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  • Tan, Aik-Choon  (10)
  • English  (10)
  • Medicine  (10)
  • XA 36000  (10)
  • 1
    Online Resource
    Online Resource
    Inhibiting Translation Elongation with SVC112 Suppresses Cancer Stem Cells and Inhibits Growth in Head and Neck Squamous Carcinoma
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 5 ( 2020-03-01), p. 1183-1198
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 5 ( 2020-03-01), p. 1183-1198
    Abstract: Cancer stem cells (CSC) drive growth, therapy resistance, and recurrence in head and neck squamous cell carcinoma (HNSCC). Regulation of protein translation is crucial for normal stem cells and CSCs; its inhibition could disrupt stemness properties, but translation inhibitors are limited clinically due to toxicity. SVC112 is a synthetic derivative of bouvardin, a plant-derived translation elongation inhibitor. SVC112 had greater antiproliferative effects on HNSCC cells compared with the FDA-approved translation inhibitor omacetaxine mepesuccinate (HHT). SVC112 preferentially inhibited cancer cells compared with patient-matched cancer-associated fibroblasts, whereas HHT was equally toxic to both. SVC112 reduced sphere formation by cell lines and CSCs. SVC112 alone inhibited the growth of patient-derived xenografts (PDX), and SVC112 combined with radiation resulted in tumor regression in HPV-positive and HPV-negative HNSCC PDXs. Notably, CSC depletion after SVC112 correlated with tumor response. SVC112 preferentially impeded ribosomal processing of mRNAs critical for stress response and decreased CSC-related proteins including Myc and Sox2. SVC112 increased cell-cycle progression delay and slowed DNA repair following radiation, enhancing colony and sphere formation radiation effects. In summary, these data demonstrate that SVC112 suppresses CSC-related proteins, enhances the effects of radiation, and blocks growth of HNSCC PDXs by inhibiting CSCs. Significance: Inhibiting protein elongation with SVC112 reduces tumor growth in head and neck squamous cell carcinoma and increases the effects of radiation by targeting the cancer stem cell pool.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-19-3232
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 2
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    Homeoprotein Six2 Promotes Breast Cancer Metastasis via Transcriptional and Epigenetic Control of E-Cadherin Expression
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 24 ( 2014-12-15), p. 7357-7370
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 24 ( 2014-12-15), p. 7357-7370
    Abstract: Misexpression of developmental transcription factors occurs often in human cancers, where embryonic programs may be reinstated in a context that promotes or sustains malignant development. In this study, we report the involvement of the kidney development transcription factor Six2 in the metastatic progression of human breast cancer. We found that Six2 promoted breast cancer metastasis by a novel mechanism involving both transcriptional and epigenetic regulation of E-cadherin. Downregulation of E-cadherin by Six2 was necessary for its ability to increase soft agar growth and in vivo metastasis in an immunocompetent mouse model of breast cancer. Mechanistic investigations showed that Six2 represses E-cadherin expression by upregulating Zeb2, in part, through a microRNA-mediated mechanism and by stimulating promoter methylation of the E-cadherin gene (Cdh1). Clinically, SIX2 expression correlated inversely with CDH1 expression in human breast cancer specimens, corroborating the disease relevance of their interaction. Our findings establish Six2 as a regulator of metastasis in human breast cancers and demonstrate an epigenetic function for SIX family transcription factors in metastatic progression through the regulation of E-cadherin. Cancer Res; 74(24); 7357–70. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-14-0666
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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    detail.hit.zdb_id: 1432-1
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  • 3
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    Abstract 2705: Novel functions of the homeoprotein SIX2 in mediating anchorage independence and metastasis in breast cancer.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2705-2705
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2705-2705
    Abstract: Homeobox genes encode for transcription factors that are master regulators of embryogenesis, and their misexpression has been implicated in multiple cancers. The role of the homeoprotein Six2 in developing kidney has been well demonstrated; however, its role in cancer progression is largely unknown. Here, we demonstrate, for the first time, that Six2 is causally involved in mammary tumor progression. When Six2 is knocked down (KD) in the 66cl4 mammary carcinoma cells, lung metastasis is significantly decreased compared to control KD; however, Six2 KD conferred no significant effect on growth of the primary tumor or on tumor-associated angiogenesis/lymphangiogenesis, in contrast to its closely related family member, Six1, which has been implicated in all the aforementioned properties; suggesting that Six2 may participate in later stages of the metastatic cascade. Expression of Six2 in the 4TO7 mammary carcinoma cell line (a cell line that is syngeneic with 66cl4, but expresses very low levels of endogenous Six2) led to changes in cell morphology, increased growth in soft agar, increased resistance to anoikis, and significantly enhanced lung metastasis in Balb/c mice. To determine the mechanism by which Six2 mediates metastasis, microarray analysis was performed on 4TO7-control and Six2 expressing cells. Interestingly, genes which have been implicated in lung metastasis (MMP, ANGPTL4, VCAM1) are significantly up-regulated in Six2 overexpressing 4TO7 cells; while the epithelial marker, E-Cadherin, is dramatically decreased. Finally, analysis of SIX2 expression from public microarray datasets indicates that SIX2 is increased in breast cancers compared to normal breast tissue. In addition, high expression of SIX2 correlates with poor prognosis (distant metastasis free survival, overall survival and relapse free survival) in 1881 human breast tumors examined using the GOBO (Gene Expression-Based Outcome for Breast Cancer Online) database, and upon further investigation we found that SIX2 expression is particularly associated with poor prognosis in luminal A, normal-like and ER-positive breast tumors. Together, our studies define a novel role of Six2 in breast cancer metastasis. Citation Format: Chu-An Wang, Paul Jedlicka, Vadym Zaberezhnyy, Aik-Choon Tan, Heide Ford. Novel functions of the homeoprotein SIX2 in mediating anchorage independence and metastasis in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2705. doi:10.1158/1538-7445.AM2013-2705
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-2705
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 4
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    TWIST1-Induced miR-424 Reversibly Drives Mesenchymal Programming while Inhibiting Tumor Initiation
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 9 ( 2015-05-01), p. 1908-1921
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 9 ( 2015-05-01), p. 1908-1921
    Abstract: Epithelial-to-mesenchymal transition (EMT) is a dynamic process that relies on cellular plasticity. Recently, the process of an oncogenic EMT, followed by a reverse mesenchymal-to-epithelial transition (MET), has been implicated as critical in the metastatic colonization of carcinomas. Unlike governance of epithelial programming, regulation of mesenchymal programming is not well understood in EMT. Here, we describe and characterize the first microRNA that enhances exclusively mesenchymal programming. We demonstrate that miR-424 is upregulated early during a TWIST1 or SNAI1-induced EMT, and that it causes cells to express mesenchymal genes without affecting epithelial genes, resulting in a mixed/intermediate EMT. Furthermore, miR-424 increases motility, decreases adhesion, and induces a growth arrest, changes associated with a complete EMT that can be reversed when miR-424 expression is lowered, concomitant with an MET-like process. Breast cancer patient miR-424 levels positively associate with TWIST1/2 and EMT-like gene signatures, and miR-424 is increased in primary tumors versus matched normal breast. However, miR-424 is downregulated in patient metastases versus matched primary tumors. Correspondingly, miR-424 decreases tumor initiation and is posttranscriptionally downregulated in macrometastases in mice, suggesting the need for biphasic expression of miR-424 to transit the EMT–MET axis. Next-generation RNA sequencing revealed miR-424 regulates numerous EMT and cancer stemness-associated genes, including TGFBR3, whose downregulation promotes mesenchymal phenotypes, but not tumor-initiating phenotypes. Instead, we demonstrate that increased MAPK–ERK signaling is critical for miR-424–mediated decreases in tumor-initiating phenotypes. These findings suggest miR-424 plays distinct roles in tumor progression, potentially facilitating earlier, but repressing later, stages of metastasis by regulating an EMT–MET axis. Cancer Res; 75(9); 1908–21. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-14-2394
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 5
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    Abstract 4550: Correlations between tumor mutation burden, inflammatory profile and histological characteristics of tumor microenvironment in early-stage squamous cell lung carcinoma
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 4550-4550
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 4550-4550
    Abstract: Background: Anti-PD1/PD-L1 immunotherapy has demonstrated success in the treatment of advanced non-small cell lung cancer (NSCLC). Clinical data have shown that both the expression of PD-L1 in patient tumors and high tumor mutation burden (TMB) predicts the likelihood of a positive response to anti-PD-1/PD-L1 immunotherapy. Also, tumor microenvironment (TME) is the constitutive element in cancer immunity, in which analysis of characteristics reflects the potential existing immune reaction. Method: Histologic sections from 150 squamous cell lung carcinoma (SqCLC) were evaluated by two pathologists independently for percentage and character of intratumoral inflammatory cells and percentage and character of para-tumoral infiltrate. The ratios of infiltrating inflammatory cells to tumor cells were estimated in 10% increments by microscopic inspection. The proportions of immune cell populations were deconvulated using the CIBERSORT method based on Affymetrix gene expression profiles. PD-L1 protein expression by IHC was evaluated using the Dako PD-L1 22C3 pharmDx kit and scoring was determined according to the Dako tumor proportion score (TPS). Tumor Mutation Burden (TMB) was calculated based on data from targeted genome sequencing. CD4 and CD8 mRNA levels were determined from Affymetrix gene expression data from frozen specimens. Results: The infiltrates could be divided into intratumoral and paratumoral patterns according to their location in relation to microscopic tumor cell nests. Using the CIBERSORT assay, we confirmed our histological findings by microscopic examination that the SqCLC cohort can be subtyped into plasma cell dominant (74.8%) or other immune infiltrates dominant (such as macrophages), based on the proportions of immune cell populations. We found by regression analysis that TMB had a negative correlation with the percentage of intratumoral inflammatory cells (P=0.014), but did not significantly correlate with paratumoral infiltrates. The TMB demonstrated a significant negative correlation with CD4 mRNA level (P=0.017), but not with CD8 mRNA level. No correlation was determined for TMB and the immune cells dominant subgroup. Interestingly, we didn’t find any association for PD-L1 protein expression with the percentage of intra- or para-tumoral infiltrates, plasma cells dominant group and CD4 and CD8 mRNA levels. Conclusions: TMB was negatively correlated with the percentage of intratumoral inflammatory cells and CD4 mRNA level, which indicate that high TMB may promote an immune suppression environment. In addition, we did not find any association of PD-L1 expression with characteristics of TME in this early-stage SqCLC cohort. Further studies are needed to verify these interesting results. Citation Format: Hui Yu, Daniel T. Merrick, Ming-Sound Tsao, William G. Richards, Lucian R. Chirieac, Mark A. Watson, Christopher J. Rivard, David H. Harpole, Raphael Bueno, Adrie van Bokhoven, Aik-Choon Tan, Fred R. Hirsch, Wilbur A. Franklin. Correlations between tumor mutation burden, inflammatory profile and histological characteristics of tumor microenvironment in early-stage squamous cell lung carcinoma [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 4550.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-4550
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 6
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    Abstract 5594: ALK-driven lung cancer: Potential therapeutic strategies for treatment and prevention of drug resistance
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 5594-5594
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 5594-5594
    Abstract: The identification of oncogenic molecular drivers in non-small cell lung cancer (NSCLC) has allowed biologically targeted therapies to improve clinical outcomes in the treatment of NSCLC. ALK gene rearrangements are observed in a sub-set of NSCLC patients who demonstrate high response rates to treatment with the oral kinase inhibitor, crizotinib. Unfortunately, disease progression is inevitable, either through intrinsic or acquired resistance. A recently completed series of crizotinib-resistant, ALK+ NSCLC patients by our group demonstrates two broad categories of resistance: (1) continued reliance on ALK signaling (via secondary mutations in the ALK kinase domain or ALK gene fusion copy number gain) or (2) loss of reliance on ALK signaling (e.g. via reliance on alternate oncogene signaling). Here we investigate potential therapeutic strategies when ALK signaling is retained. In an effort to minimize drug resistance to crizotinib in ALK+ NSCLC, we performed a genome-wide shRNA synthetic lethal screen to identify genes whose depletion synergizes with crizotinib in ALK+ NSCLC lines. We identified several genes involved in nucleotide synthesis and DNA metabolism, including dihydrofolate reductase (DHFR) and the trifunctional enzyme encoded by GART, which are substrates for inhibition with pemetrexed. Indeed, ALK+ NSCLC cell lines show increased sensitivity to pemetrexed in vitro. Identification of this cellular process as critical for ALK+ NSCLC is also consistent with clinical data demonstrating that patients with ALK+ NSCLC exhibit an increased clinical benefit on pemetrexed compared to other molecular subgroups of NSCLC. We also identified genes involved in chaperone function in our synthetic lethal screen. As such, we investigated whether proper folding and prevention of degradation was essential for continued reliance on ALK signaling. Both non-mutated EML4-ALK wild-type and EML4-ALK containing kinase domain mutations (including a novel mutation, G1269A) are sensitive to HSP inhibition with 17AAG. By identifying critical cellular processes in ALK+ lung cancer and employing therapies that target these pathways, improved treatment strategies can be derived to treat and prevent resistance in this molecular subtype of NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5594. doi:1538-7445.AM2012-5594
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-5594
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
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    Abstract 3037: Mer receptor tyrosine kinase is a novel therapeutic target in melanoma.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3037-3037
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3037-3037
    Abstract: Metastatic melanoma is one of the most aggressive forms of cutaneous cancers. While recent therapeutic advances have prolonged patient survival, prognosis remains dismal. Mer is a receptor tyrosine kinase with oncogenic properties that is often overexpressed or activated in various malignancies. Using both protein immunohistochemistry and microarray analyses, we demonstrate that Mer expression correlates with disease progression. Mer expression was highest in metastatic melanomas followed by primary melanomas whereas the lowest expression was observed in nevi. In addition, over 50% of melanoma cell lines overexpressed Mer compared to normal human melanocytes, however overexpression did not correlate with mutations in BRAF or RAS. Stimulation of melanoma cells with the Mer ligand Gas6 resulted in activation of several downstream signaling pathways including MAPK/ERK, PI3K/Akt, and Jak/STAT. Mer inhibition via shRNA reduced Mer-mediated downstream signaling, reduced colony formation by up to 59% (p & lt;0.05) and diminished tumor volume by 60% (p & lt;0.05) in a human melanoma xenograft murine model. Treatment of melanoma cells with UNC1062, a novel Mer-selective small molecule tyrosine kinase inhibitor, reduced activation of Mer-mediated downstream signaling, induced apoptosis in culture, reduced colony formation in soft agar and inhibited invasion of melanoma cells. In addition, Mer inhibition synergized with mutant BRAF inhibition in signaling and apoptosis assays. This work establishes Mer as a therapeutic target in melanoma and provides rationale for the continued development of Mer-targeted therapies. Citation Format: Jennifer Schlegel, Maria Sambade, Susan Sather, Stergios Moschos, Aik-Choon Tan, Amanda Winges, Deborah DeRyckere, Craig C. Carson, Dimitri G. Trembath, John J. Tentler, Gail Eckhardt, Pei-Fen Kuan, Ronald L. Hamilton, Lyn M. Duncan, C. Ryan Miller, Nana Nikolaishvili-Feinberg, Bentley R. Midkiff, Xiaodong Wang, Jing Liu, Weihe Zhang, Chao Yang, Stephen V. Frye, H. Shelton Earp, Janiel Shields, Douglas K. Graham. Mer receptor tyrosine kinase is a novel therapeutic target in melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3037. doi:10.1158/1538-7445.AM2013-3037
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-3037
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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  • 8
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    Abstract 812: Lack of intra-tumoral heterogeneity in lung adenocarcinoma supports gene fusions involving ALK as early clonal events
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 812-812
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 812-812
    Abstract: Adenocarcinomas account for half of the non-small cell lung carcinomas (NSCLC) in the US. Lately, molecularly distinct subtypes of lung adenocarcinomas have been described with EGFR, KRAS and ALK genes as major drivers. Gene fusions activating ALK tyrosine kinase function have been described in approx 3% of unselected NSCLC; but in over 20% of adenocarcinomas without mutations in RAS and EGFR from never /light smokers. The most frequent ALK partner in lung cancer is EML4; other reported partners are KIF5B and TFG. There are recent compelling reports that ALK inhibitors are especially efficacious in advanced NSCLC carrying ALK rearrangements. However, questions have been raised regarding the role of ALK fusions in lung cancer development because (a) EML4-ALK fusions were reported in non-tumor cells of NSCLC specimens by PCR-based assays and (b) not all tumor cells harbored the rearrangement in FISH-based assays, which was taken to indicate that ALK fusions were either late-stage aberrations and/or not primary cancer drivers. To test these hypotheses, we investigated the patterns of fluorescence signals generated by the ALK Break Apart FISH probe (Abbott Molecular) in tumor and non-tumor cells of multiple lung areas from 50 patients diagnosed with adenocarcinoma (25 positive and 25 negative for ALK rearrangements). The FISH probe includes sequences contiguous to the 5’ end of ALK (promoter) and the 3’ end of ALK (tyrosine kinase domain). A fused 3’/5’ signal is observed when ALK gene is in native status and split or single signals are observed when a rearrangement involving ALK occurs. However, split or single signals may be due to technical artifacts such as nuclear truncation. Cells carrying split signals or single 3’ ALK were considered positive for rearrangement and when representing & gt;20% of scored cells the tumor was classified as ALK positive. Among the 25 ALK negative patients, there was no difference in the frequencies of cells positive for rearrangement between tumor and non-tumor areas, all ranging between 0 to 20%. Similar results were found among the non-tumor areas of the 25 ALK positive patients. Conversely, these patients showed & gt;30% of cells positive for rearrangement in & gt;90% of tumor areas. Five tumor areas were required to correctly detect positive and negative specimens. The positive cells were always diffusely distributed along the tumor areas and lower frequencies in some areas were likely due to nuclear truncation and scoring criteria (gap of ≥2 signal diameters between the 3’ and 5’ signals required to be called split). When the minimum gap was decreased to 1 signal diameter, & gt;10% cells were additionally called positive. In conclusion, our findings (a) support the hypothesis that ALK rearrangement is not a focal phenomenon in advanced adenocarcinoma but rather an early tumorigenesis event, and (b) highlight the importance of immediate standardization of technical procedures. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 812.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-812
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 9
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    Obesity and Overfeeding Affecting Both Tumor and Systemic Metabolism Activates the Progesterone Receptor to Contribute to Postmenopausal Breast Cancer
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 24 ( 2012-12-15), p. 6490-6501
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 24 ( 2012-12-15), p. 6490-6501
    Abstract: Obese postmenopausal women have increased risk of breast cancers with poorer clinical outcomes than their lean counterparts. However, the mechanisms underlying these associations are poorly understood. Rodent model studies have recently identified a period of vulnerability for mammary cancer promotion, which emerges during weight gain after the loss of ovarian function (surgical ovariectomy; OVX). Thus, a period of transient weight gain may provide a life cycle–specific opportunity to prevent or treat postmenopausal breast cancer. We hypothesized that a combination of impaired metabolic regulation in obese animals prior to OVX plus an OVX-induced positive energy imbalance might cooperate to drive tumor growth and progression. To determine if lean and obese rodents differ in their metabolic response to OVX-induced weight gain, and whether this difference affects later mammary tumor metabolism, we performed a nutrient tracer study during the menopausal window of vulnerability. Lean animals preferentially deposited excess nutrients to mammary and peripheral tissues rather than to the adjacent tumors. Conversely, obese animals deposited excess nutrients into the tumors themselves. Notably, tumors from obese animals also displayed increased expression of the progesterone receptor (PR). Elevated PR expression positively correlated with tumor expression of glycolytic and lipogenic enzymes, glucose uptake, and proliferation markers. Treatment with the antidiabetic drug metformin during ovariectomy-induced weight gain caused tumor regression and downregulation of PR expression in tumors. Clinically, expression array analysis of breast tumors from postmenopausal women revealed that PR expression correlated with a similar pattern of metabolic upregulation, supporting the notion that PR+ tumors have enhanced metabolic capacity after menopause. Our findings have potential explanative power in understanding why obese, postmenopausal women display an increased risk of breast cancer. Cancer Res; 72(24); 6490–501. ©2012 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-12-1653
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 10
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    CDK1 Interacts with Sox2 and Promotes Tumor Initiation in Human Melanoma
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 23 ( 2018-12-01), p. 6561-6574
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 23 ( 2018-12-01), p. 6561-6574
    Abstract: Cancers are composed of heterogeneous subpopulations with various tumor-initiating capacities, yet key stem cell genes associated with enhanced tumor-initiating capacities and their regulatory mechanisms remain elusive. Here, we analyzed patient-derived xenografts from melanoma, colon, and pancreatic cancer tissues and identified enrichment of tumor-initiating cells in MHC class I-hi cells, where CDK1, a master regulator of the cell cycle, was upregulated. Overexpression of CDK1, but not its kinase-dead variant, in melanoma cells increased their spheroid forming ability, tumorigenic potential, and tumor-initiating capacity; inhibition of CDK1 with pharmacologic agents reduced these characteristics, which was unexplained by the role of CDK1 in regulating the cell cycle. Proteomic analysis revealed an interaction between CDK1 and the pluripotent stem cell transcription factor Sox2. Blockade or knockdown of CDK1 resulted in reduced phosphorylation, nuclear localization, and transcriptional activity of Sox2. Knockout of Sox2 in CDK1-overexpressing cells reduced CDK1-driven tumor-initiating capacity substantially. Furthermore, GSEA analysis of CDK1hi tumor cells identified a pathway signature common in all three cancer types, including E2F, G2M, MYC, and spermatogenesis, confirming a stem-like nature of CDK1hi tumor cells. These findings reveal a previously unrecognized role for CDK1 in regulating tumor-initiating capacity in melanoma and suggest a novel treatment strategy in cancer via interruption of CDK1 function and its protein-protein interactions. Significance: These findings uncover CDK1 as a new regulator of Sox2 during tumor initiation and implicate the CDK1–Sox2 interaction as a potential therapeutic target in cancer.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-18-0330
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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