bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6007: Post-fasting refeeding enhances intestinal stem cell-mediated regeneration and tumorigenesis
Authors: Imada Shinya 
Published: September 2020

Abstract
Although short-term fasting interventions improve intestinal stem cell (ISC) function, little is known about how much of this benefit comes from fasting versus the post-fasting refeeding response. Given the central role that ISCs play in driving injury-induced repair and in initiating early intestinal tumors, it is possible that fasting by boosting ISC function not only improves regeneration but also unexpectedly elevates intestinal tumorigenesis. To understand how fasting/refeeding interventions influence the role of ISCs in regeneration and early tumor formation, we assessed the function of ISCs to repair the intestinal lining after injury and to contribute to intestinal tumors. Notably, we find that 24 hours post-fasting refeeding boosts intestinal stem and progenitor cells proliferation and increases ISC function in organoid and in fate mapping assays compared to AL and fasted cohorts. Mechanistically, elevated mammalian target of rapamycin (mTOR) activity mediates the effects of refeeding in ISCs as treatment with mTOR inhibitor blocks these effects. Surprisingly, loss of the APC tumor suppressor gene in ISCs increased intestinal tumor numbers in the refed state compared to the AL and fasted states in an mTOR dependent manner. We propose that refeeding through mTOR signaling stimulates ISC function and in a context-dependent manner this can either improve repair after injury or promote intestinal tumorigenesis.
Citation Format: Shinya Imada. Post-fasting refeeding enhances intestinal stem cell-mediated regeneration and tumorigenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6007.
Abstract 6030: Role of immature CD44 o-glycosylation in enrichment of cancer stem cell population for aggressive pancreatic cancer
Authors: Leon Frank , Nimmakayala Rama K. , Chugh Seema , Gupta Rohitesh , Rachagani Satyanarayana , Batra Surinder K. , Ponnusamy Moorthy P. 
Published: September 2020

Abstract
Pancreatic cancer (PC) is an aggressive malignancy expected to be the second leading cause of cancer death by 2030. Accumulating reports demonstrate that truncated o-glycans are largely observed in PC and correlates with poor prognosis and reduced patient survival. We have previously shown that loss of C1GALT1 (Core 1 n-acetylgalactose transferase) expression in PC results in the upregulation of genes associated with aggressive PC and metastasis. To study the involvement of immature O-glycophenotype in pancreatic cancer stem cells (CSCs), we selected the single-transmembrane CD44 glycoprotein based on our unbiased approach using proteomics and RNA-sequence analysis.This highly o-glycosylated protein with diverse cellular activity is essential in cell-cell recognition and is a widely occurring CSC marker identified in several cancers. However, the functional properties of CD44 o-glycan variation in pancreatic CSCs are not well understood. Thus, we hypothesize that truncation of o-glycans on CD44 imparts activation of downstream targets responsible for self-renewal and maintenance of CSC in aggressive PC. Using a proteomics approach of enriched truncated o-glycans, we discovered CD44 as one of the top identified proteins in CRISPR/Cas9 C1GALT1 knockout PC cells. We observed enhanced expression of markers responsible for CSC self-renewal and characteristics as measured by FACS-based side-population analysis and tumor sphere formation as a result of a loss in C1GALT1. To determine a potential mechanism by which truncated o-glycans on CD44 enhances CSC properties, we deleted C1GALT1 and CD44 in PC cells. A loss of CD44 o-glycan truncation significantly reduced expression of the self-renewal CSC marker Nanog and phosphorylated p65, a major component in the NF-κB signaling pathway. Furthermore, pancreatic tumorigenesis was significantly reduced in athymic mice injected with PC cells as a result of C1GALT1 and CD44 deletion. These results provide a novel mechanism by which truncated o-glycans on CD44 is responsible for activating downstream targets for self-renewal and maintenance of CSCs. Our findings begin to contextualize the contributions of aberrant glycosylation on glycoproteins to accelerate metastatic properties by enhanced expression and characteristics of pancreatic CSC.
Citation Format: Frank Leon, Rama K. Nimmakayala, Seema Chugh, Rohitesh Gupta, Satyanarayana Rachagani, Surinder K. Batra, Moorthy P. Ponnusamy. Role of immature CD44 o-glycosylation in enrichment of cancer stem cell population for aggressive pancreatic cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6030.
Abstract 6044: BR101801: A potent and selective inhibitor of DNA-PK, potentiates the activity of topoisomerase II inhibitor in vitro and causes tumor inhibition in cancer models
Authors: Son Mi Kwon , Wang Seungho , Lee Bo Ram , Jeon Byeongwook , Kim Soo jung , Yang Enhui , Park Min , Lee Joo han , Myung Jayhyuk 
Published: September 2020

Abstract
Introduction: The DNA-dependent protein kinase (DNA-PK) plays an instrumental role in the overall survival and proliferation of cells. As a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, DNA-PK is best known as a mediator of the cellular response to DNA damage. DNA-PK plays a key role in the repair of DNA double-strand breaks (DSBs) that are probably the most deleterious form of DNA damage. Inhibition of DNA-PK has been considered as an attractive approach to decrease resistance to therapeutically induced DNA DSBs. In this context, DNA-PK has emerged as an intriguing therapeutic target in the treatment of a variety of cancers, especially when used in conjunction with genotoxic chemotherapy. We have developed a high potent and selective inhibitor of DNA-PK, BR101801, which inhibits topoisomerase II inhibitor-induced γ-H2AX with an IC50. In this study, BR101801, a first-in class inhibitor of DNA-PK, will be introduced as a novel candidate of human cancer therapy.
Methods: The enzyme selectivity of BR101801 was determined by Eurofins kinase profiling services. To assess the effect of BR101801 on DNA-PK in LoVo cell, cells were pre-incubated with etoposide for 2 hours and then exchanged into new media containing BR101801 or other compounds without etoposide. Activity of BR101801 was evaluated based on prolongation of γ-H2AX using western blot. In vitro GI50 was tested by WST-based viability assay in various cancer cell lines. Synergy of the combination with cytotoxic agents was analyzed using CT-26 mouse model, respectively.
Results: In the enzymatic analysis, BR101801 showed selectivity on DNA-PK. (IC50 DNA-PK = 6 nM, respectively). The combined inhibitory effect of DNA-PK was comparable to the effect of BR101801. The several cytotoxic agents that are known as a booster of γ-H2AX, including doxorubicin and etoposide were selected and all combination treatments of BR101801 with the cytotoxic agents showed significant result by having less than a combination index value of 0.5. The in vivo efficacy of the combination with doxorubicin and oxaliplatin was assessed in a CT-26 colon cancer model
Conclusions: These data confirm that DNA-PK inhibition of BR101801 enhanced the efficacy of rage of DSB inducing agent in vitro and in vivo, providing a clear rationale for its clinical use.
Citation Format: Mi Kwon Son, Seungho Wang, Bo Ram Lee, Byeongwook Jeon, Soo jung Kim, Enhui Yang, Min Park, Joo han Lee, Jayhyuk Myung. BR101801: A potent and selective inhibitor of DNA-PK, potentiates the activity of topoisomerase II inhibitor in vitro and causes tumor inhibition in cancer models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6044.
Abstract 6071: Role of nitric oxide in the invasive pancreatic cancer cells
Authors: Fujita Mayumi , Somasundaram Veena , Basudhar Debashree Basudhar , Cheng Robert Y.s. , Ridnour Lisa A. , Imadome Kaori , No Jae Hong , Bharadwaj Gaurav , Wink David A. 
Published: September 2020

Abstract
Pancreatic cancer is a metastatic tumor with an extremely low 5-year survival rate. Metastasis is a main cause of patient mortality as it is extremely difficult to treat. Thus, understanding the characteristics of cancer cell populations exhibiting the invasive phenotype is fundamental for developing novel strategies to counter metastasis and improve therapeutic efficacy. To characterize these invasive phenotypes, we compared the human PANC-1 parent cell line with PANC-1 cells (INV) that invaded through transwell inserts. INV cells exhibited increased invasiveness and higher resistance to Carbon-ion radiation compared to whole cultured, control PANC-1 cells (WCC). PANC-1 invasion was reduced by nitric oxide synthase (NOS) inhibitors, suggesting that nitric oxide (NO) plays a cardinal role in PANC-1 invasion. Cell invasion through extracellular membrane (ECM) involves complex regulation of cell adhesion and de-adhesion to ECM proteins. Suspended INV cells, as well as INV cells undergoing de-adhesion, showed enhanced NO production as well as induction of several pro-metastatic, and stemness-related genes. NOS inhibitor, L-NAME, reduced the expression of these pro-metastatic or stemness-related genes, and hampered spheroid formation ability, suggesting that NO can potentially influence PANC-1 aggressiveness. In addition, in vitro studies indicated that a MEK-ERK-dependent, JAK-independent mechanism promoted NOS/NO modulation of PANC-1 invasion. Furthermore, xenograft studies with INV and WCC in an NSG mouse model revealed a higher ability of INV in liver metastasis than WCC, and L-NAME diminished the metastasis observed in INV injected mice. In summary, these results implicate NO as a key mediator of therapeutic resistance to Carbon-ion radiation and metastasis of PANC-1 cells; inhibition of NOS demonstrates therapeutic potential as observed in the animal model by specifically targeting the metastatic cells.
Citation Format: Mayumi Fujita, Veena Somasundaram, Debashree Basudhar Basudhar, Robert Y.s. Cheng, Lisa A. Ridnour, Kaori Imadome, Jae Hong No, Gaurav Bharadwaj, David A. Wink. Role of nitric oxide in the invasive pancreatic cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6071.
Abstract 6077: The role of STAT3 and Snai2 in ovarian cancer metastasis
Authors: Walker David F. , Lacroix Sarah J. , Makar Yuri , Walker Sarah R. 
Published: September 2020

Abstract
Ovarian cancer remains a deadly disease due in part to ovarian cancer metastasis. Recent work has demonstrated that ovarian cancer forms clusters of cells (spheroids) that attach to the peritoneum by clearing the mesothelial cell layer and then invade the underlying matrix to metastasize. Understanding the key pathways and downstream transcription factors that are driving ovarian cancer metastasis may allow us to develop new therapies to treat metastatic ovarian cancer. Importantly, we have found that the STAT3 transcription factor is necessary for mesothelial clearance by ovarian spheroids. To identify key downstream STAT3 target genes involved in ovarian cancer metastasis, we analyzed publicly available STAT3 chromatin immunoprecipitation (ChIP)-seq datasets for genes associated with epithelial-to-mesenchymal transition. One of the genes that we identified was the transcriptional modulator Snai2 (Slug). To verify that Snai2 was downstream of STAT3, we transfected ovarian cancer cells with siRNA to STAT3 and analyzed Snai2 gene expression. We found reduced expression of Snai2 with siRNA to STAT3 suggesting that STAT3 upregulates Snai2 expression. To determine the effects of Snai2 on mesothelial clearance by ovarian spheroids, we transfected ovarian cancer cells with siRNA to Snai2 or control, generated spheroids, and performed a mesothelial clearance assay. We found that reduced expression of Snai2 decreased the ability of the ovarian cancer cells to clear the mesothelial cell layer suggesting that Snai2 plays an important role in the early stages of ovarian cancer metastasis. Recognizing that Snai2 is a transcriptional modulator, we were interested in determining if Snai2 affected STAT3 activity. Analysis of available Snai2 ChIP-seq data identified three putative Snai2 binding sites associated with the STAT3 gene, suggesting that Snai2 may also regulate STAT3 gene expression. To determine if Snai2 affects STAT3 gene expression, ovarian cancer cells were transfected with siRNA to Snai2 and STAT3 mRNA expression was analyzed. From this, we found that reducing Snai2 expression also reduced STAT3 expression. Taken together, our data suggests that STAT3 and Snai2 form a feedforward loop promoting upregulation of each other and together they promote the early stages of ovarian cancer metastasis. Therefore, developing an inhibitor to one of these transcription factors would affect both proteins and may be beneficial to prevent or treat metastatic ovarian cancer.
Citation Format: David F. Walker, Sarah J. Lacroix, Yuri Makar, Sarah R. Walker. The role of STAT3 and Snai2 in ovarian cancer metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6077.
Abstract 6078: Suppression of tumor-intrinsic IFNγ signaling in ARF6-mediated metastatic progression of melanoma
Authors: Rich Coulson P. , Rogers Aaron , Yoo Jae Hyuk , Wolff Roger , Odelberg Shannon J. , Holmen Sheri L. , Grossmann Allie H. 
Published: September 2020

Abstract
ARF6 is a small GTPase that controls the subcellular location of proteins to regulate invasion, proliferation and tumor microvesicle shedding. ARF6 is aberrantly activated in cutaneous melanoma and stimulates invasion in BRAFV600E-melanoma by controlling localization and activation of beta-catenin and PI3K/AKT. In uveal melanoma, ARF6 facilitates GNAQQ209L signaling to drive tumor growth by trafficking GNAQ to cytoplasmic vesicles. Although distinct diseases, pharmacologic inhibition of ARF6 reduces disease progression in both uveal and cutaneous melanoma models. These data underscore the importance of intracellular trafficking mechanisms in cancer and highlight the potential clinical utility of targeting this machinery by inhibiting ARF6. In order to genetically dissect the role of ARF6 in melanomagenesis, we utilized RCAS-mediated delivery of Cre recombinase, with or without constitutively activated ARF6 (Arf6Q67L), specifically to melanocytic cells to induce constitutive activation of BRAFV600E (BrafCA), deletion of Cdkn2a (Cdkn2af/f) and (Arf6f/f). Activation of ARF6 accelerates spontaneous metastasis while loss of Arf6 delays tumor onset and reduces tumor incidence and growth, dramatically improving survival of BrafCA;Cdkn2af/f mice, including in the presence of Pten loss. Unexpectedly, tumors expressing ARF6Q67L show significantly reduced expression of interferon-gamma (IFNγ) response genes, reduced CD8 (T cell) transcripts and an anti-apoptotic proteomics profile. Knockdown of Arf6 sensitizes BRAFV600E melanoma cells to IFNγ treatment reducing cell viability in vitro. Together these data demonstrate that ARF6 modulates BRAFV600E-driven tumor progression and suggest that ARF6 activation suppresses tumor intrinsic IFNγ signaling to evade the anti-tumor immune response during metastatic progression. Our in vivo models provide a new paradigm for understanding vulnerabilities in BRAF-mediated oncogenesis and implicate intracellular trafficking mechanisms as potentially actionable machinery in melanoma development, immune evasion and disease progression.
Citation Format: Coulson P. Rich, Aaron Rogers, Jae Hyuk Yoo, Roger Wolff, Shannon J. Odelberg, Sheri L. Holmen, Allie H. Grossmann. Suppression of tumor-intrinsic IFNγ signaling in ARF6-mediated metastatic progression of melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6078.
Abstract 6080: IL1RAP augments Cysteine metabolism and drives oxidative stress adaptation and lung metastasis in Ewing sarcoma
Authors: Zhang Hai-Feng , El-Naggar Amal M. , Cheng Hongwei , Prudova Anna , Delaidelli Alberto , He Jian-Zhong , Negri Gian Luca , Lizardo Michael , Yang Tianqing , Morin Gregg , Li Wei , Dimitrov Dimiter S. , Sorensen Poul H. 
Published: September 2020

Abstract
The high oxidative stress cancer cells experience during the metastatic cascade is an important determinant of metastasis. How cancer cells adapt to those stressful conditions remains elusive. Here our global translatome and proteome analyses have uncovered novel signatures exploited by oncogene-transformed cells to adapt and survive oxidative stress. We revealed that various oncoproteins promote the expression of the IL1RAP to alleviate oxidative stress and facilitate stress adaptation. Mechanistically, IL1RAP controls Cysteine metabolism, a key substrate and determinant of antioxidant glutathione synthesis. CTH, a crucial enzyme for de novo Cysteine synthesis and redox regulation, was identified as a key functional mediator of IL1RAP. Moreover, global interactome analysis uncovered IL1RAP as a novel component and enhancer of the System Xc− transporter (SLC7A11), which is involved in Cystine uptake. Thus, IL1RAP enhances Cysteine supply via both uptake and biogenesis. IL1RAP depletion rendered Ewing sarcoma cells susceptible to oxidative stress and ferroptosis in vitro, and dramatically mitigated local invasion and lung metastasis in mice. In patients with Ewing sarcoma, high-expression of IL1RAP in the tumors correlated with poor event-free survival. Therefore, we have defined a novel pro-metastatic mechanism driven by IL1RAP-mediated Cysteine metabolism and redox regulation.
Citation Format: Hai-Feng Zhang, Amal M. El-Naggar, Hongwei Cheng, Anna Prudova, Alberto Delaidelli, Jian-Zhong He, Gian Luca Negri, Michael Lizardo, Tianqing Yang, Gregg Morin, Wei Li, Dimiter S. Dimitrov, Poul H. Sorensen. IL1RAP augments Cysteine metabolism and drives oxidative stress adaptation and lung metastasis in Ewing sarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6080.
Abstract 6114: Host and neoplastic cells utilize Axl for breast cancer bone metastasis
Authors: Tanaka Mai , Siemann Dietmar W. 
Published: September 2020

Abstract
Breast cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related death for women in the United States. Approximately 90% of cancer-related death results from metastasis, and the bone is the most common site of metastasis for breast cancer. Upregulation of signaling pathways can promote the metastatic phenotypes of neoplastic cells, including cell migration, invasion, proliferation and angiogenesis. In addition, when breast cancer cells disseminate to the bone, neoplastic cells upregulate signaling pathways to activate osteoclast-induced bone resorption. A key pathway involved in metastatic spread of cancer cells is the receptor tyrosine kinase Axl. Genetic and pharmacologic Axl inhibition in both human and rodent breast cancer cell lines (MDA-MB-231 and 4T1) impaired tumor cell migration and invasion. Intracardiac inoculation of Axl knockdown (KD) MDA-MB-231 cells significantly decreased the number of bone metastases compared to the scrambled control MDA-MB-231 cells. Another mechanism by which Axl inhibition impaired bone metastasis is through the modulation of osteoclast maturation and activity. Co-culture of Axl KD breast cancer cells with murine osteoclast precursor cells (Raw264.7) significantly reduced the number of tumor cell-induced osteoclast resorption pits on bone slices. In addition, genetic and pharmacologic inhibition of Axl in Raw264.7 cells as well as bone marrow derived osteoclast precursor cells, significantly reduced osteoclast formation and activity. Scrambled control and Axl KD Raw264.7 cells were cultured in serum free medium for 24 hours, and their conditioned media were collected. The conditioned media of Axl KD Raw264.7 cells revealed significantly decreased levels of monocyte chemoattractant protein 1 (MCP-1), which known to promote osteoclastogenesis, compared to the scrambled control Raw264.7 cells. In summary, we have demonstrated that inhibition of Axl decreases breast cancer metastasis to the bone through modulation of the host and neoplastic cell functions. Collectively, these data indicate that Axl signaling may be a promising therapeutic target to impair tumor progression and metastasis.
Citation Format: Mai Tanaka, Dietmar W. Siemann. Host and neoplastic cells utilize Axl for breast cancer bone metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6114.
Abstract 6119: RNAi rat models for drug discovery
Authors: Wang Chia-Lin , Yang Yu-ting , Vasileva Ana , Maurice Allison , Dow Lukas , Zuber Johannes , Lowe Scott , Premsrirut Prem K. 
Published: September 2020

Abstract
The cost of drug development has skyrocketed to an estimated $2.6B for every FDA approved drug primarily due to failures from lack of efficacy or safety. This suggests that our current preclinical validation process has been insufficient in predicting therapeutic potential and toxicity in humans. While genetically engineered mice have become the gold standard for dissecting cancer mechanisms and evaluating novel drug targets in vivo, the rat has historically been the major model species in many biomedical fields, notably toxicology and carcinogenicity testing; and for many scientists, the rat still remains the preferred rodent due to their larger size for surgical manipulation, repeat blood sampling, and their cognitive and physiological characteristics that more closely resemble humans than their mouse counterparts. Moreover, many hormone-dependent tumors cannot be engineered in mouse models and are better modeled in rats. Here, we take advantage of our two-step engineering approach and exploit the efficiency of CRISPR-based targeting to develop RNAi rat models that enable inducible and reversible gene silencing to simulate therapeutic regimes. We demonstrate that our approach allows us to rapidly generate RNAi rat models and mimic the function of the targeted small molecule inhibitors, such as BET inhibitors targeting Brd4. These results demonstrate that our high-throughput system currently used to generate RNAi mice is also applicable to the rat system and, by extension, other mammalian models. Inducible RNAi rat models will undoubtedly be powerful tools that can be used to model human cancers, to mimic the action of putative drugs, and to assess the potential of therapeutic targeting strategies in vivo prior to the costly drug development, ultimately guiding the development of safer and more effective drugs.
Citation Format: Chia-Lin Wang, Yu-ting Yang, Ana Vasileva, Allison Maurice, Lukas Dow, Johannes Zuber, Scott Lowe, Prem K. Premsrirut. RNAi rat models for drug discovery [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6119.