bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1442: Identifying the molecular basis by which βIII-tubulin promotes tumor cell survival and drug resistance in non-small cell lung cancer
Authors: Brayford Simon , Teo Wee Siang , Parker Amelia , McVeigh Laura , McCarroll Joshua A. , Kavallaris Maria 
Published: September 2020

Abstract
Lung cancer is the leading cause of cancer-related mortality worldwide with the most common sub-type, non-small cell lung carcinoma (NSCLC), accounting for &gt;80% of cases. Despite advances in treatments, 5-year survival rates for this disease remain dismal. Advanced NSCLC responds poorly to current therapy and the mechanisms underlying its resistance and aggressive nature are not well defined. Microtubules form a component of the cell cytoskeleton and alterations in the expression of microtubule proteins are increasingly correlated with more aggressive and treatment-refractory cancers. βIII-tubulin is a neuronal-specific isotype that is aberrantly expressed in a range of cancers including NSCLC, and has been found to be correlated with reduced patient survival.
Our group has recently demonstrated that βIII-tubulin contributes to activation of the PI3K/AKT cell-survival pathway in NSCLC cells[1]. One of the key negative regulators of this pathway is the tumor suppressor PTEN. PTEN can inhibit cell growth, migration and invasion, and a loss of PTEN function is often associated with cancer progression through AKT hyperactivation.
Here, using forced-genetics cell models, we show that AKT activation is reduced by βIII-tubulin knockdown, and that re-expression of βIII-tubulin restores these levels in NSCLC cells. Interestingly, we also found that βIII-tubulin knockdown resulted in increased PTEN mRNA along with altered levels of Snail-1/β-catenin, suggesting a possible role for βIII-tubulin in regulating the transcriptional pathway of the PTEN tumor suppressor. Building on these findings, we also identified, through a high-throughput cell-based drug screen, several receptor tyrosine kinase inhibitors that synergize with βIII-tubulin knockdown to reduce NSCLC cell proliferation and tumoroid growth.
Together, our data demonstrate an important role for βIII-tubulin in modulating the activation and/or expression levels of signaling proteins which form part of a major pro-survival pathway in NSCLC. In addition, our results suggest that inhibition of βIII-tubulin in combination with drugs that target multiple kinases may offer a novel therapeutic strategy for the treatment of NSCLC to improve patient outcomes.
[1] McCarroll et al., TUBB3/betaIII-tubulin acts through the PTEN/AKT signaling axis to promote tumorigenesis and anoikis resistance in non-small cell lung cancer. Cancer Research. 2015;75:415-425.
Citation Format: Simon Brayford, Wee Siang Teo, Amelia Parker, Laura McVeigh, Joshua A. McCarroll, Maria Kavallaris. Identifying the molecular basis by which βIII-tubulin promotes tumor cell survival and drug resistance in non-small cell lung 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 1442.
Abstract 1443: Inhibiting HMG-CoA reductase suppresses non-small cell lung carcinogenesis
Authors: Wang Qiushi , Zhang Tianshun , Bai Ruihua , Wang Keke , Li Xiang , Liu Kangdong , Wang Ting , Chang Xiaoyu , Ma Weiya , Bode Ann , Xia Qingxin , Song Yongping , Dong Zigang 
Published: September 2020

Abstract
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR) is a rate-limiting enzyme in the mevalonate pathway and is associated with the development of several tumor types. However, the role of HMGCR in non-small cell lung cancer (NSCLC) is still unknown. In the present study, we found that HMGCR is overexpressed in human lung adenocarcinoma tissues compared with normal tissues. Knockdown of HMGCR in NSCLC cells attenuated growth and induced apoptosis in vitro and in vivo. Furthermore, we found that fluvastatin, an inhibitor of HMGCR, suppressed NSCLC cell growth and induced apoptosis. Intriguingly, fluvastastin functions by inhibiting the HMGCR-driven Braf/MEK/ERK1/2 and Akt signaling pathways. Notably, fluvastatin attenuated tumor growth in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis and in a patient-derived xenograft (PDX) lung tumor model. Overall, our findings suggest that fluvastatin might be promising chemopreventive or potential therapeutic drug against NSCLC tumorigenesis, providing hope for rapid clinical translation.
Citation Format: Qiushi Wang, Tianshun Zhang, Ruihua Bai, Keke Wang, Xiang Li, Kangdong Liu, Ting Wang, Xiaoyu Chang, Weiya Ma, Ann Bode, Qingxin Xia, Yongping Song, Zigang Dong. Inhibiting HMG-CoA reductase suppresses non-small cell lung carcinogenesis [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 1443.
Abstract 1447: Elucidating the mechanism of Dock7-mediated cellular transformation
Authors: Pumar Oriana Y. Teran , Wilson Kristin F. , Cerione Richard A. 
Published: September 2020

Abstract
Akt is a serine/threonine protein kinase that receives signals from a plethora of external and internal stimuli in order to promote survival and regulate cellular growth and metabolism. Akt is part of the highly conserved PI3K/Akt signaling axis and is classically regulated by its interaction with the phosphoinositide, PIP3, and its subsequent phosphorylation at S473 and S308 by the mTOR complex 2 (mTORC2) and 3-Phosphoinositide-dependent protein kinase 1 (PDK1), respectively. Altered Akt activity has been linked to numerous diseases, such as cancer, diabetes and neurodegenerative diseases. Specifically, PI3K/Akt deregulation occurs in approximately one third of human cancers and ~40% of breast cancers.
My research focuses on Dock7, a Guanine Nucleotide Exchange Factor (GEF) for the small GTPases Cdc42 and Rac1, and a novel player in the regulation of Akt activity and stability. Dock7 belongs to the Dock family of atypical GEFs and contains two evolutionarily conserved domains, DHR1 (a putative lipid binding domain) and DHR2 (the catalytic GEF domain). The expression level of Dock7 correlates with an unfavorable prognosis in liver cancer patients, and it is highly expressed in triple-negative breast cancers. Studies in our laboratory showed Dock7 is essential for the transformed properties of several cancer cell lines, and that it interacts with Akt in co-immunoprecipitation assays. In order to decipher the mechanism by which Dock7 mediates transformation, I created a Crispr-Cas9 Dock7 Knock-out HeLa cell line. I proceeded to confirm that these cells are not able to grow in an anchorage independent manner nor in serum free conditions, two hallmarks of transformation. Furthermore, in comparison to the phosphorylation status of Akt in parental HeLa cells, I found that in Dock7 KO HeLa cells, Akt is not phosphorylated at the S473 site in the absence of growth factors, indicative of lower basal activity. Accordingly, phosphorylation of downstream effectors of Akt is also downregulated. Besides promoting the phosphorylation state of Akt, Dock7 plays a role in the stability of the Akt protein during certain cellular stresses, highlighting a versatile and important role for Dock7 in Akt regulation and a potential target for therapeutic intervention in tumors where Akt is deregulated.
Citation Format: Oriana Y. Teran Pumar, Kristin F. Wilson, Richard A. Cerione. Elucidating the mechanism of Dock7-mediated cellular transformation [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 1447.
Abstract 1449: The molecular dissection of pro-tumorigenic activity of mesothelin in pancreatic cancer
Authors: Joseph Sarah Mary , Avula Leela Rani , Zhang Xianyu , Alewine Christine Campo 
Published: September 2020

Abstract
Mesothelin (MSLN) is a cancer-specific antigen that is differentially expressed in many human cancers, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. The MSLN gene encodes a 71 kD precursor protein, that is reportedly cleaved by the intracellular protease furin to produce a 31 kD N-terminal fragment called megakaryocyte potentiating factor (MPF) and mature 40 kD MSLN C-terminal fragment. Mature MSLN is localized to the cell surface by a GPI-linkage. We synthesized a series of mutant MSLN constructs containing sequence modifications predicted to disrupt the canonical signaling sequences for furin cleavage and GPI-linkage. These constructs were then expressed in a MSLN knock-out pancreatic cancer cell line. We used flow cytometry to detect cell surface MSLN expression and immunoblotting for MSLN proteins to assess the effect of mutation. We expected that a 23aa C-terminal truncation that removed a predicted hydrophobic signaling sequence for GPI-linkage would eliminate plasma membrane insertion of MSLN. However, this truncation did not suppress cell surface expression. A deeper 31aa truncation which eliminated two potential anchoring sites at Ser599 and Ser606 was required to successfully eliminate surface expression. We are currently evaluating the growth of this pancreatic cancer cell line expressing GPI-truncated soluble MSLN in vitro and in vivo. Our results suggest that MSLN may have an alternate means for membrane insertion besides GPI-linkage. For the panel of furin site mutants, non-conservative mutations were made to disrupt the reported consensus recognition motif for furin 290-RPRFRR-295 (R290H, R292Q, RR294-5GG) or the entire motif region was deleted (289_315del). Mutants were also made to disrupt the putative furin cleavage site (R286A) and neighboring basic residues that were potential protease cleavage sites (R282A, K306Q, K307Q). These furin site mutants were expected to eliminate cleavage of the 71 kD precursor protein to 40 kD mature MSLN. We found that all mutants did increase levels of precursor but did not ablate formation of mature MSLN. Similarly, expression of WT full-length MSLN into the LoVo cell line, which lacks furin activity, still resulted in formation of 40 kD mature MSLN predominately. In conclusion, we found that precursor processing to mature MSLN still took place despite extensive mutation of the putative furin cleavage site and in the absence of active furin. These results suggest that additional proteases besides furin can perform MSLN precursor cleavage.
Citation Format: Sarah Mary Joseph, Leela Rani Avula, Xianyu Zhang, Christine Campo Alewine. The molecular dissection of pro-tumorigenic activity of mesothelin in 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 1449.
Abstract 1459: Selective killing of SMARCA4-deficient gynecologic cancers by mitochondria oxidative phosphorylation inhibitors
Authors: Wang Yemin , Ong Dionzie , Chen Shary Yuting , Li Eunice , Orlando Krystal , Raupach Elizabeth , Ji Jennifer , Weissman Bernard , Pirrotte Patrick , Humtsman David 
Published: September 2020

Abstract
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) and dedifferentiated carcinoma of the ovary or endometrium are rare but highly aggressive types of gynecologic cancers. We and others have recently demonstrated that genetic inactivation of SMARCA4, one of the two ATPases of the SWI/SNF chromatin remodeling complex, along with protein loss is the only recurrent somatic mutation of SCCOHT. Furthermore, SMARCA4 loss appears as a key event in the development of a subset of dedifferentiated carcinoma of the ovary, endometrium or other organs. These SMARCA4-deficient dedifferentiated tumors and SCCOHT usually lose the expression of SMARCA2, the alternative ATPase of the SWI/SNF complex. Through mining the publicly available genome-wide CRISPR screen database from the Broad Institute DepMap Project for about 500 cell lines, we identified that SMARCA4/A2-dual deficient ovarian cell lines are selectively sensitive to the genetic ablation of multiple components of mitochondria electron transfer chain (ETC). Using seahorse metabolism assays, we revealed that SCCOHT cells have reduced glycolysis in comparison to other ovarian cancer cells and utilize mitochondria respiration for energy production regardless of the availability of glucose. Accordingly, both SCCOHT and SMARCA4-deficient dedifferentiated ovarian carcinoma cell lines are remarkably more sensitive to several inhibitors of ETC complex I, and tigecycline, a selective inhibitor of the mitochondria ribosomal translation, than other ovarian cancer cells, such as SMARCA4-intact ovarian high-grade serous carcinoma cells and clear cell ovarian carcinoma cells regardless of the expression level of ARID1A, a SWI/SNF complex subunit frequently lost in clear cell ovarian carcinoma. Re-expression of SMARCA4 increased the expression of SLC2A1, encoding the glucose transporter GLUT1, and decreased the sensitivity of SCCOHT cells to ETC complex I inhibitors, suggesting that SMARCA4 loss may reduce the transport of glucose leading to reduced glycolysis and increased reliance on mitochondria respiration, which is currently under investigation. Therefore, our data suggest that selective targeting mitochondria respiratory complex function can be an effective strategy for SCCOHT and other SMARCA4-deficient dedifferentiated cancers of gynecologic tract or other organs.
Citation Format: Yemin Wang, Dionzie Ong, Shary Yuting Chen, Eunice Li, Krystal Orlando, Elizabeth Raupach, Jennifer Ji, Bernard Weissman, Patrick Pirrotte, David Humtsman. Selective killing of SMARCA4-deficient gynecologic cancers by mitochondria oxidative phosphorylation inhibitors [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 1459.
Abstract 1485: E7011, a novel anti-angiogenesis inhibitor targeting Notch4 receptor signal pathway
Authors: Adachi Yusuke , Sakamoto Yoshimasa , Nakazawa Youya , Tachino Sho , Ito Ken , Abe Takanori , Minoshima Yukinori , Hoshino-Negishi Kana , Ogasawara Hideaki , Kawakatsu Tomomi , Nishimura Miyuki , Shimizu Masashi , Tahara Kazuhiro , Sato Toshitaka , Suzuki Katsuhisa , Agarwala Kishan , Iwata Masao , Funahashi Yasuhiro , Nomoto Kenichi , Ozawa Yoichi , Matsui Junji , Imai Toshio , Kato Yu 
Published: September 2020

Abstract
Notch4 is selectively expressed on tumor endothelial cells and hypothesized to contribute to cancer malignancy through mechanisms including tumor angiogenesis regulation and promoting drug resistance. We developed E7011, a humanized IgG2κ antibody targeting Notch4 receptor signaling. To obtain anti-human Notch4 monoclonal antibody, human Notch4 3EGFR (epidermal growth factor repeat) domain - NRR (negative regulatory region) - SEAP (secreted alkaline phosphatase) - His protein was immunized to mice and 6698 hybridomas were obtained. By screening these clones with the Notch4 binding assay and Notch4-specific gal4-fusion luciferase reporter assay, mouse anti-human Notch4 mAb clone (6-3-A6) was selected. The CDRs (complementarity determining regions) of 6-3-A6 were grafted into the variable regions of human IgG2κ, and E7011, novel humanized anti-human Notch4 monoclonal antibody, was developed by screening in assays above. The biomolecular interaction analysis showed that E7011 is able to bind to human and mouse Notch4-NRR domain-SEAP-His, and inhibit human Notch4 receptor signaling in an antibody-dose dependent manner as well as 6-3-A6. IHC analysis showed that Notch4 was expressed on CD31 positive endothelial cells in Calu6 human non-small cell lung carcinoma xenograft tumor. Intravenous administration of E7011 at 1, 3, 10 mg/kg in twice a week significantly decreased tumor growth compared with control IgG treatment without severe body weight loss. We also investigated the functional tumor angiogenesis by hoechest dye-perfusion and staining with anti-CD31 antibody in the Calu6 xenograft model. E7011 treatment significantly decreased hoechst-positive perfusion area compared with vehicle treatment. In conclusion, E7011 is a novel antitumor agent that is a specific signal inhibitor targeting the Notch4 receptor and suppresses tumor growth through decreasing tumor vessel function in based on preclinical studies.
Citation Format: Yusuke Adachi, Yoshimasa Sakamoto, Youya Nakazawa, Sho Tachino, Ken Ito, Takanori Abe, Yukinori Minoshima, Kana Hoshino-Negishi, Hideaki Ogasawara, Tomomi Kawakatsu, Miyuki Nishimura, Masashi Shimizu, Kazuhiro Tahara, Toshitaka Sato, Katsuhisa Suzuki, Kishan Agarwala, Masao Iwata, Yasuhiro Funahashi, Kenichi Nomoto, Yoichi Ozawa, Junji Matsui, Toshio Imai, Yu Kato. E7011, a novel anti-angiogenesis inhibitor targeting Notch4 receptor signal pathway [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 1485.
Abstract 1486: Exosomal miR-141 promoted tumor angiogenesis via KLF12 in small cell lung cancer
Authors: Mao Shuangshuang , Lu Zhiliang , Zheng Sufei , Zhang Guochao , Huang Jianbing , Sun Nan , He Jie 
Published: September 2020

Abstract
Background: Angiogenesis, the basic requirement for the survival of tumor cells, has been considered to be one of the malignant characteristics of small cell lung cancer (SCLC) and was closely related to the poor outcomes of SCLC patients. MiR-141 has been found to play a pro- or anti-angiogenetic role in different cancers while its role in SCLC angiogenesis has never been explored.
Methods: We isolate total RNA from plasm exosomes and serum samples from two cohorts of SCLC patients respectively to detect the expression of circulating miR-141 in SCLC patients using qRT-PCR. miR-141 was overexpressed in SCLC cell-secreted exosomes to investigate its effects on cell migration, tube formation and microvessel sprouting capabilities of human umbilical vein vascular endothelial cells (HUVECs) both in vitro and in vivo. A dual-luciferase assay was conducted to validate the direct target gene of miR-141.
Results: We showed that the level of circulating miR-141 was significantly upregulated in a total of 116 SCLC patients compared with normal volunteers, and the increased miR-141 was revealed to be associated with advanced patient TNM stages which implying the potential oncogenic role of miR-141 in SCLC malignances. In vitro experiments indicated that miR-141 was packaged into SCLC cell-secreted exosomes and was delivered to HUVECs via exosomes to strengthen the migration, invasion, tube formation and microvessel sprouting capabilities of HUVECs. Moreover, mouse models demonstrated that exosomal miR-141 derived from SCLC cells induced neo-angiogenesis in vivo and subcutaneous tumor nodules developed from SCLC cells with miR-141 overexpression showed higher microvessel densities and faster tumor growth than which developed from negative control cells. Combining miRNA target prediction tools with a dual-luciferase assay, we identified that KLF12 was the direct target gene of miR-141 and the angiogenetic promotion effect of miR-141 on HUVECs was abrogated by overexpressing KLF12.
Conclusions: Our results elaborated the specific function of exosomal miR-141/KLF12 pathway in SCLC angiogenesis for the first time and provided potential novel targets for anti-angiogenetic therapies in SCLC patients. Our study highlighted the critical role of exosomal miRNAs in SCLC microenvironments and cell communications which offered novel clues for the future exploration of molecular mechanisms of SCLC malignances.
Citation Format: Shuangshuang Mao, Zhiliang Lu, Sufei Zheng, Guochao Zhang, Jianbing Huang, Nan Sun, Jie He. Exosomal miR-141 promoted tumor angiogenesis via KLF12 in small cell lung 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 1486.
Abstract 1511: A highly plastic cell state emerges during lung adenocarcinoma evolution
Authors: Chan Jason Earl , Marjanovic Nemanja Despot , Hofree Matan , Canner David , Wu Katherine , Hartmann Griffin , Smith Olivia C. , Kim Jonathan , Hudson Anna , Subramanian Ayshwarya , Pitter Kenneth , Rekhtman Natasha , Massion Pierre P. , Poirier John T. , Rudin Charles M. , Jacks Tyler , Regev Aviv , Tammela Tuomas 
Published: September 2020

Abstract
The role of tumor heterogeneity in the progression of lung adenocarcinoma remains poorly understood. In order to understand how tumor heterogeneity impacts tumor evolution, we profiled single cell transcriptomes from genetically engineered mouse lung tumors at various stages. We observed a set of reproducible transcriptional states whose diversity increased over time. Additionally, we identified a highly plastic cell state that arose in every tumor we obtained. We profiled this cell state and identified a robust potential for phenotypic switching, an increased potential for spheroid formation in tumor sphere cultures, and an enrichment of the highly plastic cell state after chemotherapeutic stress in vivo. Our work suggests that the highly plastic cell state plays a significant role, and perhaps even drives, tumor progression and resistance to therapy in lung adenocarcinoma.
Citation Format: Jason Earl Chan, Nemanja Despot Marjanovic, Matan Hofree, David Canner, Katherine Wu, Griffin Hartmann, Olivia C. Smith, Jonathan Kim, Anna Hudson, Ayshwarya Subramanian, Kenneth Pitter, Natasha Rekhtman, Pierre P. Massion, John T. Poirier, Charles M. Rudin, Tyler Jacks, Aviv Regev, Tuomas Tammela. A highly plastic cell state emerges during lung adenocarcinoma evolution [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 1511.
Abstract 1572: Single cell sequencing reveals the microenvironment network in multifocal pulmonary nodules
Authors: Liu Dongcheng , Pan Pan , Li Shixuan , Cheng Zhiqiang , Wang Guangsuo , Zou Chang 
Published: September 2020

Abstract
Tumor microenvironment plays an important role in tumorigenesis in cancer development, however, little is known about its heterogeneity and evolution progression during early stage of lung cancer. In this study, single cell sequencing was applied to uncover the transcriptome in the microenvironment and the complex ecosystem of stromal cells in pulmonary nodules including atypical adenomatous hyperplasia (AAH) adenocarcinoma in situ (AIS), invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IA). Although the expression or mutation of driver genes were detected in different stage of pulmonary lesion tissues that might contribute to the development of lung cancer, tumor environment including immune system are found to be important for the progression of tumorigeneses. This study provided evidence that the different evolutionary selection and microenvironment network in multifocal pulmonary nodules in the same individual resulted in various cancer progression stages. To our knowledge, this study first provides an overview of the genetic basis and tumor environment of human lung nodule by single-cell sequencing.
Keywords: Single cell sequencing; heterogeneous; microenvironment; multifocal pulmonary nodules
Citation Format: Dongcheng Liu, Pan Pan, Shixuan Li, Zhiqiang Cheng, Guangsuo Wang, Chang Zou. Single cell sequencing reveals the microenvironment network in multifocal pulmonary nodules [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 1572.