bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 1475: Therapeutic responses in a novel patient-derived xenograft mouse model for rare acinar cell pancreatic carcinoma
Authors: Marlow Laura A. , Mathias Adam C. , Dawson Louis K. , Durham William F. , Meshaw Kenneth A. , Mullin Robert J. , Synnott Aidan J. , Paz-Fumagalli Ricardo , Krishna Murli , Von Hoff Daniel , Small Daniel L. , Colon-Otero Gerardo , Copland John A.
Published: August 2015

Acinar cell carcinoma of the pancreas (ACC) is an uncommon malignancy, accounting for less than 1% of all pancreatic neoplasms. Because of its rarity, only a few retrospective studies are available to help guide management. We previously reported the case of a patient with metastatic ACC who achieved prolonged survival with doxorubicin as a result of personalized treatment designed in part on the basis of molecular and in-vitro data collected on analysis of the tumor and primary cells in culture developed from the liver metastasis. We now report the characterization of a patient derived xenograft (PDX) mouse model originating from this patient's ACC liver metastasis tissue. Antitumor activity of multiple drugs (5-FU, irinotecan, oxaliplatin, gemcitabine, bevacizumab, erlotinib, doxorubicin and imatinib) used as single agent therapy is demonstrated. Of the targeted and cytotoxic therapies used, oxaliplatin produced a dramatic and prolonged response to therapy even after withdrawal of treatment. Bevacizumab produced a significant response, as well. Serum lipase and tissue amylase levels correlated with the antitumor response to therapy. Thus, we have developed and characterized an ACC PDX model that may be used in drug discovery for the treatment of this rare cancer for which no standard of care exists.

Note: This abstract was not presented at the meeting.

Citation Format: Laura A. Marlow, Adam C. Mathias, Louis K. Dawson, William F. Durham, Kenneth A. Meshaw, Robert J. Mullin, Aidan J. Synnott, Ricardo Paz-Fumagalli, Murli Krishna, Daniel Von Hoff, Daniel L. Small, Gerardo Colon-Otero, John A. Copland. Therapeutic responses in a novel patient-derived xenograft mouse model for rare acinar cell pancreatic 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 1475. doi:10.1158/1538-7445.AM2015-1475
Abstract 1476: Effect of target therapies in liver cancer PDX tumor models: Response, resistance and predictive biomarkers
Authors: Yu Tengfei , Yan Ying , Du Wei , Hua Liang , Yang Xuqin , Tan Tingting , Gu Jiali , Jiang Jingjing , Ye Xin K. , Gu Zhenyu
Published: August 2015

Liver cancer is one of the leading causes of cancer mortality worldwide. Hepatocelluar carcinoma (HCC) is the most common form of liver cancer, followed by intrahepatic cholangiocarcinoma (IHCC). HCC has dismal clinical outcome, whereas the prognosis is even worse for IHCC as it is more difficult to diagnose and to treat comparing to HCC. Surgical resection and local ablation remain the top choices of therapy for early liver cancer while chemoembolization-TACE is commonly used to treat intermediate HCC. Sorafenib is the only FDA approved target therapy for advanced HCC and its clinical utility in IHCC is still being examined in clinical trials. On-going clinical trials are also testing therapeutic modalities against oncogenic pathways including RTK signaling pathways, PI3K/Ras pathways and the angiogenesis pathway.

PDX tumor models recapitulate the clinical complexity of the original human cancers. At GenenDesign, we have established over 800 PDX tumor models and conducted extensive drug response tests in a mouse trial format. GenenDesign liver cancer PDX tumor panel comprises of 36 HCC and over 10 IHCC models. Our in-house mouse trials in liver PDX tumor models include treatment with sorafenib as well as XL184, a multi-kinase inhibitor currently being evaluated in clinical trials. In addition, crizotinib (a cMET inhibitor) and AZD4547 (an FGFR inhibitor) as mono-therapies as well as in combination with sorafenib are also tested in search of therapeutic signals. From these studies, we have identified both drug sensitive and de novo drug resistant models. Through long-term treatment, acquired resistance models and reversible resistance models are also established.

Currently, GD liver cancer PDX tumors are being analyzed by genetic and genomic profiling (hot-spot mutational analysis, exome-seq, RNA-seq, SNP array and gene expression array). Bioinformatics analysis is on-going to identify genomic signatures with the potential as predictive biomarkers for sorafenib and other targeted therapies in liver cancer. Together with genomic profiling, signal search in PDX mouse trials promise to be effective in generating preclinical datasets to facilitate clinical trial designs.

Citation Format: Tengfei Yu, Ying Yan, Wei Du, Liang Hua, Xuqin Yang, Tingting Tan, Jiali Gu, Jingjing Jiang, Xin K. Ye, Zhenyu Gu. Effect of target therapies in liver cancer PDX tumor models: Response, resistance and predictive biomarkers. [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 1476. doi:10.1158/1538-7445.AM2015-1476
Abstract 1478: Development of novel Mi-HTX in vivo platform by reconstituting autologous immune components in patient tumor-derived xenografts
Authors: Thiyagarajan Saravanan , Radhakrishnan Padhma , Radhakrishna Vinod D , Pinto Dency D , Majumder Biswanath
Published: August 2015

Developing a clinically relevant in vivo platform for testing novel anti cancer therapeutics is hindered by lack of preservation of several critical components of tumor microenvironments. While syngenic mice model is being used traditionally for understanding action of immunomodulator compounds one major drawback of this model is it does not represent human specific targets therefore exhibit poor translational potential. Patient tumor derived xenograft (PDX) is increasingly appreciated as a surrogate of patient tumors for functional screening of anticancer drugs. However, these models also display limitation of stably maintaining active phenotypes of intra-tumor or tumor infiltrating immune cells in a dynamical setting where mice immune system is also compromised. Recently developed ex vivo CANScript platform (presenting in AACR-2015 Annual meeting) shows promises in realization of a preserved patient immune network in short term culture but have inherent constraints of determining PK/PD correlations. To overcome this limitation and meet the growing need of testing immunomodulator drugs in an immunologically relevant in vivo model here we engineer a novel human tumor xenograft platform called Mi-HTX where patient immune network was reconstituted by implanting suitably primed peripheral blood mononuclear cells from same donor. The data shows the preferential recruitment of several key immune cells (CD8, macrophage and TRegs). The PK/PD/Efficacy correlation of human anti-CTLA-4 in Mi-HTX platform shows the potential application of this model for systematically evaluating immunomodulator drugs.

Citation Format: Saravanan Thiyagarajan, Padhma Radhakrishnan, Vinod D Radhakrishna, Dency D Pinto, Biswanath Majumder. Development of novel Mi-HTX in vivo platform by reconstituting autologous immune components in patient tumor-derived xenografts. [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 1478. doi:10.1158/1538-7445.AM2015-1478
Abstract 1479: Investigation of the permeation and retention of biocompatible low-retention superparamagnetic iron oxide nanoclusters in tumors with magnetic resonance imaging
Authors: Wei Yushuang , Shan Liang , Wang Paul , Zhou Qibing
Published: August 2015

Superparamagnetic iron oxide (SPIO) nanoclusters assembled with poly-L-lysine (PLL) and hydroxyl starch show a unique bioclearance property with low retention in the liver and spleen and effective renal excretion. In the orthotopic liver tumor model, the assembled low retention biocompatible SPIO nanoclusters exhibit a high contrast enhancing capability in T2-weighted magnetic resonance imaging (MRI) at a low dose. For the orthotopic liver tumor, the T2-weighted MRI with SPIO nanoclusters is a negative imaging method to reduce the signal intensity of the normal liver tissue, whereas the potential of the retention and permeability of SPIO nanoclusters in tumors was not fully assessed. The latter becomes critically important for diagnosis and prognosis of pancreatic and prostate tumors in the non-reticuloendothelial system. Two approaches of tumor targeting were investigated and compared in this study including the passive targeting via the EPR effect of nanoparticles and the active targeting by the tumor-specific ligands such as TAT, iRGD and pH sensitive peptides. The accumulation of SPIO nanoclusters in tumors was assessed in the subcutaneous pancreatic and prostate tumor models with MRI over times, iron levels and pathological assessment. Our results showed that the retention and permeation of SPIO nanoclusters varied with multiple factors of tumors. For example, well developed tumors with large necrosis core tended to have a high level of SPIO accumulation. In contrast, the early stage solid tumor had minimal retention of SPIOs. Similar effects have been observed in both passive and active tumor targeting by SPIO nanoclusters. Moreover, the accumulation of SPIOs in tumor was achieved over a longer time period over 24 to 48 h with long retention as compared with those in the normal liver, lung, and spleen tissue (between 30 min to 3 h) with rapid clearance. Our data suggested that with well-designed tumor targeting, the biocompatible low-retention SPIO nanoclusters could be an effective MRI contrast agent for MRI of pancreatic and prostate tumors.

Citation Format: Yushuang Wei, Liang Shan, Paul Wang, Qibing Zhou. Investigation of the permeation and retention of biocompatible low-retention superparamagnetic iron oxide nanoclusters in tumors with magnetic resonance imaging. [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 1479. doi:10.1158/1538-7445.AM2015-1479
Abstract 149: Overexpression of the long non-coding RNA PVT1 and its role in cervical carcinogenesis
Authors: Iden Marissa , Fye Samantha , Ramchandran Ramani , Rader Janet S.
Published: August 2015

Although it is becoming increasingly clear that long non-coding RNAs (lncRNAs) are intricately involved in numerous cancer types, the mechanisms by which they influence carcinogenesis remain poorly understood. The plasmacytoma variant translocation 1 gene (PVT1) is a lncRNA that has been designated as an oncogene due to its contribution to the phenotype of multiple cancers. Further, our lab has recently demonstrated that human papillomavirus (HPV) integration, a hallmark of invasive cervical cancer (ICC), into the PVT1 locus occurs in multiple cervical tumors. The present study was designed to investigate the role of PVT1 in cervical carcinogenesis. PVT1 expression was measured by quantitative PCR (qPCR) in 41 ICC samples, 20 normal cervix samples, and four cervical cell lines (SiHa, HeLa, DoTc2, and E6/E7-transformed ectocervical epithelial cells). Further, we used siRNA-targeted knockdown in conjunction with functional assays to examine PVT1's effects on cervical cancer cell proliferation, migration and invasion, apoptosis, and cisplatin-resistance. Our results demonstrate that PVT1 expression is significantly increased in ICC tissue versus normal cervix. PVT1 knockdown in cervical cancer cell lines resulted in significantly decreased cell proliferation, migration and invasion. Further, apoptosis and cisplatin cytotoxicity were significantly increased in PVT1 siRNA-transfected cells. Collectively, our data suggest that PVT1 may play a crucial role in cervical carcinogenesis. Future work will focus on determining the mechanism(s) by which this lncRNA exerts its multiple effects on cancer-related processes.

Citation Format: Marissa Iden, Samantha Fye, Ramani Ramchandran, Janet S. Rader. Overexpression of the long non-coding RNA PVT1 and its role in cervical carcinogenesis. [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 149. doi:10.1158/1538-7445.AM2015-149
Abstract 1500: Syndecan-1 targeted mesoporous silica-coated gold nanorods act as theranostic agents for in vivo detection of orthotopic pancreatic tumors using multispectral optoacoustic tomography
Authors: Khanal Anil , Kimbrough Charles W. , Garbett Nichola C. , Burlison Joseph A. , Grizzle William E. , McNally Lacey R.
Published: August 2015

Detection of pancreatic cancer is especially challenging in comparison to many cancers due to severe limitations of both contrast agent delivery to pancreatic tumors and limitations of traditional imaging techniques such as poor resolution and low depth penetration. Theranostic nanoparticles encompassing both therapeutic and diagnostic capabilities can overcome limitations associated with conventional cancer diagnosis and therapy. In this study, we compared mesoporous silica coated gold nanorods (MS-GNR) and polyacrylic acid coated gold nanorods (PAA-GNR) targeted to tumor cells via Syndecan-1 ligand for detection of orthotopic pancreatic cancer in vivo. Because one of the major difficulties for translation of theranostic nanoparticles to the clinic is an inability track performance of nanoparticles in vivo, especially at depths required of orthotopic tumors, we will overcome this impediment by utilizing multispectral optoacoustic tomography (MSOT). Multispectral optoacoustic tomography provides high optical contrast images at a microscale resolution and reasonable penetration depth by combining the advantages of optical (high sensitivity) and ultrasound (increased depth of penetration). Our results indicate that the Syndecan-1 MS-GNR were superior to Syndecan-1 PAA-GNR, untargeted MS-GNR, or untargeted PAA-GNR as contrast agents to identify pancreatic cancer in vivo via MSOT. The Syndecan-1 MS-GNR particles also resulted in reduced off-target accumulation compared to Syndecan-1 PAA-GNR. This study is among the first to evaluate biodistribution of ligand-targeted nanoparticles in the context of orthotopic pancreatic cancer using multispectral optoacoustic tomography. The MS GNR can be utilized as theranostic platform due to ability of mesoporous silica to encapsulate drug and easy surface modification with cancer recognizing motif peptide.

Citation Format: Anil Khanal, Charles W. Kimbrough, Nichola C. Garbett, Joseph A. Burlison, William E. Grizzle, Lacey R. McNally. Syndecan-1 targeted mesoporous silica-coated gold nanorods act as theranostic agents for in vivo detection of orthotopic pancreatic tumors using multispectral optoacoustic tomography. [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 1500. doi:10.1158/1538-7445.AM2015-1500
Abstract 1502: DCLK1 labeling a unique pancreatic cellular lineage contributes to intraductal papillary mucinous neoplasm development
Authors: Qiu Wanglong , Su Gloria
Published: August 2015

BACKGROUND & AIMS: Recently DCLK1 has been controversial as a biomarker of progenitor cells in both intestinal tract and pancreas. Pancreatic intraductal papillary mucinous neoplasm (IPMN), in contrast to pancreatic intraepithelial neoplasia (PanIN), has been relatively less investigated. Here, we explored whether DCLK1-expressing cells were involved in the genesis of pancreatic IPMNs using mouse models. METHODS: We compared the incidence of DCLK1-positive cells in pancreatic tissue samples derived from mouse models for IPMNs, PanINs, acinar to ductal metaplasia (ADM), and human IPMN samples by immunohistochemistry. And how the DCLK1+ cells engage ADM and IPMNs and its origin were investigated by in vitro culture and in vivo lineage tracing. RESULTS: The DCLK1+ cells were identified exclusively in the pancreatic tissues with activated oncogene compared to wild-type. Mouse lineage tracing experiments showed that DCLK1+ cells might originate from a cell lineage distinct from pancreatic PDX1 (+) progenitors. The pancreatic DCLK1+ cells shared the features of tuft cells but absence of IPMN tumor biomarkers. DCLK1+ cells presented in the acinar clusters prior to formation of metaplastic ductal cells, and enriched in the “IPMN niches”. Oncogenic signaling pathways such as SHH and DLL4 were activated or upregulated in the tumor cells but not the DCLK1+ cells of IPMNs. DCLK1 was also expressed in a subpopulation of tumor cells in 20% of human IPMN patients. CONCLUSIONS: DCLK1 labels a unique pancreatic cellular lineage in mouse. The clustering of DCLK1+ cells is an early event in oncogene-induced tumorigenesis. Pancreatic DCLK1+ cells may contribute to the initiation of ADM and its progression to IPMNs.

Key words: Pancreatic IPMN; ADM; DCLK1; SOX9.

Citation Format: Wanglong Qiu, Gloria Su. DCLK1 labeling a unique pancreatic cellular lineage contributes to intraductal papillary mucinous neoplasm development. [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 1502. doi:10.1158/1538-7445.AM2015-1502
Abstract 1503: HP1-gamma's expression correlates with glioma grade and survival and is a putative marker of glioma stem like cells
Authors: Rajcevic Uros , Fritah Sabrina , Nazarov Petr V. , Popovic Mara , Kavalar Rajko , Strojnik Tadej , Podergajs Neza , Knol Jaco C. , Pham Thang V. , Piersma Sander R. , Jimenez Connie R. , Niclou Simone P.
Published: August 2015

Genetic and signaling pathways involved in the development of glioblastoma have been relatively well characterized. Gene/protein expression profiles of glioblastoma have been described that reflect stem-like phenotype of the tumor. However, no reliable individual markers exist up-to-date that differentiate glioblastoma stem-like cells from the neural stem cells. Glioblastoma appears to be of heterogenous cellular population, but detailed cellular origin of these tumors is unknown. Using a label-free proteomic approach, we analyzed two different glioma models with proven de novo tumorigenic properties, and compared them with primary neurospheres. Of almost 2000 identified proteins, we found 482 to be significantly differentially expressed among the three groups. Among the identified substrates, the clusters of proteins with highest density of protein-protein interactions were functionally enriched in RNA processing related to development and metabolic processes. We then focused on two putative quantitative markers of glioma stem-like cells, HP1-gamma (Heterochromatin Protein 1- gamma) - CBX3 (chrome box 3), an epigenetic regulator involved in RNA processing, and LDHA (Lactate Dehydrogenase A), a key metabolic enzyme of anaerobic glycolysis. We quantitated their expression in glioma tissue of different grades in a large set of patient samples and were able to show that the expression of HP1-gamma, highly upregulated in glioblastoma stem-like cells, correlates to glioma grade. Independent analysis of publicly available glioma patient data showed that LDHA expression is linked to IDH1 mutation status both in high grade and low grade gliomas. The same analysis reinforced our findings towards an increased involvement of CBX3/HP1-gamma in high grade gliomas. Altogether, CBX3/HP1-gamma and LDHA are novel biomarkers for cancer stem cell phenotype with different clinical importance in gliomas.

Citation Format: Uros Rajcevic, Sabrina Fritah, Petr V. Nazarov, Mara Popovic, Rajko Kavalar, Tadej Strojnik, Neza Podergajs, Jaco C. Knol, Thang V. Pham, Sander R. Piersma, Connie R. Jimenez, Simone P. Niclou. HP1-gamma's expression correlates with glioma grade and survival and is a putative marker of glioma stem like cells. [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 1503. doi:10.1158/1538-7445.AM2015-1503
Abstract 1506: Frequent loss of function mutations in TGFβR1 and TGFβR2 identify hair follicle bulge stem cells as the cell of origin for cutaneous squamous cell carcinoma
Authors: Cammareri Patrizia , Rose Aidan M. , Vincent David F. , Libertini Silvana , Ridgway Rachel A. , Athineos Dimitris , Coates Philip , McHugh Angela , Pourreyron Celine , Larsson Jonas , Spender Lindsay C. , Sapkota Gopal , Purdie Karin , Proby Charlotte , Harwood Catherine A. , Leigh Irene M. , Clevers Hans , Barker Nicholas , Karlsson Stefan , Pritchard Catrin , Marais Richard , South Andrew P. , Sansom Owen J. , Inman Gareth J.
Published: August 2015

Solid tumors are typically considered to arise from the accumulation of mutations within either stem or differentiated cells and to evolve over several years. However, melanoma patients treated with inhibitors of oncogenic BRAF frequently present with keratoacanthomas and/or cutaneous squamous cell carcinoma (cSCC) within weeks of treatment, possibly driven by paradoxical RAS/RAF MAPK pathway activation. Here, we identify frequent HRAS, TGFβR1 and TGFβR2 mutations in skin lesions from vemurafenib treated patients. Analysis of 98 human sporadic cSCC tumor samples and 21 cSCC cell lines revealed mutation of TGFβ receptors in 42% of samples and activating RAS mutations in 9% of samples. Functional analysis indicates that TGFβ receptor mutations frequently result in loss of canonical signaling. Analysis of normal human skin revealed localised TGFβ signaling in hair follicle bulge stem cells. In murine skin autocrine TGFβ signaling was highly localised to Lgr5+ve stem cells. We modelled hyperactivation of the MAPK pathway (through knockin of BRafV600E or KRASG12D) and the consequences of TGFβ signalling ablation (through the deletion of Tgfβr1) in Lgr5+ve cells. Whist BRaf or KRAS activation alone did not lead to cancer, homozygous deletion of Tgfβr1 enabled rapid cSCC development. Taken together, our results indicate that Lgr5+ve stem cells can act as the cell of origin for cSCC and that hyperactivation of the RAS-RAF-MAPK pathway, coupled with loss of TGFβ signalling, are driving events of skin tumorigenesis.

Citation Format: Patrizia Cammareri, Aidan M. Rose, David F. Vincent, Silvana Libertini, Rachel A. Ridgway, Dimitris Athineos, Philip Coates, Angela McHugh, Celine Pourreyron, Jonas Larsson, Lindsay C. Spender, Gopal Sapkota, Karin Purdie, Charlotte Proby, Catherine A. Harwood, Irene M. Leigh, Hans Clevers, Nicholas Barker, Stefan Karlsson, Catrin Pritchard, Richard Marais, Andrew P. South, Owen J. Sansom, Gareth J. Inman. Frequent loss of function mutations in TGFβR1 and TGFβR2 identify hair follicle bulge stem cells as the cell of origin for cutaneous squamous cell 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 1506. doi:10.1158/1538-7445.AM2015-1506
Abstract 1507: Heterogeneity of CD34 and CD38 expression in adult acute B lymphoblastic leukemia cells is reversible and not hierarchically organized
Authors: Jiang Zhiwu , Deng Manman , Lu Yi , Xu Bing , Li Peng
Published: August 2015

The existence and identification of leukemia stem cells in adult acute B lymphoblastic leukemia (B-ALL) remain controversial. We examined whether adult B-ALL is hierarchically organized into phenotypically distinct subpopulations of leukemogenic and non-leukemogenic cells or whether most B-ALL cells retain leukemogenic capacity, irrespective of their immunophenotypes. Cells from CD34+CD38-, CD34+CD38+, and CD34-CD38+ subpopulations of primary adult B-ALL xenografts were shown to be capable of reconstituting the original leukemia in NOD-scid-IL2Rg-/- mice. We found that primary leukemia cells from 11 of 25 adult B-ALL patients with different expression profiles of CD34 and CD38 proliferated robustly and became CD34-CD38+ after being co-cultured with OP9 stromal cells. Surprisingly, cultured CD34-CD38+ B-ALL cells were able to reestablish the complete leukemic phenotype in xenografts. Transcriptomic analysis of CD34+CD38-, CD34+CD38+, and CD34-CD38+ fractions purified directly from xenografts and CD34-CD38+ cells from culture revealed no significantly distinct expression profiles of transcription factors among these populations. Furthermore, 5.7% of single adult primary B-ALL cells engrafted in vivo. These observations suggest that adult B-ALL follows the stochastic stem cell model and that the heterogeneity of CD34 and CD38 expression in B-ALL is reversibly dependent on the microenvironment and is not hierarchically organized.

Citation Format: Zhiwu Jiang, Manman Deng, Yi Lu, Bing Xu, Peng Li. Heterogeneity of CD34 and CD38 expression in adult acute B lymphoblastic leukemia cells is reversible and not hierarchically organized. [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 1507. doi:10.1158/1538-7445.AM2015-1507
Abstract 1508: UV-induced Wnt7a in the human skin microenvironment specifies the fate of neural crest -like cells via suppression of Notch
Authors: Fukunaga-Kalabis Mizuho , Hristova Denitsa , Wang Joshua , Li Ling , Heppt Markus , Wei Zhi , Gyurdieva Alexandra , Webster Marie , Oka Masahiro , Weeraratna Ashani , Herlyn Meenhard
Published: August 2015

Multipotent stem cells with neural crest-like properties have been identified in the dermis of human skin. These neural crest stem cell (NCSC)-like cells display self-renewal capacity and differentiate into neural crest derivatives including epidermal pigment-producing melanocytes. NCSC-like cells share many properties with aggressive melanoma cells, such as high migratory capabilities and expression of the neural crest markers. However, little is known about which intrinsic or extrinsic signals determine the proliferation or differentiation of these neural crest-like stem cells. Here, we show that in NCSC-like cells, Notch signaling is highly activated, similar to melanoma cells. Inhibition of Notch signaling reduced proliferation of NCSC-like cells, induced cell death, and down-regulated non-canonical Wnt5a, suggesting that the Notch pathway contributes to the maintenance and motility of these stem cells. In three-dimensional skin reconstructs, canonical Wnt signaling promoted the differentiation of NCSC-like cells into melanocytes. This differentiation was triggered by the endogenous Notch inhibitor Numb, which is up-regulated in the stem cells by Wnt7a derived from UV-irradiated keratinocytes. Together, these data reveal a novel crosstalk between the two conserved developmental pathways in postnatal human skin, and highlight the role of the skin microenvironment in specifying the fate of stem cells.

Citation Format: Mizuho Fukunaga-Kalabis, Denitsa Hristova, Joshua Wang, Ling Li, Markus Heppt, Zhi Wei, Alexandra Gyurdieva, Marie Webster, Masahiro Oka, Ashani Weeraratna, Meenhard Herlyn. UV-induced Wnt7a in the human skin microenvironment specifies the fate of neural crest -like cells via suppression of Notch. [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 1508. doi:10.1158/1538-7445.AM2015-1508
Abstract 1512: Cancer stemness property incurred by inflammatory cytokine confers poor prognosis of hepatocellular carcinoma
Authors: Chang Te-Sheng , Wu Yu-Chih , Tsai Ying-Huang , Huang Yen-Hua
Published: August 2015

Purpose: To unravel the role of inflammatory cytokine IL-6 and IGF-1 receptor (IGF-1R) in expressing stemness-related properties and to evaluate the prognostic values of pluripotent transcription factor OCT4/NANOG, and IGF-1R in hepatocellular carcinoma (HCC).

Experimental Design: Frozen liver and HCC tissue samples were obtained from 191 patients who received curative hepatectomy between 2004 and 2012. Serum levels of IL-6 were detected using ELISA assays (n = 120). The effects of IL-6/IGF-1 on stemness expression in HCC were examined using OCT4/NANOG promoter luciferase reporter, RNA interference, secondary sphere formation, side population, and xenograft animal models. The OCT4/NANOG protein and phospho-IGF-1 receptor (p-IGF-1R) in tissues were detected by western blotting (n = 8) and immunohistochemical staining (n = 85). OCT4, NANOG, and IGF-1R expression levels in tissues (n = 191) were analyzed by real-time Q-PCR and was correlated with early tumor recurrence using Kaplan-Meier survival analysis.

Results: A high positive correlation between the expression levels of OCT4/NANOG and IGF-1R/p-IGF-1R in human HCC tissues was observed. The concurrent expression of OCT4/NANOG/IGF-1R was mostly confined to HBV-related HCC (HBV-HCC) and was significantly correlated with early tumor recurrence. High serum levels of IL-6 were significantly correlated with high OCT4/NANOG expression. IL-6 stimulated an autocrine IGF-1/IGF-1R expression STAT3-dependently, which stimulated stemness-related properties in both the cell lines and the xenografted mouse tumors. The inhibition of IGF-1R activation by either RNA interference or by treatment with the inhibitor picropodophyllin (PPP) significantly suppressed the IL-6-induced stemness-related properties both in vitro and in vivo.

Conclusions: The expression of pluripotency-related genes is associated with early tumor recurrence and is regulated by IL-6-induced IGF/IGF-1R activation, particularly in HBV-HCC.

Citation Format: Te-Sheng Chang, Yu-Chih Wu, Ying-Huang Tsai, Yen-Hua Huang. Cancer stemness property incurred by inflammatory cytokine confers poor prognosis of hepatocellular 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 1512. doi:10.1158/1538-7445.AM2015-1512
Abstract 1513: ALDH1 and podoplanin expression in oral leukoplakia: Correlate with malignant transformaion risk
Authors: Habiba Umma , Shindoh Masanobu
Published: August 2015

Oral leukoplakia (OL) is the clinically diagnosed preneoplastic lesion in the oral cavity with an increased oral cancer risk. However, the risk of malignant transformation of OL is still difficult to assess. The objective of this study was to examine the expression patterns of ALDH1 and Podoplanin (PD) and determine their role in predicting oral cancer development in patients with OL. In a retrospective follow-up study, the expression patterns of ALDH1 and PD were determined using immunohistochemistry in samples from 79 patients with OL, including patients with untransformed lesions (n = 42) and patients with malignant transformed lesions (n = 37). The association between protein expression patterns and clinicopathologic parameters including oral cancer free survival (OCFS) was analyzed during a mean follow up period of 3.5 years. ALDH1 and PD expression was observed in 48 (61%) and 53 (67%) patients respectively. Kaplan-Meier analysis showed that the expression of ALDH1 and PD was correlated with the risk of progression to oral cancer (P = < 0.05). Multivariate analysis revealed that ALDH1 and PD expression was associated with 3.02 folds and 2.62 folds of increase risk of malignant transformation, respectively. Meanwhile, the malignant transformation risk of OL was considerably higher in cases with both ALDH1 and PD expression (P = 0.000). Taken together, our data indicated that ALDH1 and PD expression patterns in OL were associated with oral cancer development, suggesting that ALDH1 and PD could be useful biomarkers to identify OL patient with substantially high oral cancer risk.

Citation Format: Umma Habiba, Masanobu Shindoh. ALDH1 and podoplanin expression in oral leukoplakia: Correlate with malignant transformaion risk. [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 1513. doi:10.1158/1538-7445.AM2015-1513
Abstract 1515: Inhibition of the IKK/NF-κB pathway impairs glioma stem cell function
Authors: Rinkenbaugh Amanda L. , Cogswell Patricia C. , Baldwin Albert S.
Published: August 2015

Glioma, the most frequently occurring primary brain tumor, has a median survival of less than 15 months, despite multimodal treatment combining surgery, radiation, and chemotherapy. It has been suggested that the presence of cancer stem cells (CSCs) within these tumors are responsible for resistance to treatment and high probability of recurrence. As a result, there is increasing interest in specifically targeting CSCs with new therapies to improve treatment of this disease. NF-κB has been implicated in numerous forms of cancer, as its target genes regulate hallmarks of cancer such as cell proliferation, survival, and invasion. Both glioma cell lines and tumor samples show high levels of phosphorylated p65, a marker of NF-κB activation. When comparing populations from tumor explants, NF-κB is preferentially activated in the CSC subset. We are examining the effects of IKK/NF-κB inhibition on both heterogeneous glioma explants and purified (CD133+) CSCs from these explants. Inhibition of NF-κB through either genetic or pharmacological means abrogates neurosphere formation, an in vitro measure of stem cell function. Additionally, real-time PCR analysis indicates that inhibition of NF-κB leads to a decrease in target genes implicated in glioma CSC biology, such as A20 and IL-6. Through gene expression analysis, we have identified a set of NF-κB-dependent genes that potentially contribute to the CSC phenotype, including invasion. We are using ex vivo brain slices and in vivo xenograft models to examine our findings in a pre-clinical setting. Our studies indicate a significant role for the NF-κB pathway in the biology of glioma CSCs, with possible parallels in CSCs of other tumor types.

Citation Format: Amanda L. Rinkenbaugh, Patricia C. Cogswell, Albert S. Baldwin. Inhibition of the IKK/NF-κB pathway impairs glioma stem cell function. [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 1515. doi:10.1158/1538-7445.AM2015-1515
Abstract 1516: YAP1 regulates Oct4 activity and Sox2 expression, facilitating self-renewal and vascular mimicry of stem-like cells
Authors: Bora Singhal Namrata , Nguyen Jonathan , Schaal Courtney , Perumal Deepak , Singh Sandeep , Coppola Domenico , Chellappan Srikumar
Published: August 2015

Non-small cell lung cancer (NSCLC) is highly correlated with smoking and has very low survival rates. Multiple studies have shown that cancer stem-like cells (CSCs) contribute to the genesis and progression of NSCLC. These cells have been shown to form differentiated tumor cells upon receiving appropriate microenvironmental cues and can give rise to multiple components of the tumor, including the vasculature. Earlier work from our laboratory had shown that Hoechst 33342 dye excluding side-population (SP) cells are enriched in cells having stem-like properties. SP cells displayed high self-renewal capacity, were highly drug resistant, and could form metastatic tumors in immunocompromised mice. The present study shows that the transcriptional co-activator YAP1, which is the oncogenic component of the Hippo signaling pathway, is elevated in the stem-like cells from NSCLC and contributes to their self-renewal and ability to form angiogenic tubules in matrigel. Inhibition of YAP1 by a small molecule inhibitor Visudyne or depletion of YAP1 by siRNAs suppressed self-renewal and vascular mimicry of stem-like cells. These effects of YAP1 were mediated through the embryonic stem cell transcription factor Sox2. YAP1 could associate with the Sox2 promoter and could transcriptionally induce Sox2 as seen by qRT-PCRs, ChIP assays and promoter luciferase assays; this induction was through a physical interaction of YAP1 with Oct4 protein. The binding of Oct4 to YAP1 could be detected in cell lines as well as NSCLC tumor tissues as seen by immunofluorescence, proximity ligation assays (PLA), immunoprecipitation-western blot experiments and GST binding assays. Interestingly, the interaction was elevated in NSCLC samples compared to normal tissue as seen by PLA. A peptide that could disrupt the interaction between YAP1 and Oct4 abrogated Sox2 expression, self-renewal and vascular mimicry. Depleting YAP1 reduced the expression of EMT genes and prevented the growth and metastasis of tumor xenografts in mice, while overexpression of Sox2 in YAP1 depleted cells could rescue self-renewal of stem-like cells. In conclusion, our results demonstrate that YAP1 can modulate the stem-like functions of cancer stem cells by regulating Sox2, and this regulatory pathway can potentially be targeted for combating NSCLC.

Citation Format: Namrata Bora Singhal, Jonathan Nguyen, Courtney Schaal, Deepak Perumal, Sandeep Singh, Domenico Coppola, Srikumar Chellappan. YAP1 regulates Oct4 activity and Sox2 expression, facilitating self-renewal and vascular mimicry of stem-like cells. [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 1516. doi:10.1158/1538-7445.AM2015-1516
Abstract 1529: MYC and HIF-2alpha cooperates in oral squamous carcinoma cell self-renewal during hypoxia
Authors: Li Hong , Talukdar Joyeeta , Sandhya Sora , Bhuyan Seema , Gayan Sukanya , Sarma Anupam , Mokhtari Reza Bayat , Felsher Dean W. , Yeger Herman , Das Bikul
Published: August 2015

Oral squamous cell carcinoma (OSCC) is a global health challenge. The overall survival rate of this devastating disease has not significantly changed, and the biology of this type of cancer also remain largely unexplored. To enhance the understanding of this disease through global heath cancer research collaborative effort, we have set up an international collaboration between Forsyth Institute, Cambridge, and KaviKrishna laboratory, which is located in Kamrup district of Assam, having highest incidence of oral cancer in the world. Through this collaborative effort we intend to explore the role of hypoxia in oral cancer progression, metastasis and therapy resistance. Method: We used an oral squamous cell carcinoma cell line SSC25 for this purpose, and performed several experiments using a well-described in vitro assay of CSC self-renewal under hypoxia. Results: We identified a rare ABCG2+ expressing, highly tumorigenic cell population in SSC-25 having cancer stem cell (CSC) like characteristics in the in vivo serial transplantation assay, as well as high metastatic activity to bone marrow of NOD/SCID mice. The ABCG2+ cells, when exposed to hypoxia (<0.1% O2, 24 hours), exhibited enhanced expression and transcriptional activity of MYC, and HIF-2alpha. ChIP assay revealed that HIF-2alpha directly binds to MYC in ABCG2+ cells. siRNA inhibition of HIF-2alpha significantly reduced hypoxia-induced MYC expression and transcriptional activity in ABCG2+ cells. Finally, in clinical OSCC specimens, we confirmed the expression of MYC, HIF-2alpha and ABCG2 expression by immunohistochemistry. Conclusion: These data indicate that MYC oncogene play important role in the self-renewal of oral cancer cells during hypoxia.

Citation Format: Hong Li, Joyeeta Talukdar, Sora Sandhya, Seema Bhuyan, Sukanya Gayan, Anupam Sarma, Reza Bayat Mokhtari, Dean W. Felsher, Herman Yeger, Bikul Das. MYC and HIF-2alpha cooperates in oral squamous carcinoma cell self-renewal during hypoxia. [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 1529. doi:10.1158/1538-7445.AM2015-1529
Abstract 1530: Therapeutic efficacy of cancer stem cell vaccine in an adjuvant setting
Authors: Hu Yangyang , Lu Lin , Chang Alfred E. , Egenti Martin , Owen John , Moyer Jeffrey S. , Prince Mark E.P. , Xia Jianchuan , Huang Shiang , Wicha Max S. , Li Qiao
Published: August 2015

The inability to target cancer stem cells (CSC) may be a significant factor contributing to treatment failure. Novel therapeutic strategies are needed to immunologically target CSCs. We have developed a strategy to target the CSC populations in melanoma and squamous cell carcinoma using CSC lysate-pulsed dendritic cells (DC). Using mouse models we demonstrate that DC pulsed with CSCs enriched by virtue of their expression of the CSC marker ALDH (CSC-DC) significantly inhibited local tumor growth, reduced development of pulmonary metastases and prolonged survival in the minimal tumor models. The effect was associated with down regulation of CCR7 and CCR10 in tumor cells and decreased CCL27 and CCL28 expression in lung tissue. CSC-DC vaccine significantly reduced ALDHhigh CSCs. Direct targeting of CSCs was demonstrated by specific binding of IgG produced by ALDHhigh CSC-DC vaccine-primed B cells to ALDHhigh CSCs, resulting in lysis of these target cells in the presence of complement. When administered in the adjuvant setting after surgical excision of the bulk tumor mass, administration of CSC-DC vaccine reduced development of local tumor growth as well as systemic disease and prolonged survival demonstrating the efficacy of this approach. These data suggest that the CSC-DC vaccine approach may be useful in the adjuvant setting where local and systemic relapse are high after surgery.

Note: This abstract was not presented at the meeting.

Citation Format: Yangyang Hu, Lin Lu, Alfred E. Chang, Martin Egenti, John Owen, Jeffrey S. Moyer, Mark E.P. Prince, Jianchuan Xia, Shiang Huang, Max S. Wicha, Qiao Li. Therapeutic efficacy of cancer stem cell vaccine in an adjuvant setting. [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 1530. doi:10.1158/1538-7445.AM2015-1530
Abstract 1531: Distinct roles of CXCR3 isoforms in promoting breast cancer stem-like cell properties and metastasis
Authors: Li Yanchun , Reader Jocelyn C. , Ma Xinrong , Kundu Namita , Kochel Tyler , Fulton Amy M.
Published: August 2015

Growing evidence has demonstrated that the two major isoforms of chemokine receptor CXCR3 (CXCR3-A, CXCR3-B) both contribute to breast cancer pathogenesis and metastasis, however, in different ways. Understanding the relative contribution of each isoform is critical to optimize therapeutic strategies targeting CXCR3. Furthermore, the possible involvement of either CXCR3 isoform in cancer stem-like properties has not been reported. We examined the contribution of each isoform to metastasis using a panel of breast cell lines and a xenograft model of breast cancer; we also explored the role of major CXCR3 isoforms in the behavior of stem-like cells. CXCR3-A is more abundantly expressed than CXCR3-B in both primary human breast cancer tissue and in breast cancer cell lines. On the contrary, immortalized normal MCF-10A cells are CXCR3-B dominant. In basal-like MDA-MB-231 cells, CXCR3 ligand-stimulated proliferation is inhibited by CXCR3-B overexpression, with concurrent reduced activation of ERK1/2 and p38 kinases. Similarly, higher levels of CXCR3-B inhibit migration and invasion in vitro and metastasis in vivo. Accordingly, reduced CXCR3-B expression by gene-silencing enhances lung colonization in the xenograft model. Although exhibiting anti-proliferative and anti-metastatic roles in the non-stem cell population, CXCR3-B supports a cancer stem-like cell phenotype. In mammosphere-forming MDA-MB-231 cells, CXCR3-B is markedly up-regulated and mammosphere-forming capacity is further increased when overexpressing CXCR3-B. Likewise, soft agar growth is promoted by CXCR3-B overexpression. Accordingly, silencing CXCR3-B by shRNA inhibits stem-like properties. In conclusion, both isoforms need to be targeted to inhibit the pro-proliferative and pro-metastasis functions of CXCR3-A and the stem cell-promoting actions of CXCR3-B.

Citation Format: Yanchun Li, Jocelyn C. Reader, Xinrong Ma, Namita Kundu, Tyler Kochel, Amy M. Fulton. Distinct roles of CXCR3 isoforms in promoting breast cancer stem-like cell properties and metastasis. [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 1531. doi:10.1158/1538-7445.AM2015-1531
Abstract 1541: Secreted serglycin in tumor microenvironment promotes tumor malignancies in a CD44-dependent manner
Authors: Guo Jing-You , Tyan Shiaw-Wei , Hsu Han-Shui , Li Fen-Yau , Chen Jeou-Yuan
Published: August 2015

Tumor microenvironment (TME) plays an important role in cancer progression; however, the communication between TME and cancer cells remains largely unclear. CD44, a type I cell surface receptor functioning in cell-cell and cell-extracellular matrix interactions, has been implicated in tumor formation and progression. Using gain-of-function and loss-of-function approaches, we report in this study that serglycin (SRGN), a glycoprotein secreted from cancer-associated fibroblasts (CAFs) as well as aggressive cancer cells, works to promote the malignant behaviors of non-small cell lung cancer cells through its interaction with CD44. We showed that SRGN promotes cell transformation and tumor formation and metastasis using in vitro and in vivo tumorigenic assays. Furthermore, we showed that SRGN induced lung cancer cell stemness in a CD44-dependent manner. SRGN enhanced cancer cells sphere formation via Nanog induction, accompanied with increased drug resistance and resistance to anoikis. We also demonstrated that SRGN promotes cell migratory activity through promoting epithelial-mesenchymal transition (EMT) and enhancing adhesions turnover by upregulating vimentin expression and SRC activity via CD44/NF-KB/Claudin-1 axis. In support, Claudin-1 expression was tightly associated with SRGN expression in primary lung cancer tissues (p < 0.0001). In summary, we demonstrate that the crosstalk between tumor cells and TME promotes malignant phenotypes through the interaction of tumor-borne CD44 and CAF- or tumor-derived SRGN, suggesting that targeting CD44 or its ligands may represent an attractive strategy for development of cancer therapy.

Citation Format: Jing-You Guo, Shiaw-Wei Tyan, Han-Shui Hsu, Fen-Yau Li, Jeou-Yuan Chen. Secreted serglycin in tumor microenvironment promotes tumor malignancies in a CD44-dependent manner. [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 1541. doi:10.1158/1538-7445.AM2015-1541