bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 881: Dissecting chromatin dynamics in malignant progression
Authors: Yang Hanseul , Schramek Daniel , Adam Rene , Levorse John , Keyes Brice , Wang Ping , Zheng Deyou , Fuchs Elaine 
Published: July 2016

Abstract
Tumor-initiating cells within a cancer exhibit distinct patterns of transcription factors and gene expression compared to stem cells within their healthy tissue. Little is known about the key transcription factors that dictate chromatin remodeling and the accompanying transcriptional changes that ultimately hardwire the malignant behavior of tumor-initiating stem cells. Here, by in vivo chromatin and transcription profiling, we show that dramatic shifts in large open-chromatin (super-enhancer) landscapes underlie these differences. Focusing on one of the most common and life-threatening cancers world-wide, squamous cell carcinoma (SCC), we show that super-enhancers of SCC-stem cells contain the binding sites for a distinct set of putative master transcription factors. Many of their genes, including Ets2 and Elk3, are themselves regulated by SCC super-enhancers, suggesting a cooperative feed-forward loop. Malignant progression requires these genes, whose knockdown severely impairs tumor growth and prohibits progression from benign papillomas to SCCs. Interestingly, ETS2 is known to be phosphorylated and activated by RAS/MAPK signaling, and knockdown of ETS2 results in loss of expression of SCC super-enhancer-associated genes. Conversely, in vivo forced expression of an active ETS2 version harboring a phosphomimetic substitution at the MAPK-activation residue is sufficient to trigger cellular transformation without oncogenic RAS. Moreover, ETS2-overactivation in epidermal progenitors rewires the super-enhancer landscape and induces SCC super-enhancer associated genes including Fos, Junb, Klf5 and Elk3. Finally, we identify dramatic remodeling of the Cxcl1/2 locus from an H3K27me3-repressed to an ETS-regulated, super-enhancer-activated state, and provide evidence for their autocrine oncogenic role in SCCs through a cognate receptor Cxcr2. Together, our findings unearth an essential regulatory network required for the SCC chromatin landscape and unveil its importance in malignant progression.
This work was funded by grants from the National Institutes of Health (R01-AR31737) and NYSTEM #CO29559.
Citation Format: Hanseul Yang, Daniel Schramek, Rene Adam, John Levorse, Brice Keyes, Ping Wang, Deyou Zheng, Elaine Fuchs. Dissecting chromatin dynamics in malignant progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 881.
Abstract 901: Transgenerational inheritance of increased mammary cancer risk in the offspring of high fat diet fed dams: Changes in oxidative stress pathways
Authors: Nguyen Nguyen M. , Andrade Fabia O. , DeAssis Sonia , Cruz Idalia , Benitez Carlos , Godschalk Roger , Hilakivi-Clarke Leena 
Published: July 2016

Abstract
Maternal high fat diet has been shown to increase mammary cancer risk among female offspring. We investigated here if the increase is seen across multiple generations. For that purpose, pregnant C57BL/6NTac dams (F0) were fed either a control (CON, 6% corn oil) or an isocaloric high n-6 polyunsaturated fat (HF) diet (18% corn oil) between gestation days 8 and 21. Offspring in subsequent generations (F1-F3) were not exposed to any further dietary modifications, and kept on CON diet. Mammary tumors were initiated by priming the mammary glands with 15 mg medroxyprogesterone (MPA) at week 6, followed by a 1 mg dose of 7,12-dimethylbetz(a)anthracene (DMBA) given on weeks 7-9 for a total of 3 doses. Animals were monitored for 20 weeks after the final dose of DMBA for tumors. Both F1 and F3 generation female HF offspring exhibited a significantly higher mammary tumor incidence and tumor burden than the control offspring. In F3 generation, the increase was seen from week 12 of tumor monitoring until the end of the study. The increase in risk was preceded by a higher number of terminal end buds in the F1 and F3 generation mammary glands. Malondialdehyde (MDA) adduct levels were found to be significantly elevated in the HF group of F3 offspring, suggesting that the increased mammary cancer risk in this generation was attributed to oxidative stress. Western blot analysis of mammary glands identified significantly elevated Keap1 (a repressor of the antioxidant response) and PERK levels in HF F3 offspring; and elevated levels of Beclin-1 and p62 in both F1 and F3 generations compared with CON offspring, corroborating with the idea that oxidative stress was the culprit. miRNA analysis of F3 mammary glands showed decreased expression of mir-324-5p, mir-136 and mir-378 that target Keap1 and p62, potentially explaining the increase in Keap1 and p62 levels. Our results suggest that oxidative stress and antioxidant response plays a role in explaining transgenerational increase in mammary cancer risk among offspring exposed to high fat diet through F0 dams.
Citation Format: Nguyen M. Nguyen, Fabia O. Andrade, Sonia DeAssis, Idalia Cruz, Carlos Benitez, Roger Godschalk, Leena Hilakivi-Clarke. Transgenerational inheritance of increased mammary cancer risk in the offspring of high fat diet fed dams: Changes in oxidative stress pathways. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 901.
Abstract 905: Pterostilbene (PTER) suppresses breast cancer brain metastasis by targeting a c-Met mediated inflammation network
Authors: Xing Fei , Liu Yin , Sharma Sambad , Wu Kerui , Watabe Kounosuke 
Published: July 2016

Abstract
At the late stage of breast cancer, most patients develop metastatic lesions and the brain is one of the major metastatic sites. Brain metastasis profoundly affects the cognitive and sensory function as well as morbidity of patients, and the one year survival rate among these patients remains less than 20%. The result of our newly developed gene set enrichment analysis (GSEA)-based pathway screening indicates that c-Met pathway is highly activated among the patients who developed early brain metastasis. To identify a novel target of c-Met pathway in brain metastasis, we performed the microarray analysis in two brain metastatic cell lines with the expression of doxycycline-inducible sh-cMet. Our results indicate that a group of inflammatory cytokines including IL1b, IL8 and CXCL1 were significantly induced by c-Met activation. Furthermore, we found that IL1b was able to induce the secretion of HGF (hepatocyte growth factor) from tumor associated astrocytes (TAA) which in turn activates c-Met pathway in cancer cells. Our results of endothelial cell tube formation assays also strongly suggest that cMet-induced IL8 and the activation of its receptor, CXCL1, promote tumor angiogenesis which is essential for the metastatic growth of cancer cells. Natural compounds (NC) have been extensively studied for their anti-tumor effects. However, much less studies have been done on NC for the treatment/prevention of brain tumors mainly due to the obstacle of Blood-brain-barrier (BBB) permeability. To identify the NCs that can be used for treating brain metastasis, we performed pathway analysis which only focused on BBB-permeable NC. The results of GSEA indicate that Resveratrol-targeting genes were significantly enriched among those patients who developed brain metastasis compared to metastasis-free patients. Furthermore, we found that the one of derivatives of Resveratrol, Pterostilbene (PTER), showed significantly more potent activity than Resveratrol and suppressed brain metastasis in vitro and in vivo by targeting the c-Met oncogene. These findings suggest that TAA-mediated c-Met activation plays a key role in brain metastasis and that PTER is a potential therapeutic agent to treat brain metastasis by suppressing the c-Met expression.
Citation Format: Fei Xing, Yin Liu, Sambad Sharma, Kerui Wu, Kounosuke Watabe. Pterostilbene (PTER) suppresses breast cancer brain metastasis by targeting a c-Met mediated inflammation network. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 905.
Abstract 906: Exosomes from mutant TP53 cancer cells polarize tumor associated macrophages
Authors: Cooks Tomer , Pateras Ioannis S. , Patel Keval M. , Forshew Tim , Gorgoulis Vassilis G. , Harris Curtis C. 
Published: July 2016

Abstract
Introduction: TP53 mutants are involved in the pathogenesis of most solid tumors and are known to gain oncogenic functions distinct from their original wild-type form. The existence of such gain-of-function (GOF) activities is supported by ample evidence, however only in a cell-autonomous fashion. Since tumor-associated-macrophages (TAM) are also a hallmark of solid tumors typically correlated with poor prognosis, we investigated the link between mutations in the TP53 gene (mutp53) occurring in epithelial tumor cells and the formation of a surrounding TAM population in-situ.
Methods: By designing a co-culture system we incubated human primary monocytes together with colorectal cancer (CRC) cells differing in their p53 status. Relevant macrophages markers were evaluated on RNA level and protein level. In addition, co-cultured macrophages were subjected to various functional assays (phagocytosis, migration, and invasion). In attempt to confirm clinical relevance, samples from a cohort of human CRC patients were analyzed using genomic and immunohistochemical methods. To identify the interaction between the tumor cells and the macrophages, we isolated exosomes from the CRC cells and subjected them to a Nanostring analysis to learn about their microRNAs composition.
Results: In this study, we discovered that mutp53 exerts a non-cell-autonomous effect over neighboring macrophages by using specific microRNAs (miRs) which are shuttled through an exosomal transfer resulting with a phenotype change of the affected macrophages. Mutp53-specific exosomes containing cargoes such as miR-1246 were shown to be used by macrophages at the receiving end, thus promoting the formation of TAM subset also observed in surgical specimens resected from cancer patients.
Conclusions: Altogether, these findings are consistent with a microenvironmental role for specific “hot-spot” p53 mutants tightening the interaction between the tumor cell and the immune compartment. Additionally, this study is the first to show a non-cell-autonomous role played by mutant p53 - the most common form of mutation found in human cancers. Deciphering the intricate regulation shared by the tumor cell and its surrounding macrophages may give rise to novel prognostic and diagnostic tools as well as to therapeutic approaches targeting TAM, specific tumor-promoting miRs and mutp53-specific subsets of exosomes.
Citation Format: Tomer Cooks, Ioannis S. Pateras, Keval M. Patel, Tim Forshew, Vassilis G. Gorgoulis, Curtis C. Harris. Exosomes from mutant TP53 cancer cells polarize tumor associated macrophages. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 906.
Abstract 907: Brain microenvironment induced PTEN loss by microRNAs promotes brain metastasis
Authors: Zhang Lin , Zhang Siyaun , Yao Jun , Lowery Frank J. Lowery , Zhang Qingling , Huang Wen-Chien , Li Ping , Li Min , Wang Xiao , Zhang Chenyu , Wang Hai , Ellis Kenneth , Cheerathodi Mujeeburahiman , McCarty Joseph , Palmieri Diane , Steeg Patricia , Saunus Jodi S , Lakhani Sunil , Huang Suyun , Sahin Aysegul , Aldape Kenneth , Yu Dihua 
Published: July 2016

Abstract
Metastasis is the number one cause of cancer-related mortality. Major neoplastic diseases such as melanoma, lung, breast, and colon cancers have high incidences of brain metastases. One-year survival after diagnosis of brain metastasis is less than 20%. Cancer cells dynamically interacts with specific organ microenvironments to establish metastasis as depicted by the “seed and soil” hypothesis. Yet it is unclear when and how disseminated tumor cells acquire the essential traits from the brain microenvironment that primes their subsequent metastatic outgrowth.
Here we found that primary tumor cells with normal PTEN expression lose PTEN after dissemination to the brain, but not to other organs. Metastatic brain tumor cells that have experienced PTEN loss have PTEN levels restored once they leave the brain. This brain microenvironment-dependent, reversible PTEN mRNA and protein down-regulation is epigenetically regulated by microRNAs (miRNAs) from astrocyte-derived exosomes. Furthermore, this adaptive PTEN loss in brain metastatic tumor cells leads to an increased secretion of cytokine chemokine (C-C motif) ligand 2 (CCL2), which recruits Iba1+ myeloid cells that reciprocally enhance outgrowth of brain metastatic tumor cells via enhanced proliferation and reduced apoptosis.
Our findings signify the dynamic and reciprocal cross-talk between tumor cells and other brain stromal cells. Disseminated tumor cells acquire the essential traits from the microenvironment of brain that prime their outgrowth. Importantly, our finding provides new opportunities for effective anti-metastasis therapies: inhibiting CCL2 might be an effective therapeutic intervention of life-threatening brain metastases.
Citation Format: Lin Zhang, Siyaun Zhang, Jun Yao, Frank J. Lowery Lowery, Qingling Zhang, Wen-Chien Huang, Ping Li, Min Li, Xiao Wang, Chenyu Zhang, Hai Wang, Kenneth Ellis, Mujeeburahiman Cheerathodi, Joseph McCarty, Diane Palmieri, Patricia Steeg, Jodi S Saunus, Sunil Lakhani, Suyun Huang, Aysegul Sahin, Kenneth Aldape, Dihua Yu. Brain microenvironment induced PTEN loss by microRNAs promotes brain metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 907.
Abstract 912: Mist1+ secretory progenitor cells can give rise to cancer in the intestine and colon
Authors: Hayakawa Yoku , Sakitani Kosuke , Kim Woosook , Tailor Yagnesh , Nagar Karan , Koike Kazuhiko , Asfaha Samuel , Wang Timothy C. 
Published: July 2016

Abstract
Intestinal crypts are maintained by long-lived intestinal stem cells (ISCs) which reside near the base of glands. Above the ISC pool, there are short-lived progenitors that can supply lineage-specific differentiated cell types into the villus. Notch and Wnt pathways play a key role for determining the stem/progenitor cell function and their cell fate, and regulating cancer development in the gastrointestine. Although it has been well established that ISCs are a major origin of intestinal cancer, it remains unknown whether intestinal progenitor population can give rise to cancer. We use Mist1-CreERT mice and induce Notch and Wnt activation by mating with LSL-Notch1-IC mice and/or Apc flox mice. We found that a bHLH transcriptional factor Mist1 is expressed in Paneth cells (Lysozyme+CD24high) as well as short-lived secretory progenitors (Lysozyme-CD24low) in the intestine. Mist1+ secretory progenitors are radio- and chemo-resistant, but do not show stem cell interconversion even after intestinal injury or Lgr5 ablation. However, aberrant Notch activation changes Mist1+ cells to Lgr5+ long-lived enterocyte progenitors, with loss of secretory lineage differentiation. Mist1+CD24low progenitor population can form intestinal organoids with Notch activation in vitro. Mist1+ secretory progenitors can give rise to intestinal cancer by simultaneous Notch and Wnt activation by loss of Apc gene, while loss of Apc in Mist1 lineage alone does not develop cancer. In the colon, Mist1 marks colonic secterory progenitors that become to lineage trace and can be a cancer-initiating cell after Notch activation or DSS-induced colonic injury. These results provide the clear evidence of cellular plasticity dependent on Notch signaling in the gut, and suggest short-lived progenitors as another cellular origin of cancer besides ISC pool.
Citation Format: Yoku Hayakawa, Kosuke Sakitani, Woosook Kim, Yagnesh Tailor, Karan Nagar, Kazuhiko Koike, Samuel Asfaha, Timothy C. Wang. Mist1+ secretory progenitor cells can give rise to cancer in the intestine and colon. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 912.
Abstract 916: Slit2 inhibits breast cancer growth and metastasis by modulating tumor microenvironment
Authors: Ahirwar Dinesh K. , Nasser Mohd W. , Elbaz Mohamad , Shilo Kontestine , Ganju Ramesh 
Published: July 2016

Abstract
Breast cancer (BC) continues to be a major health issue particularly in developed countries. The Slit2 gene is hyper-methylated in BC and acts through Roundabout Homolog1 (Robo1) receptor. Slit2/Robo1 signaling has been shown to inhibit the migration of a variety of cells including BC cells. Recently, it has also been reported to improve chemotherapy outcome in intestinal cancer. However, Slit2/Robo1-mediated mechanisms that regulate tumor growth and metastasis are not well known. Using syngeneic mouse model, we report that the over-expression of Slit2 using Adeno-Slit2 transduction successfully restrains tumor growth and also restrict the metastasis to lung, compared to Adeno-null control. To explore the Slit2 mediated cellular events, we analyzed the stromal cells recruitment to the tumor and observed reduced number of tumor associated macrophages (TAMs) in the Adeno-Slit2 group compared to Adeno-null group. We further analyzed the underlying molecular mechanisms and found that the soluble Slit2 inhibits TGF-β1 mediated alternative activation of macrophages to TAMs. Treatment with TGF-β1 significantly enhances the markers of TAMs by upregulating β-catenin levels. Interestingly, we observed that Soluble Slit2 inhibits TGF-β1 mediated activation of TAMs by inhibiting downstream signaling molecules Smad2 and β-catenin. We also analyzed Slit2 expression in human breast cancer TMA and an inverse correlation of Slit2 expression was observed with the incidence of breast cancer, metastasis and macrophage recruitment. This study highlights the ability of Slit2 to prevent macrophage alternative activation to TAMs, thereby restrict tumor growth and lung metastasis. Anti-cancer activity of Adeno-Slit2 suggests therapeutic potential of Slit2 to treat advanced breast cancer.
Citation Format: Dinesh K. Ahirwar, Mohd W. Nasser, Mohamad Elbaz, Kontestine Shilo, Ramesh Ganju. Slit2 inhibits breast cancer growth and metastasis by modulating tumor microenvironment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 916.
Abstract 921: Pericellular-interactions promote malignant progression of glioblastoma via novel NOTCH-1/HIF-1α pathway
Authors: Kim Eunsoo , Lee Jungwhoi , Ryu Seung-Wook , Choi Chulhee , Choi Kyungsun 
Published: July 2016

Abstract
Malignant tumors generally develop hypoxic condition in the core region of tumor mass, which induces stabilization of hypoxia inducible factor-1 alpha (HIF-1α) by preventing proteasome-dependent degradation. HIF-1α has been shown to regulate various oncogenes for malignant progression of many types of tumors including glioblastoma multiforme (GBM). In the present study, we showed that cell-to-cell interactions at high density can induce malignant transformation of tumor cells by activation of HIF-1α even under normoxic condition. To delineate the biological effect of cell culture density, we maintained cancer cells in different density. Four types of GBM cell lines (U251-MG, LN215-MG, U373-MG, and CRT-MG) were used to examine the oncogenic phenotypes of cancer cells cultured in different densities. Cells cultured in a high-density condition showed higher rate of proliferation and migration activity and higher resistance to temozolomide, an anti-cancer drug commonly used for GBM treatment. We found that the pericellular interactions stimulate the cleavage of notch-1 intracellular domain (NICD), and the cleaved NICD protects the HIF-1α from hydroxylation and subsequent proteasomal degradation, resulting in nuclear translocation of HIF-1α. Collectively, we suggest that the cell-cell interactions in high-density culture conditions induce NICD-mediated HIF-1α activation, which leads to malignant phenotypic changes. Therefore, treatment of gamma-secretase inhibitor (GSI), which can block NOTCH-1 signaling pathway, in combination with TMZ could be a promising therapeutic strategy in TMZ-resistant tumor cells.
This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number : HI14C0042)
Citation Format: Eunsoo Kim, Jungwhoi Lee, Seung-Wook Ryu, Chulhee Choi, Kyungsun Choi. Pericellular-interactions promote malignant progression of glioblastoma via novel NOTCH-1/HIF-1α pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 921.
Abstract 922: PGE2/HuR/CEBPD axis in macrophages contributes to immunosuppression and inhibits phagocytosisof nasopharyngeal carcinoma
Authors: Hsiao Yu-Wei , Wang Ju-Ming 
Published: July 2016

Abstract
The association of inflammation and cancer progression via modulation of phagocytosis and suppression of adaptive immunity by tumor-associated macrophages (TAM) to promote tumorigenesis has been implicated in a number of recent studies. To date, the underlying mechanisms involving the interactions of these two cellular processes remain elusive, particularly in the involvement of posttranscriptional regulation. In this study, we demonstrate that prostaglandin E2 (PGE2) activates transcription factor CCAAT/enhancer binding protein delta (CEBPD) in macrophages by inducing nucleocytoplasmic shuttling of RNA binding protein Hu antigen R (HuR), which plays a direct role in stabilizing CEBPD mRNA in macrophages. Increase of CEBPD resulted in elevated expression of IL-10, a well-studied immunosuppressor, and PTX3, which contribute to suppression of phagocytosis of cancer cells by macrophages. In addition, the conditioned medium of CEBPD-transfected macrophages showed an immunosuppressive effect to attenuate phagocytosis of cancer cells by macrophages, suggesting an autocrine mode of regulation. Immunohistochemistry studies demonstrated that the cytosolic level of HuR protein correlates with increased CEBPD in TAM and malignant nasopharyngeal carcinoma (NPC). Collectively, these results provide new evidences that the inflammatory PGE2/HuR/CEBPD axis in macrophages plays protumor roles in controlling immunosuppression and attenuating phagocytosis of cancer cells by macrophages.
Citation Format: Yu-Wei Hsiao, Ju-Ming Wang. PGE2/HuR/CEBPD axis in macrophages contributes to immunosuppression and inhibits phagocytosisof nasopharyngeal carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 922.