruvengadam , Ramachandran Vijaya , Logsdon Craig 
Published: October 2015

Abstract
Background: Pancreatic Ductal Adenocarcinoma (PDAC) is resistant to conventional chemotherapy. Cancer Stem-Like Cells (CSLCs) are drug resistant and can act as tumor initiating cells. Evidence suggests that CSLCs can be selected by chemotherapy that targets the more sensitive somatic cancer cells. In the current study we found that Gem treatment can not only select CSLCs, but can also induce transformation of somatic cancer cells into CSLCs. We also observed that p21 is required to maintain CSLCs in a quiescent state. Methods: Cell growth, cell cycle and apoptosis were analyzed by using MTS and FACS analysis. ALDH and p21 were localized by immunohistochemistry and immunofluorescence. CLSCs were analyzed by ALDH assay, clonogenic in vitro assays and in vivo tumor initiation. Both in vitro and in vivo silencing of p21 was accomplished using nanoparticle coupled siRNA. Results: Gem treatment induced the p21 and led to a transient cytostasis and chemoresistance in PDAC cell lines. Analysis of resected tumor samples revealed that Gem treatment also induced p21 expression and ALDH positivity in tumors of Gem treated but not untreated patients. In vitro studies indicated that Gem induced the acquisition of a CSLC phenotype and the expression of pluripotent transcription factors (PFTs). Silencing of p21 blocked the both basal and Gem induced CSLC numbers, the maintenance of quiescence, and resistance to Gem in vitro. In vivo, silencing of p21 greatly increased the effectiveness of Gem treatments to inhibit tumor growth and did not increase toxicity. Conclusion: These data indicate that p21 maintains chemotherapy induced CSLCs quiescence and drug resistance such that targeting p21 in combination with cytotoxic therapies is beneficial in eradicating both basal and Gem transformed CSLCs.
Note: This abstract was not presented at the conference.
Citation Format: Thiruvengadam Arumugam, Vijaya Ramachandran, Craig Logsdon. Eradication of cancer stem-like cells in PDAC. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A112.
Abstract A121: Suppression of orthotopic pancreatic cancer growth by sulforaphane is associated with activation of FOXO transcription factors
Authors: Yu Wei , Srivastava Rakesh , Shankar Sharmila 
Published: October 2015

Abstract
FoxO (forkhead box O) transcription factors are crucial regulators of cell fate. This function of FoxO proteins relies on their ability to control diverse functions such as proliferation, differentiation, DNA repair and apoptosis. Constitutively active AKT and ERK in cancer cells have been shown to phosphorylate FoxO transcription factors (FKHR, FKHRL1 and AFX), which bind to protein 14-3-3 and sequester in the cytoplasm. In the absence of survival signals, FoxO proteins dephosphorylate, translocate to the nucleus and upregulate a series of target genes, thereby promoting cell cycle arrest and apoptosis. Sulforaphane a naturally occurring isothiocyanate, exerts anti cancer effects through diverse mechanisms. In this study we have shown that sulforaphane acts both by suppressing cell proliferation and inducing apoptosis in pancreatic tumors orthotopically implanted in nude mice. Sulforaphane regulates cell survival and cell death by modulating the expression of two interacting survival signaling pathways. The inhibition of PI3K/AKT and MEK/ERK pathways by sulforaphane resulted in the inhibition of cytoplasmic phosphorylation of FOXOs, and enhanced their nuclear translocation and transcriptional activities leading to apoptosis. Furthermore, deletion of FOXO1, FOXO3 and FOXO4 genes by shRNA abrogated sulforaphane-induced cell cycle arrest and apoptosis whereas the phosphorylation deficient triple mutants of FOXOs enhanced sulforaphane-induced FOXO transcriptional activity and apoptosis by nuclear translocation of FOXO. Sulforaphane-treated mice showed significant inhibition in tumor growth which was associated with reduced phosphorylation of ERK, PI3K, AKT, FOXO1 and FOXO3a, cyclin D1 and induction of FOXO’s target genes Bim, p21/CIP1, and p27/KIP1. These data suggest that inhibition of ERK and AKT pathways act together to activate FOXO transcription factors which are involved in sulforaphane-mediated pancreatic tumor growth suppression, thus supporting the use of sulforaphane as a chemopreventive agent for the treatment of pancreatic cancer.
Citation Format: Wei Yu, Rakesh Srivastava, Sharmila Shankar. Suppression of orthotopic pancreatic cancer growth by sulforaphane is associated with activation of FOXO transcription factors. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A121.
Abstract A20: Molecular dissection of pancreatic cancer invasion and metastasis
Authors: Chiou Shin-Heng , Winslow Monte 
Published: October 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly fatal malignancy of the exocrine pancreas. Although several factors contribute to the poor prognosis of this disease, the ability of cancer cells to disseminate and establish inoperable metastases before diagnosis is a major impediment to successful therapy. Unfortunately, strategies that enable efficacious treatment or early detection of the disease do not exist, highlighting an urgent need for a critical understanding of PDAC progression and dissemination. To identify novel molecular mechanisms that drive metastasis, we compared the transcriptomes of “invasive” and “non-invasive” cancer cells isolated from tumors that are derived from a previously described autochthonous PDAC model (KrasLSL-G12D;p53LSL-R172H;Pdx1-cre or KPC mice). This mouse model was chosen because it recapitulates many aspects of the human disease, including cellular heterogeneity, abundant stromal responses, and great propensity for metastasis. To isolate pure PDAC cells, we first excluded the infiltrating, non-cancer cells by incorporating a Cre-reporter allele (R26LSL-Tomato) into the KPC mice. Our strategy to distinguish “invasive” from “non-invasive” cancer cells was based on our previous observations that the high mobility group AT-hook 2 protein (Hmga2), which is otherwise not expressed in most of adult tissues, is specifically expressed in cancer cells with mesenchymal phenotype. To label cancer cells that express Hmga2, we generated a conditional Hmga2-GFP reporter mouse. When a single Hmga2GFP allele is present in the KPC;R26LSL-Tom mice, we were able to sort both Hmga2-positive (GFP+Tomato+) and Hmga2–negative (GFP-Tomato+) cancer cells. Intravenous transplantations indicated that the GFP+ cancer cells have significantly higher metastatic ability. Furthermore, transcriptomic profiling of the sorted, un-passaged cells through RNA-Seq indicated that Hif1α activity is highly enriched in the invasive GFP+ cancer cells. Consistent with the RNA-Seq data, the expression of the Hif1α target Glut1 correlates with Hmga2 under immunohistochemical staining. We hypothesized that during PDAC progression, hypoxia induces the both up- and down-regulation of a set of genes, including both Hif1α-dependent and –independent ones, that are necessary to drive cancer metastasis. Future experiments will functionally interrogate, both in vitro and in vivo, the candidate genes selected based on presence of human orthologs, cross-examination with co-purified myofibroblast transcriptomic profiles, fold change, and novelty. Our study will help identify important molecular mechanisms that drive PDAC metastasis.
Citation Format: Shin-Heng Chiou, Monte Winslow. Molecular dissection of pancreatic cancer invasion and metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A20.
Abstract A22: CXCL12-CXCR4 chemotactic pathway modulates metastasis and perineural invasion in pancreatic cancer
Authors: Xu Qinhong , Duan Wanxing , Lei Jianjun , Ma Jiguang , Wu Erxi , Ma Qingyong 
Published: October 2015

Abstract
Perineural invasion (PNI) is considered as an alternative route for metastatic spread of pancreatic cancer cells; however the molecular changes leading to PNI are still poorly understood. In this study, we show that CXCL12/CXCR4 axis, which is one of the most widely studied chemokines signaling, plays a pivotal role in the neurotropism of pancreatic cancer cells to local peripheral nerves. We conducted a co-culture model, which used newborn rat dorsal root ganglia (DRG) and pancreatic cancer cells, and a sciatic nerve invasion model by nude mice. We provide in vitro and in vivo evidence to study the function of CXCL12/CXCR4 signaling in PNI progression and pathogenesis. The results showed that the activation of CXCL12/CXCR4 axis significantly increased the invasion of pancreatic cancer cells and promoted the outgrowth of DRG. The chemotaxis migration of pancreatic cancer cells to the neurites of DRG is evidently suppressed by blocking the pathway. In vivo analyses revealed that the abrogation of the activated signaling could inhibit tumor growth and invasion of the sciatic nerve toward the spinal cord. These data indicated that CXCL12/CXCR4 axis is involved in PNI, and inhibition of the signaling pathway may be a promising new therapeutic strategy for the recurrence and metastasis of pancreatic cancer.
Citation Format: Qinhong Xu, Wanxing Duan, Jianjun Lei, Jiguang Ma, Erxi Wu, Qingyong Ma. CXCL12-CXCR4 chemotactic pathway modulates metastasis and perineural invasion in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A22.
Abstract A27: Redefining the role of Notch in acinar to ductal metaplasia
Authors: Halbrook Christopher J. , Crawford Howard C. 
Published: October 2015

Abstract
The EGFR and Notch signaling pathways have been widely implicated in relation to both chronic pancreatitis and pancreatic ductal adenocarcinoma in humans, however the link between the two pathways has remained obscure. Acinar to ductal metaplasia (ADM,) a phenomenon where acinar cells undergo a morphological change and begin expressing markers normally found only in ductal cells while losing markers typical of acinar cells, has been linked to both the Notch and EGFR signaling pathways. ADM is highly proliferative with the potential to develop into pancreatic intraepithelial neoplasia, a precursor lesion to pancreatic cancer. Recently we and others have shown that genetic ablation of EGFR in the pancreas effectively prevents acinar to ductal metaplasia in cerulein model of pancreatitis in mice, and prevents tumorigenesis driven by oncogenic Kras. Additionally, we have found that acinar cells harvested from EGFRf/f;Ptf1aCre/+ mice (EKO) mice are resistant to ADM in vitro upon cerulein treatment, or by the expression of oncogenic Kras. Activation of EGFR by treatment of WT collagen embedded acinar cell explants with the EGFR ligand TGF-α has previously been shown to induce ADM in a manner requiring Notch pathway activation. Furthermore, it has also been demonstrated that expression of Notch2 intracellular domain (N2ICD) is sufficient to induce ADM in WT acinar cells. To directly investigate the relationship of the EGFR, Kras, and Notch signaling pathways in ADM, we examined the effect of Notch signaling in acinar cells harvested from EKO mice. Interestingly, these acinar cells fail to transdifferentiate in vitro upon transduction of N2ICD in 3D culture; however the transdifferentiation event can be rescued by co-expression of oncogenic Kras with N2ICD in acinar cells lacking EGFR. These results indicate that EGFR is important in Notch induced ADM, however there are other pathways that possibly can be utilized by acinar cells expressing oncogenic Kras to drive ADM.
Citation Format: Christopher J. Halbrook, Howard C. Crawford. Redefining the role of Notch in acinar to ductal metaplasia. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A27.
Abstract A39: The activation of β1-integrin by type i collagen coupling with the Hedgehog pathway promotes the epithelial-mesenchymal transition in pancreatic cancer cells
Authors: Duan Wanxing , Ma Qingyong , Ma Jiguang , Xu Qinhong , Lei Jianjun , Wu Erxi 
Published: October 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal gastrointestinal cancers, is characterized by the excessive deposition of extracellular matrix (ECM) that has been thought to contribute to the malignant behaviour. However, the detailed mechanism and the contribution of excessive deposition of ECM in PDAC progression remain unclear. A better understanding of the mechanism involved in this process is essential for the design of new effective therapies. In this study, we demonstrated that pancreatic cancer cells exhibited increased proliferation and decreased apoptosis in response to type I collagen. In addition, exposed to type I collagen, PDAC cells lost the expression of E-cadherin and increased expression of mesenchymal markers, including N-cadherin and vimentin, which was correlated with enhanced cell migration and invasiveness. Conversely, the knockdown of β1-integrin abolished the effects induced by type I collagen. Further investigation revealed that type I collagen activates β1-integrin accompanied with significant up-regulation of Gli-1. siRNA specific to Gli-1 reversed the effects of type I collagen on PDAC invasion and epithelial-mesenchymal transition (EMT). These results suggest that there is cross-talk between the β1-integrin signaling pathway and the Hedgehog (HH) pathway in pancreatic cancer and the abnormal activation of the HH pathway plays a key role in the type I collagen-induced effects on pancreatic cancer. Therefore, our findings may have potential significance for the development of new therapeutic strategies to treat this highly aggressive malignancy.
Citation Format: Wanxing Duan, Qingyong Ma, Jiguang Ma, Qinhong Xu, Jianjun Lei, Erxi Wu. The activation of β1-integrin by type i collagen coupling with the Hedgehog pathway promotes the epithelial-mesenchymal transition in pancreatic cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A39.
Abstract A48: CD4+ T lymphocyte ablation prevents pancreatic carcinogenesis in mice
Authors: Zhang Yaqing , Yan Wei , Mathew Esha , Bednar Filip , Wan Shanshan , Collins Meredith A. , Evans Rebecca A. , Welling Theodore H. , Vonderheide Robert H. , Magliano Marina Pasca di 
Published: October 2015

Abstract
This abstract is also being presented as a short talk in Session 6: Immunology. A full abstract is printed in the Proffered Abstracts section (PR11) of the Conference Proceedings.
Citation Format: Yaqing Zhang, Wei Yan, Esha Mathew, Filip Bednar, Shanshan Wan, Meredith A. Collins, Rebecca A. Evans, Theodore H. Welling, Robert H. Vonderheide, Marina Pasca di Magliano. CD4+ T lymphocyte ablation prevents pancreatic carcinogenesis in mice. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A48.
Abstract A54: Ly6Chi inflammatory monocytes mediate tumor regression in a mouse model of spontaneously arising pancreatic ductal adenocarcinoma
Authors: Gladney Whitney L. , Tooker Graham M. , Beatty Gregory L. 
Published: October 2015

Abstract
Macrophage infiltration into solid malignancies most often portends a poor prognosis. In pancreatic ductal adenocarcinoma (PDAC), macrophages dominate the leukocyte infiltrate with effector T lymphocytes remaining scarce. Strategies to restore productive immunosurveillance in PDAC have largely focused on inducing anti-tumor T cell immunity. However, we have previously shown in patients and a mouse model of PDAC that immune modulation with a CD40 agonist can induce macrophages to facilitate tumor regression. Thus, strategies that restore innate immunosurveillance may hold promise in the treatment of PDAC. To further investigate the role of macrophages as targets for anti-tumor immunotherapy, we utilized the KrasG12D; Trp53R172H; Pdx-1 Cre (KPC) genetically engineered mouse model of PDAC. We previously reported a role for liposomal targeted macrophages in facilitating tumor regression induced with CD40 therapy. However, unexpectedly we found by immunohistochemistry that macrophages targeted by liposomes do not infiltrate PDAC tumors in response to CD40 therapy. This finding suggested a role for additional leukocyte subsets in mediating the anti-tumor effect. Using immunohistochemistry, we found that systemic CD40 activation induced the infiltration of Ly6C+ myeloid cells into KPC tumors. Based on this finding, we hypothesized that macrophages may regulate the infiltration of Ly6Chi inflammatory monocytes, which are the critical effector myeloid cells mobilized in the peripheral blood by CD40 agonist therapy. In support of this hypothesis, we found that tumor regression induced with a CD40 agonist was abrogated by treatment with the anti-Ly6C/Ly6G RB6-8C5 depleting antibody. Flow cytometric analysis of peripheral blood revealed that RB6-8C5 and liposomes target distinct myeloid subsets. Whereas RB6-8C5 was found to deplete Ly6ChiCCR2+ inflammatory monocytes, CEL depleted Ly6Cneg myeloid cells. Our findings suggest that CD40-induced tumor regression in PDAC is mediated by inflammatory monocytes which infiltrate tumor lesions under the regulation of extra-tumoral macrophages.
Citation Format: Whitney L. Gladney, Graham M. Tooker, Gregory L. Beatty. Ly6Chi inflammatory monocytes mediate tumor regression in a mouse model of spontaneously arising pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A54.
Abstract A73: De-convoluting therapeutic resistance in a pancreatic cancer model: Pharmacogenomic evaluation of intratumoral clonal heterogeneity
Authors: Vietsch Eveline E. , Simmons John K. , Peran Ivana , Stenstra Marianne , Mock Beverly A. , Wellstein Anton 
Published: October 2015

Abstract
Background: The duration of therapeutic response in pancreatic adenocarcinoma to both targeted therapies and conventional chemotherapeutics is abysmal, greatly contributing to the 5-year survival rate of this disease remaining in the single digits. Given the high proliferative rate of these tumors, and the frequent occurrence of mutations in genes critical for maintaining genomic integrity, we hypothesized that rapid therapeutic resistance may largely be the consequence of intratumoral heterogeneity present at the onset of therapy.
Materials and Methods: To address this question, an integrated genomic and pharmacologic survey was performed on a panel of clonal cell lines generated from a tumor arising in a Kras/Trp53 mutant mouse model (p48-Cre; LSL-KrasG12D; LSL-Trp53R172H).
Results: All lines screened maintained tumorigenicity upon allografting, and exhibited metastatic capacity. Whole exome sequencing confirmed that 94% of driver mutations found in the clonal lines were also present in the tumor. Importantly, each clonal line contains unique passenger mutations. Exposure of these lines to conventional chemotherapeutics in vitro (i.e. gemcitabine, doxorubicin, and vincristine) showed high variance in sensitivity, with 10-fold ranges of IC50s among the lines. Screening of the clonal cell lines with a kinase inhibitor library of 200 compounds, showed distinct vulnerabilities to targeted pathways between the lines. Gene expression profiling and pathway analysis highlighted variation in critical cellular pathways between the lines.
Conclusions: Our results in this model system implicate ab initio drug resistance in these heterogeneous tumors as a major contributor to the poor therapeutic outcomes in this disease. This applies to conventional chemotherapy as well as targeted inhibitors.
Citation Format: Eveline E. Vietsch, John K. Simmons, Ivana Peran, Marianne Stenstra, Beverly A. Mock, Anton Wellstein. De-convoluting therapeutic resistance in a pancreatic cancer model: Pharmacogenomic evaluation of intratumoral clonal heterogeneity. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A73.
Abstract A77: Investigating the role of ADAM10 in pancreatic tumor differentiation
Authors: Peverley Louise V. , Halbrook Christopher J. , Hall Jason C. , Ardito Christine M. , Crawford Howard C. 
Published: October 2015

Abstract
Pancreatic adenocarcinoma (PDAC) is the 4th most common cause of cancer related deaths in the United States and has a dismal 5-year survival rate of 6%. This prognosis is attributed the disease’s fast and asymptomatic progression to metastasis, leading to late diagnosis upon which time there are few treatment options available. The A Disintegrin and Metalloproteinase (ADAM) family are sheddase proteins known to regulate cell adhesion and function. This regulation can allow ADAMs to influence the ability of tumor cells to disseminate from the primary tumor and metastasize to distant organs. ADAM10, which is seen to be up-regulated in both chronic pancreatitis and PDAC, cleaves a variety of substrates including several cell adhesion molecules such as L1-CAM, N-Cadherin, and E-Cadherin. Using a conditional knockout for ADAM10 in the Kras+/G12D;Ptf1a+/Cre (KC) mouse model of pancreatic cancer, we have observed an absence of metastasis when ADAM10 is genetically ablated. To investigate the potential role that ADAM10 plays in this, we used a shRNA approach to knock-down ADAM10 expression in various human pancreatic cancer cells lines. Analysis of these cell lines suggests a partial restoration of a less aggressive, differentiated phenotype, consistent with the increased longevity of the ADAM10 knockout KC mice.
Citation Format: Louise V. Peverley, Christopher J. Halbrook, Jason C. Hall, Christine M. Ardito, Howard C. Crawford. Investigating the role of ADAM10 in pancreatic tumor differentiation. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A77.