bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1119: S100A4 alters mitochondrial metabolism to promote invasion and metastasis of non-small cell lung cancer cells through upregulation of NDUFS2
Authors: Liu Lili , Qi Lei , Knifley Teresa , Piecoro Dava W. , Rychahou Piotr , Liu Jinpeng , Mitov Mihail I. , Martin Jeremiah , Wang Chi , Wu Jianrong , Weiss Heidi L. , Butterfield D. Allan , Evers B. Mark , O'Connor Kathleen L. , Chen Min 
Published: August 2019

Abstract
It is generally accepted that alterations in metabolism are critical for the metastatic process; however, the mechanisms by which the metabolic changes are controlled by the major drivers of the metastatic process remain elusive. Here, we find that S100A4, a major metastasis-promoting protein, alters metabolic plasticity to drive tumor invasion and metastasis. Investigating how S100A4 regulates metabolism, we find that depletion of S100A4 decreases oxygen consumption rate, mitochondrial activity, and ATP production, and shifts cell metabolism to be more glycolytically active. We further identify that the 49 KD mitochondrial complex I subunit NADH dehydrogenase (ubiquinone) Fe-S protein 2 (NDUFS2) is regulated in an S100A4-dependent manner and that S100A4 and NDUFS2 exhibit co-occurrence at significant levels in various cancer types (cBioPortal). Importantly, we find that knockdown of NDUFS2 inhibits mitochondrial complex I activity, reduces cellular ATP level, and decreases the invasive capacity in three-dimensional (3D) growth, thus mimicking the biological effect resulting from S100A4 knockdown in A549 cells. Likewise, silencing S100A4 and NDUFS2 dramatically decreases the rate of metastasis as well as tumor growth in vivo. Finally, we provide evidence that cells with S100A4 and NDUFS2 depletion shift metabolism toward glycolysis through upregulating hexokinases expression and that suppressing S100A4 signaling sensitizes lung cancer cells to glycolysis inhibition. Together, our findings uncover a novel function of S100A4 in mitochondrial metabolism and highlight the importance of NDUFS2 in regulating the plasticity of mitochondrial metabolism by S100A4 to promote the invasion and metastasis in lung cancer.
Citation Format: Lili Liu, Lei Qi, Teresa Knifley, Dava W. Piecoro, Piotr Rychahou, Jinpeng Liu, Mihail I. Mitov, Jeremiah Martin, Chi Wang, Jianrong Wu, Heidi L. Weiss, D. Allan Butterfield, B. Mark Evers, Kathleen L. O'Connor, Min Chen. S100A4 alters mitochondrial metabolism to promote invasion and metastasis of non-small cell lung cancer cells through upregulation of NDUFS2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1119.
Abstract 1123: Bcl-xL promotes metastasis via a novel nuclear function
Authors: Zhang Tiantian , Li Sha , Na Joseph , Chi Soyoung , Zhang George , Du Yi-Chieh Nancy 
Published: August 2019

Abstract
Cancer cells often evade apoptosis through upregulation of anti-apoptotic proteins and/or downregulation of pro-apoptotic proteins. Bcl-xL, a negative regulator of mitochondria-mediated apoptosis, is frequently overexpressed in cancer cells. Bcl-xL has long been known for its function in regulating apoptosis during embryonic development and in pathological conditions. Any role that Bcl-xL might play in tumor metastasis has been ascribed to its anti-apoptotic function; i.e. Bcl-xL may increase metastasis by lending survival advantage to the tumor cells during the course of metastasis. However, we have demonstrated that Bcl-xL’s metastatic function is independent of its canonical anti-apoptotic activity and instead requires a novel nuclear function in cancer. We found that Bcl-xL promotes migration, even when cells are defective in mitochondria-mediated apoptosis. Consistently, Bcl-xL mutants lacking anti-apoptotic activity can still promote migration, induce epithelial-mesenchymal transition (EMT), upregulate TGFβ, and increase migration and invasion of pancreatic neuroendocrine tumor cells and breast cancer cells. Importantly, our data demonstrated that forcible localization of Bcl-xL outside the nucleus impairs its metastatic function.
As a mitochondrial membrane protein in healthy cells, Bcl-xL’s transmembrane domain prevents its nuclear import. This suggests that Bcl-xL enters the nucleus by an active nuclear transport. We hypothesized that unique transporters likely exist so as to transport this normally mitochondria membrane-bound Bcl-xL protein to the nucleus. By using immunoprecipitation in combination with mass spectrometry, we identified a novel interacting partner of Bcl-xL. We are investigating whether this protein transports Bcl-xL into the nucleus to promote metastasis.
Citation Format: Tiantian Zhang, Sha Li, Joseph Na, Soyoung Chi, George Zhang, Yi-Chieh Nancy Du. Bcl-xL promotes metastasis via a novel nuclear function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1123.
Abstract 1126: Association of CXCR4 expression with lymph node metastasis in distal cholangiocarcinoma
Authors: Yagawa Yohsuke , Aruga Atsushi , Takeshita Nobuhiro , Higuchi Ryota , Yazawa Takehisa , Tanigawa Keishi , Yamamoto Masakazu 
Published: August 2019

Abstract
BACKGROUND: The standard treatment of resectable distal bile duct cancer is pancreatoduodenectomy. However, prognosis is still poor because of a high rate of lymph node (LN) metastasis, underlining the need to further clarify the mechanism of LN metastasis. Recently accumulated evidence has shown that cancer cells can take advantage of the homeostatic mechanism of lymphocyte homing to metastasize to LNs. The CXCL12-CXCR4 axis modulates lymphocyte homing by inducing continuous migration of dendritic cells and T cells that are expressing chemokine receptor CXCR4 to LNs where chemokine CXCL12 is homeostatically secreted.
OBJECTIVE: The aim of this study is to elucidate whether distal bile duct cancer cells express CXCR4 and investigate a possible association with LN metastasis.
METHODS: This study enrolled 32 patients with resectable distal bile duct cancer including 19 patients with LN metastasis and 13 without. All patients underwent pancreatoduodenectomy at our department between 2002 and 2008 and have been followed up (Median observation period: 50.5 (4-184) months). Histopathologically, 27 cases were tubular adenocarcinoma, and 5 cases were other types of cancer. Immunostaining with resected specimens was undertaken to examine the expression of CXCR4 in cancer cells and determine whether its expression level is associated with lymph node metastasis. When 10% and more of tumor cells were stained, specimens were diagnosed as positive for CXCR4. The result of staining level was visually assessed.
RESULTS: Cancer cells were stained heterogeneously by antibody for CXCR4. Normal cells of the bile duct were not stained, while damaged or desquamated cells were stained. With regard to the staining pattern, the cytoplasm and membrane were stained but the nucleus was not stained. 19 out of 32 cases were positive for CXCR4 expression (59.4%). 15 of 19 cases with LN metastasis were positive whereas 4 of 13 cases without LN metastasis were positive (p=0.0107). CXCR4 expression on cancer cells increased with advancing cancer cell undifferentiation in tubular adenocarcinoma; cancer cells were positive for CXCR4 in 0 of 5 (0%), 6 of 16 (37.5%), and 6 of 6 (100%) cases in tubular 1, tubular 2, and tubular 3 adenocarcinoma, respectively.
CONCLUSIONS: Our results indicated that the expression of CXCR4 in cancer cells may be associated with LN metastasis in distal bile duct cancer.
Citation Format: Yohsuke Yagawa, Atsushi Aruga, Nobuhiro Takeshita, Ryota Higuchi, Takehisa Yazawa, Keishi Tanigawa, Masakazu Yamamoto. Association of CXCR4 expression with lymph node metastasis in distal cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1126.
Abstract 1143: The circulating tumor cell (CTC) microenvironment visualized by color coded imaging
Authors: Suetsugu Atsushi , Satake Tomoyuki , Nakamura Miki , Shimizu Masahito , Saji Shigetoyo , Moriwaki Hisataka , Hoffman Robert M. 
Published: August 2019

Abstract
Background/Aim: An important question is whether cancer cells circulate with stromal cells. A color-coded mouse model of metastatic lymphoma was utilized to investigate the microenvironment of CTC clusters using fluorescent-protein imaging.
Materials and Methods: EL-4 mouse lymphoma cells expressing red fluorescent protein (RFP) were injected into the spleen of transgenic C57BL6-green fluorescent protein (GFP) mice. The cellular composition of CTC clusters both in heart blood and portal blood was imaged with confocal microscopy.
Results: CTC clusters comprised 8.8% of CTCs determined by color-coded imaging. Heterotypic CTC clusters containing other types of cells were distinguishable from homotypic CTCs. Heterotypic CTC clusters comprising cancer cells and fibroblasts were more rare than homotypic ones. Heterotypic CTC clusters with fibroblasts were observed only in portal blood, not in heart blood.
Conclusion: CTCs can form clusters, which may contain fibroblast or other stromal cells that may play a role in promoting CTC metastasis.
Citation Format: Atsushi Suetsugu, Tomoyuki Satake, Miki Nakamura, Masahito Shimizu, Shigetoyo Saji, Hisataka Moriwaki, Robert M. Hoffman. The circulating tumor cell (CTC) microenvironment visualized by color coded imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1143.
Abstract 1145: Biomarker-driven molecular imaging of prostate cancer using the PEG10 promoter
Authors: Shapovalova Mariya 
Published: August 2019

Abstract
The retrotransposon-derived paternally expressed gene 10 (PEG10) protein is ordinarily expressed at high levels in the placenta. The over-expression of PEG10 has been documented in a number of malignancies including hepatocellular carcinoma and leukemia. Recently, it was discovered that PEG10 isoforms promoted the progression of prostate adenocarcinoma to a highly lethal non-androgen receptor (AR) driven subtype called aggressive variant prostate cancer (AVPC).
In this study, we found that PEG10 was also expressed in castration-resistant PCa possessing constitutively active AR-splice variants in addition to AR-negative AVPC. We subsequently developed a molecular genetic imaging strategy for the non-invasive imaging of PCa by utilizing the cancer specificity of the PEG10 promoter to drive the expression of reporter genes. The transcriptional output of the PEG10 promoter was enhanced to enable high expression of reporter genes by multiple imaging modalities and immunoassay. By using this PEG10 promoter upstream of a reporter gene in a plasmid, we were able to detect PCa by fluorescence and positron emission tomography (PET) imaging after systemic administration of the plasmid in mice. This method also allowed for the detection of PCa by an immunoassay of mouse urine.
Our study demonstrates a pre-clinical proof-of-concept that the PEG10 promoter is a powerful and specific tool that can be utilized for non-invasive detection of highly lethal PCa subtypes. This biomarker imaging technology has the potential to improve detection and can be further modified for therapeutic applications.
Citation Format: Mariya Shapovalova. Biomarker-driven molecular imaging of prostate cancer using the PEG10 promoter [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1145.
Abstract 1148: Recombinant cancer-stromal cells Identified in the metastatic tumor microenvironment By color-coded imaging
Authors: Nakamura Miki , Suetsugu Atsushi , Matsuura Kana , Satake Tomoyuki , Shimizu Masahito , Saji Shigetoyo , Moriwaki Hisataka , Hoffman Robert M. 
Published: August 2019

Abstract
Background/Aim:The relationship of cancer and stromal cells is poorly understood, including their ability to fuse or otherwise their genetic materials. Materials and Methods:Red-fluorescent protein (RFP-expressing) mouse colon 26 cancer cells were initially injected subcutaneously in green-fluorescent protein (GFP) nude mice. The resulting subcutaneous tumors were harvested and cultured. Using the Olympus FV1000 confocal microscope, the cells cultured from tumors were visualized. After 14 days culture, the cells were injected into the spleen. Results:After splenic injection, colon 26 metastases were observed in the liver, ascites, and bone marrow. RFP colon cancer cells, GFP stromal cells derived from host GFP nude mice, and recombinant yellow-fluorescent cells were observed in each organ. In addition, in the liver, areas with only GFP stromal cells were observed and assured to be a pre-metastatic niche. Conclusion:Color-coded imaging demonstrated the dynamics of colon cancer and stromal cells at different metastatic sites including the formation of recombinant cancer stromal cells. The significance of which will be evaluated in future experiments.
Citation Format: Miki Nakamura, Atsushi Suetsugu, Kana Matsuura, Tomoyuki Satake, Masahito Shimizu, Shigetoyo Saji, Hisataka Moriwaki, Robert M. Hoffman. Recombinant cancer-stromal cells Identified in the metastatic tumor microenvironment By color-coded imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1148.
Abstract 1151: Real-time visualization of brain metastasis in vivo
Authors: Tsuji Takahiro , Wake Hiroaki , Ozasa Hiroaki , Haruwaka Koichiro , Ajimizu Hitomi , Yasuda Yuto , Sakamori Yuichi , Nomizo Takashi , Kim Young Hak , Hirai Toyohiro 
Published: August 2019

Abstract
Research into physiological phenomena has taken a leap forward by recent advanced optical bio imaging techniques. Traditionally, physiological phenomena including cell division, cell function, molecular transport and expression, and signal transduction were detected by biochemical methods. However, this information lacked high resolution spatial or temporal information. Using recent bio imaging techniques, both spatial and temporal information can be integrated across the molecular, cellular and systems levels that allow us to further investigate the hierarchical interaction of organ systems. Here, we have developed an in vivo imaging method to visualize brain metastasis of lung cancer which provides real-time information of their proliferation, metastasis and the immune reaction for cancer cells. CMT167 and LLC1 cell lines which expressed mCherry or Venus were established. The fluorescently labeled cell lines were administered into the brain via the carotid artery or direct injection to the CX3CR1-GFP mice, transgenic mice in which microglia was specifically labeled with GFP. The metastasis cancer and the immune reaction were visualized using 2-photon microscopy for 14 days. Interaction between cancer cells and microglia was observed. We identified heterogeneity of the interaction between microglia and cancer cells. Some microglia cells showed phagocytosis-like response to cancer. Other microglia touched, surrounded, and released cancer cells without phagocytotic response. These interactions between microglia and cancer cells could be observed by 3-6 hours continuous real-time in vivo imaging. Further study to address detailed mechanism for microglia reaction is in progress. This research has potential to provide the information of brain metastasis in vivo and to be a new solution to elucidate the process of immunity and niche.
Citation Format: Takahiro Tsuji, Hiroaki Wake, Hiroaki Ozasa, Koichiro Haruwaka, Hitomi Ajimizu, Yuto Yasuda, Yuichi Sakamori, Takashi Nomizo, Young Hak Kim, Toyohiro Hirai. Real-time visualization of brain metastasis in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1151.
Abstract 1159: Association of ALDH7A1 overexpression with chemotherapy resistance and cancer stem cell in lung cancer
Authors: Yasuda Yuto , Sakamori Yuichi , Ozasa Hiroaki , Ajimizu Hitomi , Oguri Tetsuya , Maeno Ken , Tsuji Takahiro , Nomizo Takashi , Yamamoto Tomoko , Yoshida Hironori , Hirai Toyohiro , Kim Young Hak 
Published: August 2019

Abstract
Aldehyde dehydrogenases (ALDHs) play a major role in the oxidation of aldehydes. Certain isoforms of ALDH is related to cancer stem cells (CSCs) responsible for tumor initiating, drug resistance and metastasis. ALDH1A1 and ALDH3A1 have been known for CSC markers of lung cancer. Since these two isoforms and ALDH7A1 are involved in cellular structural and osmoregulatory function, we focused on function of ALDH7A1 in lung cancer. We established SN-38 resistant DMS53 (DMS53-SR) and SN-38 or gemcitabine resistant NCI-H23 (H23-SR or H23-GR, respectively) by intermittent and dose-escalating exposure of the agent. The expression of ALDH7A1 was upregulated in DMS53-SR and H23-SR/H23-GR compared with DMS53 and NCI-H23, respectively. ALDH7A1 expression was altered using a plasmid to overexpress ALDH7A1 in DMS53. ALDH7A1 overexpression led to a slight increase of IC50 of SN-38, upregulation of SOX2, and tumor sphere formation. Overexpression of ALDH7A1 in DMS53 have enhanced tumorigenic capacity in vivo. These data suggested that ALDH7A1 might be a marker of CSC and a therapeutic target of lung cancer.
Citation Format: Yuto Yasuda, Yuichi Sakamori, Hiroaki Ozasa, Hitomi Ajimizu, Tetsuya Oguri, Ken Maeno, Takahiro Tsuji, Takashi Nomizo, Tomoko Yamamoto, Hironori Yoshida, Toyohiro Hirai, Young Hak Kim. Association of ALDH7A1 overexpression with chemotherapy resistance and cancer stem cell in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1159.
Abstract 1171: Identifying small molecules that specifically inhibit glioma stem cells
Authors: Sloan Anthony R. , Spina Raffaella , Voss Dillon M. , Laye Sophie , Bar Eli E. 
Published: August 2019

Abstract
Glioblastomas (GBM) are the most common primary malignant brain tumor in adults and are recognized as one of the deadliest forms of cancer. Despite aggressive therapy consisting of maximal surgical resection followed by concomitant radiation and temozolomide (TMZ) chemotherapy, GBM remains to have a median survival time of ~ 15 months. Glioblastoma stem cells (GSCs) are suggested to play a critical role in the GBM phenotype; GSC have tumor initiation ability, propagation ability, and have been shown to be a driver in promoting GBM resistance to current therapeutic interventions. Due to these poor clinical outcomes and resistance to current treatments, more potent and preferably more specific pharmacological therapies are needed in order to target cellular-molecular pathways to eradicate GSCs and effectively treat GBM. In an effort to identify agents that specifically inhibit GSC growth, we recently conducted a drug screen of over 3,000 small molecules. HSR020913 patient derived neurospheres were treated for 72 hours with library agents at a concentration of 10 µM and cell growth was observed for a period of 5 days. We identified twelve highly potent compounds in the primary screen that inhibited the growth of HSR020913 neurospheres by over 50%. Subsequently, the potency of these compounds was tested on five additional GBM patient derived neurosphere lines (HSR040622, HSR040822, CCF3691, CCF3832, and CCF08-387) at even lower concentrations. We next sought to determine the specificity of these compounds in killing GSCs but not normal cells. To this aim we tested these compounds against immortalized human neural stem cells (v-Myc hNSCs) and normal human astrocytes (NHA). Of the twelve potent compounds identified in the primary screen, three compounds (AGSC9, AGSC11, AGSC12) showed to have negligible to minimal effect, only at higher doses, on normal neural stem cells. The respective half maximal inhibitory concentration (IC50) was determined for all the neurosphere lines utilized. Subsequent studies determined the inhibitory effect of these compounds on clonogenic capacity and enzymatic activity. Future studies are warranted to identify molecular pathways targeted by these compounds and determine their effect on tumor progression and survival in vivo.
Citation Format: Anthony R. Sloan, Raffaella Spina, Dillon M. Voss, Sophie Laye, Eli E. Bar. Identifying small molecules that specifically inhibit glioma stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1171.
Abstract 1173: A novel high throughput platform for head & neck cancer organoids drug screening
Authors: Queiroz Karla , Driehuis Else , Bonilla Silvia , Lanz Henriëtte , Clevers Hans , Joore Jos , Vulto Paul 
Published: August 2019

Abstract
Head and neck (HN) cancer is a broad category of tumor types arising from various anatomic structures including the craniofacial bones, soft tissues, salivary glands, skin, and mucosal membranes. Treatment often involves an intensive combination of surgery, radiotherapy and chemotherapy. Despite this, tumour recurrence rates remain high and survival rates are relatively poor. Here, we describe a novel high throughput drug screening platform combining the OrganoPlate, a microfluidic based 3D culture plate, and HN cancer-derived organoids. MIMETAS develops Organ-on-a-Chip-based models for evaluation of new medicines. Our unique microfluidic technology enables testing of compounds on miniaturized 3D organ models in high-throughput. These models are expected to show better predictivity as compared to laboratory animals and conventional 2D cell culture models, without compromising throughput or ease of use. Hereby we show the establishment of HN cancer-derived organoids in 2-lane OrganoPlate, and its usefulness for phenotypic drug screenings. The aim of the study is to evaluate the 2-lane OrganoPlate as a platform for growing HN cancer organoids and drug screening. Organoid lines (T2, T3 and T4) were embedded in the 2-lane OrganoPlate as single cells in an Extracellular Matrix gel. At day 3, cultures were treated with Cisplatin or Carboplatin for 120 hours. Drug response was evaluated by assessment of morphology (phase contrast), Cell Viability (Alamar blue) and proliferation (EdU incorporation). Organoids cultures grow well under perfusion in the 2-lane OrganoPlate and different sensitivity to cisplatin is captured by the used readouts. The high-throughput, microfluidic 2-lane OrganoPlate platform offers an attractive method for growing HN cancer-derived organoids, supporting development of individualized tumour models for phenotypic drug screenings.
Citation Format: Karla Queiroz, Else Driehuis, Silvia Bonilla, Henriëtte Lanz, Hans Clevers, Jos Joore, Paul Vulto. A novel high throughput platform for head & neck cancer organoids drug screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1173.