bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1144: Novel prostate cancer mouse models for testing targeted chemopreventive potential of pterostilbene
Authors: Hemani Rutu , Inamdar Ninad , Kumar Avinash , Donovan Virginia , Levenson Anait S. 
Published: September 2020

Abstract
Metastasis-associated protein 1 (MTA1) plays role in prostate cancer progression and metastasis. We have previously reported on the MTA1-targeted chemopreventive and therapeutic efficacy of pterostilbene (Pter) in the prostate-specific Pten heterozygous (Pten+/f; Pb-Cre+) and Pten null (Ptenf/f; Pb-Cre+) mice. To investigate the exact role of MTA1 in prostate cancer tumorigenesis and its early stages, we developed appropriate mouse models, namely prostate-specific MTA1-knocked in (MTA1-tg) and MTA1-tg on the background of prostate-specific Pten heterozygosity (MTA+/+, Pten+/f; Pb-Cre+). In the current project, we asked three major questions: 1) whether prostate MTA1 overexpression in the context of Pten loss promotes an earlier onset, greater total incidence and accelerated PIN or tumor growth rate; 2) what MTA1-associated molecules are involved in prostate cancer progression; and 3) whether Pter supplemented diet can provide beneficial effects. Identified from our ChIP-Seq data MTA1-associated molecules included CyclinD1, Notch2, and two neuroendocrine markers, namely CHGA and SYP. Using two prostate cancer cell lines, DU145 and PC3M and their corresponding MTA1 knockdown (shMTA1) clones, we validated the direct link between MTA1 and these markers on mRNA and protein levels. Further, we generated 28 prostate-specific MTA1+/+; Pten+/f; Pb-Cre+ mice and randomized them into two major groups: 1) mice on control diet (Ctrl-Diet) and 2) mice on Pter-Diet. After 5 months of feeding with corresponding diets (AIN-76A phytoestrogen free diets supplemented or not with Pter at 100 mg/kg/diet), mice were sacrificed and prostate tissues were isolated for histological, immunochemical and molecular analysis. Results demonstrated the contribution of MTA1 in more aggressive histological phenotype (Ki67, PCNA, p27, SMA, CK8), increased levels of oncogenic MTA1-guided molecules (CyclinD1, Notch2, CHGA, SYP, AR) and the potential for Pter in prostate cancer chemoprevention.
Citation Format: Rutu Hemani, Ninad Inamdar, Avinash Kumar, Virginia Donovan, Anait S. Levenson. Novel prostate cancer mouse models for testing targeted chemopreventive potential of pterostilbene [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 1144.
Abstract 1146: Development of CRISPR human Skp2 knock-in in the prostate of mouse and the associated prostate organoids for testing Skp2 targeting agents
Authors: Song Liankun , Xu Shan , Arabzadehkaffash Kia , Fazelpour Ali , Fu Dongjun , Tippin Matthew , Zi Xiaolin 
Published: September 2020

Abstract
S-phase kinase associated protein 2 (Skp2) is a promising drug target as studies have demonstrated that Skp2 is required for spontaneous tumor development that occurs in the retinoblastoma protein (pRb), Pten or p53 deficient mice. We therefore have aimed to establish CRISPR human Skp2 (hSkp2) knock-in in the prostate of mouse to examine its role in prostate carcinogenesis. In addition, Skp2 overexpressing organoids are being developed for convenient and efficient screening of specific Skp2 inhibitors. cDNA of hSkp2 and porcine teschovirus-1 (P2A) was introduced into immediate upstream of mouse probasin coding sequencing using CRISPR knock-in targeting approach to establish transgenic mice specifically overexpressing hSkp2 in the prostate glands. Quantitative PCR, western blot and immunohistochemistry (IHC) were used to identify the expression levels of Skp2 and histopathological analyses were performed after H&E staining. Prostate glands were dissected and digested for organoid culture, then morphological features and viability of organoids were evaluated following treatments of potential Skp2 inhibitors. Prostate glands and other tissues from mice of three transgenic lines which were genotyped positive were dissected and hSkp2 was detected in ventral, dorsal and lateral prostate lobes, but not in testis, kidney, spleen, and liver. Line 10092 was found to have the highest expression of hSkp2 among these three lines. Prostate weight slightly increased in transgenic mice compared to that of wild-type control mice. Hyperplasia, prostatic intraepithelial neoplasia (PIN), and carcinoma were noted, which suggested that overexpression of hSkp2 in the prostate of mice promoted proliferation and prostate tumorigenesis. Organoids that were derived from the prostate of hSkp2 transgenic mice recapitulated prostatic phenotypic features and maintained a high level of hSkp2. A novel Flavokawain A derivative was found to selectively alter the morphology of hSkp2 organoids and decrease the viability. Prostatic lesions found in the hSkp2 knock-in mice demonstrated a potential role of hSkp2 in early prostate carcinogenesis and organoids overexpressing hSkp2 have the utility for screening out compounds targeting Skp2 in prostate cancer.
Citation Format: Liankun Song, Shan Xu, Kia Arabzadehkaffash, Ali Fazelpour, Dongjun Fu, Matthew Tippin, Xiaolin Zi. Development of CRISPR human Skp2 knock-in in the prostate of mouse and the associated prostate organoids for testing Skp2 targeting agents [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 1146.
Abstract 115: Hedgehog signaling pathway promotes breast cancer adaptation to hypoxia
Authors: Lama-Sherpa Tshering D. , Kammerud Sarah C. , Shevde Lalita A. 
Published: September 2020

Abstract
Breast cancer is the most commonly diagnosed cancer in women in the US. Metastasis accounts for the majority of breast cancer-related deaths. Rapidly proliferating primary tumors experience oxygen levels that are lower in comparison to the normal tissue. The proportions of these hypoxic tumor cells in breast cancer strongly correlate to the incidence of metastasis. Around 70% of breast cancers present with bone metastasis. Tumor cells that metastasize to the bone can lead to an imbalance in bone homeostasis, often leading to osteolysis. Our lab has previously reported that the activation of Hedgehog (Hh) signaling, one of the embryonic developmental pathways found to be abnormally activated in breast cancer, leads to increased osteolysis in vivo. The incidence of osteolytic metastasis at the tibio-femoral junction was significantly reduced in the Hh signaling-deficient mice. Since a hypoxic microenvironment is prevalent in bone, it is imperative to understand how Hh signaling drives tumor cell adaptation to hypoxia. The hypoxic tumor microenvironment in the primary tumor might select for metastatic cells that are better able to metastasize to the bone. We hypothesize that Hh signaling enables the adaptation of breast cancer cells to hypoxia and consequently their metastatic potential. Hh signaling can be canonically activated through smoothened (SMO)-dependent activation of the transcriptional regulator GLI. Cellular response to hypoxia is mediated by the hypoxia-inducible factors (HIFs). To understand the importance of Hh signaling activation in hypoxic condition, we inhibited the Hh signaling pathway using GLI and SMO inhibitors. Additionally, we knocked-down GLI1 in breast cancer cell lines. We have identified a feed-forward mechanism between Hh signaling and HIF signaling in hypoxic conditions leading to sustained hypoxia response by stabilization of HIF-1α. Future investigations will address the significance of Hh signaling inhibition in a murine model of TNBC. This study will help determine the therapeutic benefit of hedgehog inhibitors in controlling hypoxia-mediated metastasis and tumorigenesis.
Citation Format: Tshering D. Lama-Sherpa, Sarah C. Kammerud, Lalita A. Shevde. Hedgehog signaling pathway promotes breast cancer adaptation to hypoxia [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 115.
Abstract 1239: Role of the glutathione antioxidant system in the autophagic process outcome
Authors: Lee Yong J. 
Published: September 2020

Abstract
Ferroptosis has been reported as a unique form of cell death. However, in recent years, researchers have increasingly challenged the uniqueness of ferroptosis compared to other types of cell death. In this study, we examined whether ferroptosis shares cell death pathways with other types of cell death, especially autophagy, via the autophagic process. Here, we observed that ferroptosis inducers (artesunate and erastin) and autophagy inducers (bortezomib and XIE62-1004) led to autophagosome formation via the endoplasmic reticulum (ER) stress response. Unlike XIE62-1004, artesunate, erastin, and bortezomib, which affect glutathione production or utilization, induced oxidative stress responses - an increase in the levels of heme oxygenase-1 and lipid peroxidation. Oxidative stress responses were attenuated by deletion of autophagy related gene-5 or treatment with autophagy inhibitors (bafilomycin and chloroquine). Our studies provide an overview of common death pathways - the ER stress response-associated autophagic process in ferroptosis and autophagy. We also highlight the role the glutathione redox system plays in the outcome of the autophagic process.
Citation Format: Yong J. Lee. Role of the glutathione antioxidant system in the autophagic process outcome [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 1239.
Abstract 1247: NOX4 P62 regulates tuberculous fibrosis promoted tumorigenic potential
Authors: Hong Yoonki , Woo Seong-Ji , Kim Youngmi , Hong Ji Young 
Published: September 2020

Abstract
Background Increased incidence of lung cancer in subjects with previous tuberculous infection was reported in epidemiologic data. NOX4 signaling contributes to tuberculous pleural fibrosis and lung cancer proliferation, respectively. The objective of this study was to investigate the role of NOX4 in tuberculous pleurisy-assisted tumorigenicity both in vitro and in vivo.
Methods After pleural mesothelial cells from WT and NOX4 KO C57BL/6 mice were stimulated with Heat-Killed mycobacterium tuberculosis (HKMT) for 24 hour, cellular interactions between mesothelial cell and cancer cell were evaluated by using transwell invasion assay and wound healing assay. A murine model injected with cancer at 4 weeks after Mycobacterium bovis bacillus Calmette-Guérin (BCG) pleural infection were used to validate the contribution of tuberculous fibrosis to tumor invasion.
Results HKMT -stimulated mesothelial cells induced enhanced invasion and migration potential of lung cancer cells in a NOX4-dependent manner. The inhibition of NOX4 signaling exerted a negative effect on the metastatic potential of lung cancer by tuberculous fibrosis in mice model. The expression of inflammatory cytokines like TNF-a, TGF-β and IL-6 was enhanced in the WT-BCG+CA than WT+PBS+CA and NOX4 KO+BCG+CA. The expression of P62 in lung tissue was higher in the WT-BCG+CA than WT+PBS+CA and NOX4 KO+BCG+CA.
Discussions Our results suggest that NOX4 and autophagy signaling changed by tuberculous fibrosis could result enhanced tumorigenic potential. NOX4-P62 might seve as a target for the development of anti-tuberculous fibrosis and anti-cancer drugs.
Citation Format: Yoonki Hong, Seong-Ji Woo, Youngmi Kim, Ji Young Hong. NOX4 P62 regulates tuberculous fibrosis promoted tumorigenic potential [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 1247.
Abstract 1521: New roles of ATP in metastasis: Extracellular and macropinocytosis internalized ATP work together to induces epithelial to mesenchymal transition and other early steps of metastasis
Authors: Cao Yanyang , Wang Xuan , Evers Maria , Li Yunsheng , Zhang Haiyun , Chen Xiaozhuo 
Published: September 2020

Abstract
Metastasis is estimated to be responsible for more than 90% of all cancer-related deaths. Metastasis is initiated by induction of epithelial-mesenchymal transition (EMT) of cancer cells, but factors and mechanisms involved in EMT are far from being fully elucidated. Intratumoral extracellular ATP (eATP), at levels of 100-700 μM or 103 to 104 times higher than in normal tissues, has been known to induce epithelial-mesenchymal-transition (EMT) of cancer cells via purinergic receptor signaling. However, the exact induction mechanisms are far from fully known. We previously described that eATP is internalized by cancer cells in vitro and in vivo by macropinocytosis in human non-small cell lung cancer cells, drastically elevates intracellular ATP levels, enhances cell proliferation and resistance to anticancer drugs. In this study, we tested the hypothesis that eATP and macropinocytosis-internalized eATP also induces EMT and other early steps of metastasis. Here we report that eATP, at the concentrations reported in tumors, potently induces expression of matrix metallopeptidases (MMPs), detachment, EMT, migration, and invasion of lung cancer cells. The induction was independent of TGF-β and semi-independent of P2X7 activation. eATP performs these functions not only extracellularly, but also intracellularly after being macropinocytically internalized to further enhance P2X7-mediated EMT, filopodia formation and other early steps of metastasis. The knockout of the macropinocytosis-associated SNX5 gene significantly reduces macropinocytosis and slows down tumor growth in nude mice. Collectively, these results show that eATP functions on these processes not only from outside of cancer cells but also inside after being macropinocytotically internalized. These findings which shed light on eATP's initiator and effector roles in almost every step in early metastasis call for rethinking and rebalancing energy equations of intracellular biochemical reactions and the Warburg effect, and identify eATP and macropinocytosis as novel targets for potentially slowing down EMT, preventing metastasis, and reducing metastasis-related death in cancer patients.
Citation Format: Yanyang Cao, Xuan Wang, Maria Evers, Yunsheng Li, Haiyun Zhang, Xiaozhuo Chen. New roles of ATP in metastasis: Extracellular and macropinocytosis internalized ATP work together to induces epithelial to mesenchymal transition and other early steps of 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 1521.
Abstract 1699: IMMUcan: Broad cellular and molecular profiling of the human tumor microenvironment
Authors: Hong Henoch S. , Liechti Robin , Reinhard Christoph , Morfouace Marie M. ,   IMMUcan consortium
Published: September 2020

Abstract
The development of next generation therapeutics for cancer patients requires an improved understanding of the underlying mechanisms of resistance to existing therapies as well as novel biomarkers that can help identify patients most likely to benefit from the treatments. Most studies addressing these questions have predominantly relied on a limited set of tumor profiling techniques or have been hampered by relatively small patient numbers. In response to this need, the IMMUcan consortium has been formed. Co-led by the EORTC (Brussels, Belgium), SIB (Lausanne, Switzerland), Eli Lilly (Indianapolis, IN, USA) and Merck KGaA (Darmstadt, Germany), IMMUcan is an EU-funded, public-private partnership of expert immunologists, cell biologists, technology developers and clinical key opinion leaders. The mission of IMMUcan is to generate broad molecular and cellular profiling data of the tumor microenvironment from up to 3,000 patients derived from five indications: non-small cell lung cancer, head and neck squamous cell carcinoma, renal cell carcinoma, colorectal cancer and breast cancer. Most of these patients will be treated under standard of care and recruited via the EORTC-SPECTA infrastructure. All acquired tumor samples will undergo detailed and standardized analyses applying diverse profiling modalities including whole exome sequencing to determine the mutational landscape, total RNA sequencing for transcriptome analysis, multiplex immunofluorescence (IF) and imaging mass cytometry (IMC) facilitating the assessment of approx. 80 proteins at single cell resolution. To avoid inter-lab variations, each profiling method (sequencing, IF or IMC) will be performed by a single expert laboratory, which will process all IMMUcan samples. These data will be integrated with clinical information and centralized in a Knowledge Management System. Once published, the entire IMMUcan dataset will be made available to the scientific community for further study and interrogation. IMMUcan also acquires blood samples, including PBMCs, saliva as well as fresh-frozen stool samples. In addition, we have established workflows to generate reports documenting clinically actionable molecular alterations, which are returned to the treating physicians within 6-8 weeks. Thus far, 31 patients have been recruited and first tumor profiling data from these patients will be presented. Funding: IMI2 JU grant agreement 821558, supported by EU's Horizon 2020 and EFPIA.
Citation Format: Henoch S. Hong, Robin Liechti, Christoph Reinhard, Marie M. Morfouace, IMMUcan consortium. IMMUcan: Broad cellular and molecular profiling of the human tumor microenvironment [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 1699.
Abstract 1763: NEO2734, a novel dual bromodomain and histone acetyltransferase inhibitor, in the treatment of colorectal cancer
Authors: Kuang Chaoyuan , Cai Manbo , Risnik Denise , Giles Francis , Zhang Lin 
Published: September 2020

Abstract
Background: Oncogenic c-MYC activation is seen in a broad spectrum of cancers and is often associated with more aggressive disease and/or poor outcomes. c-MYC expression is often driven by transcriptional super-enhancers which depend on histone modifications to function. We report the results of our studies on the novel suppressor of histone reading and writing, NEO2734, and the effects on colorectal cancer cells.
Methods: Commercially and publicly available colorectal cancer cell lines were used under standard culture conditions. All small molecule treatments were performed with DMSO as the primary solvent and dilutions made in aqueous solution. Commonly employed techniques such as MTS viability assays, immunofluorescent 2-D microscopy, siRNA knockdown, western blotting, and single-color flow cytometry were used.
Results: NEO2734, a dual BET/bromodomain inhibitor and p300/CBP inhibitor, reduced cell growth more than the BET inhibitor OTX-015 and the p300/CBP inhibitor CPI-637. NEO2734 potently induced cell death and markers of apoptosis such as PUMA and TRAIL2/DR5. Inhibition of the caspase by zVAD-fmk eliminated the induction of cell death by NEO2734. Knockdown or knockout of the death proteins PUMA or DR5 additively reduced the amount of NEO2734-induced apoptosis. NEO2734 reduced the expression of downstream targets c-MYC, acetylated histone H3, and acetylated histone-H4. Strikingly, NEO2734 significantly upregulated the ER stress markers BiP and ATF3. NEO2734 also activated immunogenic cell death in vitro, as measured by HMGB1 release and membrane localization of calreticulin. Finally, examination of a panel of cell lines revealed SPOP mutant colorectal cancer cells to be exquisitely sensitive to growth inhibition by NEO2734.
Conclusions: NEO2734 causes growth inhibition and apoptosis of colorectal cancer cells. NEO2734 is more potent than single-target BET inhibitors. Anticipated targets such as c-MYC and acetylated histone are confirmed. NEO2734 appears to trigger cell death through both PUMA and TRAIL mediated apoptosis. NEO2734 also activates ER stress and immunogenic cell death. Work is ongoing to confirm the mechanism of apoptosis and test rational drug combinations such as with chemotherapy and immunotherapy.
Citation Format: Chaoyuan Kuang, Manbo Cai, Denise Risnik, Francis Giles, Lin Zhang. NEO2734, a novel dual bromodomain and histone acetyltransferase inhibitor, in the treatment of colorectal 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 1763.
Abstract 2204: Enhancing anti-tumor efficacy of MART-1-specific TCR-T cells by CRISPR-Cas9-based PD-1 disruption
Authors: Gao Qianqian , Ding Renpeng , Chen Huanyi , Xu Qumiao , Zhu Linnan , Dong Xuan , Gu Ying , Chao Cheng-chi 
Published: September 2020

Abstract
T cell function can be compromised when continuously exposed to tumor antigens by immune checkpoint signaling. Immunotherapies with T cells and inhibitors of repressive checkpoint molecules such as PD-1, CTLA-4, etc. have been shown promising results in cancer clinical trials. Inhibitors of checkpoint molecules have been solely used to block or suppress the corresponding pathways to improve the functionality of T cells and enhance the anti-tumor immunity. However, few reports combined disruption of repressive checkpoint molecules with TCR-T cell therapy for the treatment of cancer patients. In our study, new TCR sequence was attained from T cells stimulated by Melan-A (aa27-35) peptide, but the cytotoxicity of MART-1-specific TCR-T cells was found to be inhibited by expression of PD-L1 in target cells. To overcome this PD(L)-1-mediated suppression, Cas9 mRNA and gRNA were electroporated into primary T cells infected by MART-1 TCR lentivirus. CRISPR/Cas9-mediated PD-1 disruption in MART-1 TCR-T cells recovered T cell cytotoxicity inhibited by PD-L1 overexpression in target cells. In addition, secretion of IFNγ and IL-2 was also increased in PD-1-damaged TCR-T cells. Furthermore, the differences between wild-type and PD-1-disrupted TCR-T cells were characterized by single-cell RNA (scRNA) sequencing. In summary, our study illustrates enhanced therapeutic efficacy and different features of PD-1-eliminated TCR-T cells compared to the control, providing an alternative strategy for current cell therapy.
Citation Format: Qianqian Gao, Renpeng Ding, Huanyi Chen, Qumiao Xu, Linnan Zhu, Xuan Dong, Ying Gu, Cheng-chi Chao. Enhancing anti-tumor efficacy of MART-1-specific TCR-T cells by CRISPR-Cas9-based PD-1 disruption [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 2204.