bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1876: Cell cycle-dependent front polarized cell migration requires Aurora kinase A
Authors: Chu Tony Lok Heng , Zhou Lixin , Won Jennifer , Mohan Pooja , Nemirovsky Oksana , Fotovati Abbas , Nielsen Torsten , Pante Nelly , Maxwell Christopher 
Published: July 2017

Abstract
PROBLEM- Metastasis accounts for 90% of deaths from carcinomas.
BACKGROUND- To initiate migration, epithelial cells must front-rear polarize and reorganize the microtubule cytoskeleton directed toward the lamillipodia or leading edge. During mitosis, centrosome maturation, duplication, spindle pole assembly and chromosome segregation require Aurora kinase A (AURKA), which is optimally active when complexed with TPX2. Accumulating evidences identify non-mitotic functions for AURKA, such as cell migration and ciliary reorganization. Overexpression of AURKA leads to tumorigenesis in breast cancer. Mechanisms that activate non-mitotic AURKA and promote cell migration as well as metastasis are yet to be uncovered.
RESULTS- In a large breast cancer tissue microarray (n= 3,175), the abundance of phosphorylated RHAMM (a substrate of AURKA) predicted overall and relapse-free survival in ER-negative, basal-subtype, and triple negative breast tumors. We studied the AURKA-TPX2-RHAMM signaling axis in mammary (MCF10A and nMUMG-FUCCI) and HeLa cells. In scratch wound assays, migratory cells were found to have front-polarized centrosomes, which correlated with G2 cell cycle phase, phosphorylated AURKA and elevated microtubule nucleation at centrosomes. Small molecule inhibition of Aurora kinase activity impaired centrosome polarity and retarded the kinetics of cell migration. In parallel, silencing RHAMM altered TPX2 location as indicated by immunofluorescence and immuno-EM, which located TPX2 to the nuclear envelope and nuclear pore basket. Nuclear import of recombinant TPX2 was attenuated in RHAMM silenced cells and nuclear envelope accumulation was elevated.
CONCLUSION- The AURKA-TPX2-RHAMM axis regulates centrosome polarity, microtubule nucleation and directional cell migration while phosphorylated RHAMM predicts survival in aggressive forms of breast cancer.
Citation Format: Tony Lok Heng Chu, Lixin Zhou, Jennifer Won, Pooja Mohan, Oksana Nemirovsky, Abbas Fotovati, Torsten Nielsen, Nelly Pante, Christopher Maxwell. Cell cycle-dependent front polarized cell migration requires Aurora kinase A [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1876. doi:10.1158/1538-7445.AM2017-1876
Abstract 189: Development of peptidomimetic inhibitors of the ERG gene fusion product in prostate cancer
Authors: Wang Xiaoju 
Published: July 2017

Abstract
Transcription factors play a key role in the development of diverse cancers, and therapeutically targeting them has remained a challenge. In prostate cancer, the gene encoding the transcription factor ERG is recurrently rearranged and plays a critical role in prostate oncogenesis. Here, we identified a series of peptides that interact specifically with the DNA binding domain of ERG. ERG inhibitory peptides and derived peptidomimetics (EIPs) bound with high affinity and specificity leading to proteolytic degradation of ERG protein. The EIPs attenuated ERG-mediated transcription, chromatin recruitment, protein-protein interactions, cell invasion, and tumor growth. Thus, peptidomimetic targeting of transcription factor fusion products may provide a promising therapeutic strategy for prostate cancer as well as other cancers.
Citation Format: Xiaoju Wang. Development of peptidomimetic inhibitors of the ERG gene fusion product in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 189. doi:10.1158/1538-7445.AM2017-189
Abstract 1896: Soluble lung-derived selectins promote breast cancer cell migration
Authors: Khan Sami U. , Chu Jenny E. , Xia Ying , Allan Alison L. 
Published: July 2017

Abstract
Ninety percent of all breast cancer-related deaths are attributed to metastasis, as current therapies are largely non-curative in the metastatic setting. One of the most common sites of breast cancer metastasis is the lung. Previous work from our lab has demonstrated that there are over 70 soluble factors produced by murine lung tissue, many of which have been associated with cancer cell growth, migration, invasion and metastasis. However, the relative contribution of each individual factor in enhancing the metastatic behavior of breast cancer cells has not been examined in detail. Three of the identified soluble lung-derived proteins are E-, L- and P-selectin, and these were the focus of the current study. The selectins are a family of glycoproteins with known physiological roles in vascular/immune cell migration, and soluble selectins have been clinically observed to be elevated in the sera of cancer patients. We hypothesized that soluble lung-derived selectins enhance the metastatic behavior of breast cancer cells. We used a 2D ex vivo model of the soluble lung microenvironment, generated by isolating conditioned media from dissociated healthy murine lung. E-, L- and P-selectin were then individually immunodepleted from the lung-conditioned media (lung-CM) and the subsequent functional effect on breast cancer cell migration and proliferation was assessed using transwell migration and BrdU incorporation assays, respectively. MDA-MB-231 and SUM149PT human breast cancer cells demonstrated significantly enhanced cell migration toward lung-CM relative to basal media, and this migration was significantly reduced when E-, L- or P-selectin were depleted (p&lt;0.05). In contrast, although MDA-MB-231 and SUM149PT human breast cancer cells demonstrated significantly enhanced cell proliferation in response to lung-CM relative to basal media (p&lt;0.05), depletion of soluble E-, L- or P-selectin from lung-CM had no influence on reducing proliferation (p&gt;0.05). Ongoing studies are aimed at elucidating the pathways through which soluble lung-derived selectins exert their pro-migratory function. If these results implicate a common receptor and downstream signalling pathways for all three selectins, these ligand-receptor interactions may have value as potential therapeutic targets for the prevention of pulmonary metastasis in breast cancer patients.
Citation Format: Sami U. Khan, Jenny E. Chu, Ying Xia, Alison L. Allan. Soluble lung-derived selectins promote breast cancer cell migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1896. doi:10.1158/1538-7445.AM2017-1896
Abstract 1897: The role of nuclear deformation and rupture in breast cancer cell migration
Authors: McGregor Alexandra L. , Elacqua Joshua J. , Bell Emily S. , Lammerding Jan 
Published: July 2017

Abstract
Invasion of tumor cells into the surrounding tissue is a critical step in the metastatic cascade, which is responsible for the vast majority of cancer-related deaths. Recent findings have begun to demonstrate that the biophysical properties of the cell nucleus play a critical role in this process. During invasion, cancer cells must often pass through interstitial spaces much smaller than the cell nucleus. While the cell cytoplasm easily maneuvers through confined spaces, the deformability of the nucleus, which is the largest and stiffest organelle, ultimately determines how efficiently a cell can pass through a tight space. Furthermore, as the nucleus deforms to move through a confined space, it can exhibit transient loss of nuclear envelope (NE) integrity, where the nuclear membranes rupture and nuclear and cytoplasmic components interchange. We previously showed that chromatin is exposed to the cell cytoplasm during NE rupture, and cells can incur DNA damage. While this work revealed that cancer cell migration requires nuclear deformation and can involve NE rupture, it is currently unknown whether such events correlate with metastatic potential. We used a panel of human breast cancer cells lines, including claudin-low, basal-like, and lumen-like cells. Cells were stably labeled with a green fluorescent protein fused to a nuclear localization sequence (NLS-copGFP) to investigate whether some cell lines were particularly well suited to migrate through tight spaces, and if any were particularly prone to NE rupture. The cells were loaded into microfluidic devices that were designed to mimic interstitial in vivo spacing and monitored by time-lapse microscopy. Devices contained constrictions 5 µm tall and 1, 2, or 15 µm wide. We found that claudin-low cell lines such as BT-549 migrated through confined spaces (1+2 µm wide constrictions) significantly faster and more efficiently than basal-like HCC70 cancer cells. In contrast, the various cell lines displayed similar migration rates in the 15 µm wide constrictions, which do not require nuclear deformation. Thus, the differences observed between the cell lines reflect specific defects in migration through confined spaces, and not general migration defects. We are currently expanding our studies to a larger panel of cancer cell lines and to mouse breast cancer models. If confirmed, these results could indicate that highly invasive cancer cells may benefit from more deformable nuclei that facilitate movement through tight spaces encountered in the tissue microenvironment.
Citation Format: Alexandra L. McGregor, Joshua J. Elacqua, Emily S. Bell, Jan Lammerding. The role of nuclear deformation and rupture in breast cancer cell migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1897. doi:10.1158/1538-7445.AM2017-1897
Abstract 1917: AXL inhibition in ovarian cancer stem-like cells increases chemo-sensitivity
Authors: Kim Jin-Young , Chung Hyewon , Shin So-Jin , Ha Eunyoung , Cho Chi-Heum 
Published: July 2017

Abstract
Cancer stem-like cells (CSCs), a small population of cancer cells with regenerative potential, may lead to the initiation and progression of secondary tumors. Long-term chemotherapeutic drug treatment can also result in the generation of a drug resistant population of cancer stem cells. In this study we have isolated CD44+ and CD117+ enriched ovarian cancer stem-like cells from primary cultured ascites cells removed from ascites fluid of naïve ovarian cancer patients. AXL, a type I receptor tyrosine kinase family member, is found to be over-expressed in ovarian cancer stem-like cells. Cell viability assays showed that ovarian CSCs are chemo-resistant to concentration dependent paclitaxel treatment. AXL was inhibited using a R428 and cell viability assays and apoptotic assays in the presence of paclitaxel were performed, which made the CSCs chemo sensitive. Si-RNA based inhibition of AXL also displayed a similar pattern of improving the sensitivity of the stem-like cells to the chemotherapeutic drug. PI3-kinase/Akt signaling pathway has also been shown to be involved in decreasing the cell viability during the inhibition of AXL. In conclusion, this study establishes the role of AXL, a receptor tyrosine kinase, as one of the key proteins influencing the chemo resistance in ovarian cancer stem-like cells.
Citation Format: Jin-Young Kim, Hyewon Chung, So-Jin Shin, Eunyoung Ha, Chi-Heum Cho. AXL inhibition in ovarian cancer stem-like cells increases chemo-sensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1917. doi:10.1158/1538-7445.AM2017-1917
Abstract 192: Targeting stearoyl CoA desaturase 1 (SCD1) in hepatobilliary carcinoma
Authors: Copland John Alton , Marlow Laura A. , Bok Ilah , Miller James L. , Akiko Matsuda , Asmann Yan W. , Sarangi Vivekananda , Alberts Steven R. , Mody Kabir , Roberts Lewis R. , Truty Mark J. , Patel Tushar C. 
Published: July 2017

Abstract
Background: The paucity of effective therapeutic agents for hepatocellular cancer (HCC) underscores the critical need for more effective therapeutic strategies. Recent studies indicate lipid biosynthesis and desaturation is required for HCC survival. Targeting these may prove beneficial because such changes contribute to therapeutic resistance. Stearoyl CoA desaturase (SCD1), a key mediator of fatty acid (FA) biosynthesis and rate-limiting in conversion of saturated fatty acids (SFAs) to mono-unsaturated fatty acids (MUFAs), is upregulated in HCC and many other cancers. As such, we therapeutically targeted a novel lipogenic tumor survival mechanism mediated by SCD1 as a means to combat the chemoresistance associated with HCC. In so doing, we evaluated a novel lead SCD1 inhibitor in HCC.
Methods: Paraffin embedded patient HCC tissues were examined for SCD1 expression. Using combined computational and synthetic chemistry approaches, we synthesized four novel specific SCD1 inhibitors with SSI-4 being the lead SCD1 inhibitor. HCC cell lines were examined using proliferation assays for response to SSI-4. IC50 concentrations for blocking SCD1 enzyme activity was determined. Blood half-life and bioavailability of single dose SSI-4 was determined. Mechanisms of action of SCD1 were examined that included Endoplasmic reticulum (ER) stress. In vivo, antitumor activity was determined using HCC patient derived xenograft (PDX) mouse models.
Results: We identified elevated SCD1 mRNA and protein in HCCs tissues. SSI-4 dose-dependently inhibits cell proliferation in HCC cell lines with specificity demonstrated by oleic acid (MUFA) co-culture. Single dose oral gavage SSI-4 demonstrated a half-life of ~4 hours and excellent oral bioavailability. SSI-4 was well tolerated with long-term daily dosing. SSI-4 treatment of HCC cells and tumors led to endoplasmic reticulum (ER) stress followed by apoptotic cell death. Single agent SSI-4 demonstrated antitumor activity in HCC PDX mouse models with suppression of ER stress regulated proteins.
Conclusions: Targeting a novel lipid metabolic pathway in HCC may provide effective therapy for aggressive HCC.
Citation Format: John Alton Copland, Laura A. Marlow, Ilah Bok, James L. Miller, Matsuda Akiko, Yan W. Asmann, Vivekananda Sarangi, Steven R. Alberts, Kabir Mody, Lewis R. Roberts, Mark J. Truty, Tushar C. Patel. Targeting stearoyl CoA desaturase 1 (SCD1) in hepatobilliary carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 192. doi:10.1158/1538-7445.AM2017-192
Abstract 1921: Stem-like clusters of CD44+ circulating tumor cells seed metastases in breast cancer
Authors: Liu Xia , Chen Wenjing , Taftaf Rokana , Liu Huiping 
Published: July 2017

Abstract
Background: Circulating tumor cells (CTCs) are cells shed from primary tumor and circulate in the peripheral blood. They are considered the seeds of metastasis. Compared to single CTCs, clusters of multiple CTCs possess 50 times higher metastatic capacity in mouse breast cancer models. However, the mechanisms underlying the metastatic promotion effect of CTC clusters are unclear. In addition, whether clustered CTCs have cancer stem cell (CSC) properties and what stem cell markers they express have not been determined.
Methods: Immunohistochemistry (IHC) was used to detect CTCs in vascular structures, and the stem cell markers in single and clustered CTCs. Lung metastases were either monitored by bioluminescence imaging (BLI) or visualized by fluorescence microscopy. Stem cell properties were examined by mammosphere assays in vitro and tumorigenic assays in vivo. Clustering assay was performed by culturing cells in Poly-HEMA coated plates (for cell lines) or collagen-coated plates (for primary cells derived from patient-derived breast tumor xenografts, PDXs), and then monitored by IncuCyte live cell dynamic imaging.
Results: CD44+ enriched circulating tumor cell (CTC) clusters were found in the lung/liver vascular structures in vivo in both metastatic breast cancer patients and PDXs that develop spontaneous lung metastases. Comparing to single CD44+ cells, clustered CD44+ cells formed more mammospheres, increased tumorigenic potential, and promoted lung colonization. Combining siRNA-mediated knockdown and CRISPR/Cas-based knockdout, we found that CD44 is required for breast tumor cell cluster formation and lung colonization upon tail vein seeding. During cluster formation, EGFR was activated, which improved both stemness and survival of clustered CTCs. Anti-EGFR antibody mimicked CD44 knockdown to inhibit cluster formation of PDX-derived tumor cells. Administration of EGFR inhibitor Erlotinib efficiently inhibited CD44+ cells-mediated spontaneous metastases to the lungs without affecting primary tumor growth.
Conclusions: Our data provide new insights into the cellular and molecular mechanisms of stem-like clustered CD44+ cells-seeded metastasis, and implicate that targeting CD44+ CTC clusters by inhibition of EGFR activity could be a new therapeutic strategy to treat metastatic breast cancer.
Citation Format: Xia Liu, Wenjing Chen, Rokana Taftaf, Huiping Liu. Stem-like clusters of CD44+ circulating tumor cells seed metastases in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1921. doi:10.1158/1538-7445.AM2017-1921
Abstract 1924: Caveolin-1 inhibits mammary carcinogenesis via suppressing c-myc-induced metabolism reprogramming in breast cancer stem cells
Authors: Wang Zhiyu , Wang Neng , Wang Shengqi , Zheng Yifeng 
Published: July 2017

Abstract
Purpose: Caveolin-1(CAV1), a membrane constituent protein, exhibits tumor suppressor activities in multiple malignancies, whereas the underlying mechanisms remain unclear. The current study aimed to determine the significance of CAV-1 in regulating cancer metabolism and its relation to breast cancer stem cells (CSCs).
Experimental Design: The anti-carcinogenic function of CAV1 was evaluated by in vitro cell model, CAV1 knockout mice and MMTV-PyMT spontaneous breast cancer xenografts. Glycolysis activity and mitochondrial metabolism were assessed by immunoblotting, oxygen consumption and mitotacker staining analysis. Mammosphere formation, tumorigenic ability, reattachment differentiation and signaling pathway analysis were applied to study the regulation effects of CAV1 on breast CSCs. The clinical significance of CAV1 was also analyzed by human tissue microarray.
Results: In both mammary transformed cells and spontaneous breast cancer xenografts, CAV1 is found significantly downregulated and positively correlated to increased glycolysis activity and impaired mitochondrial metabolism. Cav1 knockout results in increased ductal hyperplasia, associating with increased stem cell population and glycolysis metabolism. Breast CSCs exhibits glycolytic phenotype and decreased CAV1 expression compared to normal mammary stem cells, and CAV1 overexpression significantly limits CSCs’ self-renewal via inhibiting c-myc induced glycolysis. Clinical investigation suggests that high CAV1 expression is revealed with better overall survival and decreased CSCs population.
Conclusions: CAV1 loss facilitates mammary carcinogenesis via enhancing glycolytic activity in breast CSCs, and CAV1 based therapy might become a novel strategy for breast cancer prevention.
Note: This abstract was not presented at the meeting.
Citation Format: Zhiyu Wang, Neng Wang, Shengqi Wang, Yifeng Zheng. Caveolin-1 inhibits mammary carcinogenesis via suppressing c-myc-induced metabolism reprogramming in breast cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1924. doi:10.1158/1538-7445.AM2017-1924
Abstract 1927: The significance of calreticulin in pancreatic cancer: a molecule highly expressed in pancreatic cancer stem-like cells
Authors: Matsukuma Satoshi , Yoshimura Kiyoshi , Oga Atsunori , Inoue Moeko , Fujimtoto Takuya , Kuramasu Atsuo , Fuse Masanori , Tsunedomi Ryouichi , Eguchi Hidetoshi , Matsui Hiroto , Kanekiyo Shinsuke , Tokumitsu Yukio , Tomochika Shinobu , Iida Michihisa , Tokuhisa Yoshihiro , Sakamoto Kazuhiko , Suzuki Nobuaki , Furuya-Kondo Tomoko , Itoh Hiroshi , Takeda Shigeru , Yamamoto Shigeru , Yoshino Shigefumi , Hazama Shoichi , Ueno Tomio , Nagano Hiroaki 
Published: July 2017

Abstract
Cancer stem-like cells (CSLCs) in solid tumors are thought to be resistant to conventional chemotherapy or molecular targeting therapy and to contribute to cancer recurrence and metastasis. In this study, we aimed to identify a biomarker of pancreatic CSLCs (P-CSLCs). P-CSLC-enriched population was generated from pancreatic cancer cell lines using our previously reported method and its protein expression profile was compared with that of parental cells by two-dimensional electrophoresis and tandem mass spectrometry. The results indicated that a chaperone protein calreticulin (CRT) was significantly upregulated in P-CSLCs compared to parental cells. Flow cytometry analysis demonstrated that CRT was mostly localized to the surface of P-CSLCs and did not correlate with the levels of CD44v9, another P-CSLC biomarker. Furthermore, the side population in CRThigh/CD44v9low population is much higher than that in CRTlow/CD44v9high population. CRT expression was also assessed by immunohistochemistry in pancreatic cancer tissues (n = 80) obtained after radical resection and was found to be associated with patients’ clinicopathological features and disease outcomes in the Cox’s proportional hazard regression model. Multivariate analysis identified CRT as an independent prognostic factor for pancreatic cancer patients, along with age and post-operative therapy. Our results suggest that CRT can serve as a biomarker of P-CSLCs and a prognostic factor associated with poorer survival of pancreatic cancer patients. This novel biomarker can be useful for detecting P-CSLCs independently, which had been detectable by multiple surface markers like CD24, CD44 and ESA. We will present CSLCs properties of CRThigh population in P-CSLCs.
Citation Format: Satoshi Matsukuma, Kiyoshi Yoshimura, Atsunori Oga, Moeko Inoue, Takuya Fujimtoto, Atsuo Kuramasu, Masanori Fuse, Ryouichi Tsunedomi, Hidetoshi Eguchi, Hiroto Matsui, Shinsuke Kanekiyo, Yukio Tokumitsu, Shinobu Tomochika, Michihisa Iida, Yoshihiro Tokuhisa, Kazuhiko Sakamoto, Nobuaki Suzuki, Tomoko Furuya-Kondo, Hiroshi Itoh, Shigeru Takeda, Shigeru Yamamoto, Shigefumi Yoshino, Shoichi Hazama, Tomio Ueno, Hiroaki Nagano. The significance of calreticulin in pancreatic cancer: a molecule highly expressed in pancreatic cancer stem-like cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1927. doi:10.1158/1538-7445.AM2017-1927