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  • American Association for Cancer Research (AACR)  (10)
  • 1
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    Online Resource
    ALK Amplification and Rearrangements Are Recurrent Targetable Events in Congenital and Adult Glioblastoma
    American Association for Cancer Research (AACR) ; 2023
    In:  Clinical Cancer Research Vol. 29, No. 14 ( 2023-07-14), p. 2651-2667
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 29, No. 14 ( 2023-07-14), p. 2651-2667
    Abstract: Anaplastic lymphoma kinase (ALK) aberrations have been identified in pediatric-type infant gliomas, but their occurrence across age groups, functional effects, and treatment response has not been broadly established. Experimental Design: We performed a comprehensive analysis of ALK expression and genomic aberrations in both newly generated and retrospective data from 371 glioblastomas (156 adult, 205 infant/pediatric, and 10 congenital) with in vitro and in vivo validation of aberrations. Results: ALK aberrations at the protein or genomic level were detected in 12% of gliomas (45/371) in a wide age range (0–80 years). Recurrent as well as novel ALK fusions (LRRFIP1–ALK, DCTN1–ALK, PRKD3–ALK) were present in 50% (5/10) of congenital/infant, 1.4% (3/205) of pediatric, and 1.9% (3/156) of adult GBMs. ALK fusions were present as the only candidate driver in congenital/infant GBMs and were sometimes focally amplified. In contrast, adult ALK fusions co-occurred with other oncogenic drivers. No activating ALK mutations were identified in any age group. Novel and recurrent ALK rearrangements promoted STAT3 and ERK1/2 pathways and transformation in vitro and in vivo. ALK-fused GBM cellular and mouse models were responsive to ALK inhibitors, including in patient cells derived from a congenital GBM. Relevant to the treatment of infant gliomas, we showed that ALK protein appears minimally expressed in the forebrain at perinatal stages, and no gross effects on perinatal brain development were seen in pregnant mice treated with the ALK inhibitor ceritinib. Conclusions: These findings support use of brain-penetrant ALK inhibitors in clinical trials across infant, pediatric, and adult GBMs. See related commentary by Mack and Bertrand, p. 2567
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-21-3521
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 2
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    Abstract 1942: Identification of a microRNA expression signature for radiochemosensitivity of colorectal cancer cells, involving miRNAs-320a, -224, -132 and let7g.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1942-1942
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1942-1942
    Abstract: Background: Preoperative 5-fluorouracil-based chemoradiotherapy is the standard treatment for locally advanced rectal carcinomas. However, the individual tumor response is very heterogeneous, ranging from complete resistance to regression. Therefore, ascertaining the role of microRNAs (miRNAs) in therapy response as well as identification certain miRNA as predictive markers for response remains very crucial. Materials/Methods: Using an in-vitro model of 12 colorectal cancer cell lines, we compare the pretherapeutic miRNA expression profiles of these cell lines with the previously assessed radiochemoresistance of each cell lines, respectively. Differences in treatment sensitivity of the cell lines and miRNAs expression were then correlated. Colony formation assays in two independent cell lines were used for the functional validation in-vitro. To asses the clinical applicability miRNA expressions of 64 pretherapeutic biopsies from patients with locally advanced cancer treated with 5-FU based RCT were analyzed. Results: We identified 36 miRNAs whose expression levels correlated significantly with the heterogeneous sensitivity of the cell lines to chemoradiotherapy (p & lt; 0.05). Microarray measurements were independently validated using semi-quantitative real-time PCR. miR-320, miR-132, miR-429, miR-224 and let-7g were then functionally validated in-vitro by transfection of corresponding miRNA mimics. Analysis of miRNA expression in rectal cancer patients biopsies showed high correlation of miR-224 expression with poor prognosis (p=0.043). Conclusion: We identified 36 miRNAs that associated with response to chemoradiotherapy. Functional validations of miR-320, miR-132, miR-429, miR-224 and let-7g have been undertaken in-vitro underlining the regulatory effects of the specific miRNAs. Further miR-224 found out to be significantly correlated to Disease Free Survival (DFS). An independent prospective validation in a clinical trial will be performed. Citation Format: Junius Salendo, Melanie Spitzner, Frank Kramer, Peter Jo, Tim Beissbarth, Hendrik A. Wolff, Heinz Becker, Mathias Dobbelstein, Michael Ghadimi, Marian Grade, Jochen Gaedcke. Identification of a microRNA expression signature for radiochemosensitivity of colorectal cancer cells, involving miRNAs-320a, -224, -132 and let7g. [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 1942. doi:10.1158/1538-7445.AM2013-1942
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-1942
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 3
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    Abstract 2508: Identification of potential relevant pathways and genes for resistance to chemoradiotherapy in colorectal cancer cells
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2508-2508
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2508-2508
    Abstract: The standard treatment of patients with locally advanced rectal cancers comprises preoperative 5-fluorouracil-based chemoradiotherapy followed by standardized surgery. However, the tumor response to multimodal treatment has varied greatly and ranging from complete resistance to complete pathologic regression. The prediction and treatment of these observed heterogeneous response to therapy in patients is, therefore, an important clinical need. A strategy for studying the molecular basis of this heterogeneous tumor response is to establish the clinical parameters as an in vitro model. For this purpose we used 12 colorectal cancer cell lines and exposed them to 3 µM of 5-fluorouracil and 2 Gy of radiation, which reflect the parameters used in clinical patient treatment. The sensitivity differences of the cell lines to chemoradiotherapy, measured as surviving fractions by a standard colony formation assay, were then correlated with the pretherapeutic gene expression profiles of these cell lines. The microarray measurements were independently validated for a subset of these genes using real-time polymerase chain reactions. In the 12 colorectal cancer cell lines we observed a heterogeneous response, with surviving fractions ranging from 0.28 to 0.81, closely recapitulating clinical reality. Using a linear model analysis, we identified 4,796 features whose expression levels correlated significantly with the sensitivity to chemoradiotherapy (Q & lt; 0.05), including many genes involved in the mitogen-activated protein kinase signaling pathway or cell cycle genes. These data have suggested a potential relevance of the insulin and Wnt signaling pathways for the treatment response, and we identified STAT3, RASSF1, DOK3, and ERBB2 as potential therapeutic targets. We anticipate that this analysis of a gene expression signature for the in vitro chemoradiosensitivity of colorectal cancer cells will unveil molecular biomarkers predictive of the response of rectal cancers to chemoradiotherapy and enable the identification of genes that could serve as targets to sensitize a priori resistant primary tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2508. doi:10.1158/1538-7445.AM2011-2508
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-2508
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 4
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    The Severity of Neural Invasion Is Associated with Shortened Survival in Colon Cancer
    American Association for Cancer Research (AACR) ; 2013
    In:  Clinical Cancer Research Vol. 19, No. 1 ( 2013-01-01), p. 50-61
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 19, No. 1 ( 2013-01-01), p. 50-61
    Abstract: Purpose: Neural invasion (NI) is a histopathologic feature of colon cancer that receives little consideration. Therefore, we conducted a morphologic and functional characterization of NI in colon cancer. Experimental Design: NI was investigated in 673 patients with colon cancer. Localization and severity of NI was determined and related to patient's prognosis and survival. The neuro-affinity of colon cancer cells (HT29, HCT-116, SW620, and DLD-1) was compared with pancreatic cancer (T3M4 and SU86.86) and rectal cancer cells (CMT-93) in the in vitro three-dimensional (3D)–neural-migration assay and analyzed via live-cell imaging. Immunoreactivity of the neuroplasticity marker GAP-43, and the neurotrophic-chemoattractant factors Artemin and nerve growth factor (NGF), was quantified in colon cancer and pancreatic cancer nerves. Dorsal root ganglia of newborn rats were exposed to supernatants of colon cancer, rectal cancer, and pancreatic cancer cells and neurite density was determined. Results: NI was detected in 210 of 673 patients (31.2%). Although increasing NI severity scores were associated with a significantly poorer survival, presence of NI was not an independent prognostic factor in colon cancer. In the 3D migration assay, colon cancer and rectal cancer cells showed much less neurite-targeted migration when compared with pancreatic cancer cells. Supernatants of pancreatic cancer and rectal cancer cells induced a much higher neurite density than those of colon cancer cells. Accordingly, NGF, Artemin, and GAP-43 were much more pronounced in nerves in pancreatic cancer than in colon cancer. Conclusion: NI is not an independent prognostic factor in colon cancer. The lack of a considerable biologic affinity between colon cancer cells and neurons, the low expression profile of colonic nerves for chemoattractant molecules, and the absence of a major neuroplasticity in colon cancer may explain the low prevalence and impact of NI in colon cancer. Clin Cancer Res; 19(1); 50–61. ©2012 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-12-2392
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 5
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    Abstract 1201: ALK amplification and rearrangements are recurrent targetable events in congenital and adult glioblastoma
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 1201-1201
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 1201-1201
    Abstract: Purpose: Anaplastic Lymphoma Kinase (ALK) aberrations have been identified in pediatric type infant gliomas, but their occurrence across age groups, functional effects, and treatment response have not been broadly established. Experimental Design: We performed a comprehensive analysis of ALK expression and genomic aberrations in both newly-generated and retrospective data from 371 glioblastomas (156 adult, 205 infant/pediatric and 10 congenital) with in vitro and in vivo validation of aberrations. Results: ALK aberrations at the protein or genomic level were detected in 12% of gliomas (45/371) in a wide age range (0-80 years). Recurrent as well as novel ALK fusions (LRRFIP1-ALK, DCTN1-ALK, PRKD3-ALK) were present in 50% (5/10) of congenital/infant, 1.4% (3/205) of pediatric, and 1.9% (3/156) of adult GBMs. ALK fusions were present as the only candidate driver in congenital/infant GBMs, and were sometimes focally amplified. In contrast, adult ALK fusions co-occurred with other oncogenic drivers. No activating ALK mutations were identified in any age group. Novel and recurrent ALK rearrangements promoted STAT3 and ERK1/2 pathways and transformation in vitro and in vivo. ALK-fused GBM cellular and mouse models were responsive to ALK inhibitors, including in patient cells derived from a congenital GBM. Relevant to treatment of infant gliomas, we showed that ALK protein appears minimally expressed in the forebrain at perinatal stages and no gross effects on perinatal brain development was seen in pregnant mice treated with the ALK inhibitor ceritinib. Conclusions: These findings support expanded evaluation of brain-penetrant ALK inhibitors in clinical trials across infant, pediatric, and adult GBMs. Citation Format: Anne-Florence Blandin, Ross Giglio, Maya Srikanth Graham, Guadalupe Garcia, Seth Malinowski, Jared K. Woods, Shakti Ramkissoon, Lori Ramkissoon, Frank Dubois, Kate Schoolcraft, Jessica W. Tsai, Dayle K. Wang, Robert Jones, Jayne Vogelzang, Kristine Pelton, Sarah Becker, Fiona Watkinson, Claire Sinai, Elizabeth Cohen, Matthew Booker, Michael Tolstorukov, Veerle Haemels, Liliana Goumnerova, Karen Wright, Mark Kieran, Katie Fehnel, David Reardon, Arnault Tauziede-Espariat, Rishi Lulla, Benjamin Carcamo, Stanley Chaleff, Alain Charest, Frederik De Smet, Azra H. Ligon, Adrian Dubuc, Melanie Pagès, Pascale Varlet, Patrick Wen, Brian Alexander, Susan Chi, Sanda Alexandrescu, Ralf Kittler, Robert Bachoo, Rameen Beroukhim, Pratiti Bandopadhayay, Keith L. Ligon. ALK amplification and rearrangements are recurrent targetable events in congenital and adult glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1201.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-1201
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 6
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    Abstract 487: RNAi-mediated silencing of TCF7L2 sensitizes colorectal cancer cells to radiation therapy
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 487-487
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 487-487
    Abstract: Background: The standard treatment for locally advanced rectal carcinomas consists of preoperative chemoradiotherapy (CT/RT), followed by radical surgery. However, the clinical response to this treatment strategy is very heterogeneous. To determine the molecular basis of disparate response, we recently profiled a series of responsive and resistant rectal cancers using gene expression microarrays and identified a set of differentially expressed genes. One gene that was significantly over-expressed in the resistant tumors was TCF7L2 (also known as TCF4), the main downstream effector of the Wnt signaling pathway. The aim of this study was to understand its role in treatment response by testing the hypothesis that RNAi-mediated silencing of TCF7L2 sensitizes tumor cells to radiation therapy. Methods: The colorectal cancer cell line SW480, which is relatively resistant to radiation, was transfected with two different shRNA-vectors targeting TCF7L2, and a non-silencing control. Subsequently, stable single cell clones were established, and knockdown efficiency was analyzed by Western blot analysis. For each vector, individual clones were irradiated at 2, 4, 6 and 8 Gy. Colonies were counted after 10 days to calculate the respective surviving fractions. Results: TCF7L2 protein levels were reduced to ∼ 34% for shRNA_1, and ∼ 29% for shRNA_2. This led to a ∼ 1.6-fold growth inhibition (plating efficiency) compared to the non-silencing control. Importantly, RNAi-mediated silencing of TCF7L2 significantly reduced colony-formation after radiation (dose reduction factors of ∼ 1.5 and ∼ 2.0 at 37% survival for shRNA_1 and shRNA_2, respectively). These results were validated in a second cell line (HT29). In addition, we analyzed global gene expression profiles after RNAi to analyze the global transcriptomic changes induced by silencing TCF7L2. Conclusion: TCF7L2 is over-expressed in rectal carcinomas resistant to chemoradiotherapy. RNAi-mediated silencing of this gene caused a significant growth inhibition and, importantly, radiosensitization of colorectal cancer cells. Thus, TCF7L2 might represent a potential molecular target to sensitize a priori resistant tumor cells. Additionally, these data provide first evidence that the Wnt signaling pathway might not only be central for the development of colorectal cancers, but also for the resistance to therapy. 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 487.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-487
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 7
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    Abstract 2490: Silencing of TCF7L2 sensitizes Wnt/β-catenin signaling-dependent colorectal cancer cells to radiation
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2490-2490
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2490-2490
    Abstract: Background: The clinical response of locally advanced rectal cancers to preoperative chemoradiotherapy is very heterogeneous. We recently profiled a series of responsive and resistant rectal carcinomas using gene expression microarrays and identified TCF7L2, the main downstream effector of the Wnt/β-catenin pathway, as over-expressed in the resistant tumors. The aim of this study was to explore the relevance of TCF7L2 for resistance to radiation and to study the underlining mechanisms. Methods: We transfected three microsatellite-stable colorectal cancer cell lines (SW837, SW480 and HT-29) with two different shRNA-vectors targeting TCF7L2 and a non-silencing. Next, we established single cell clone (SCC) populations, and after confirming the reduction of TCF7L2 protein levels by Western blotting, we irradiated the SCCs at 0, 1, 2, 4, 6 and 8 Gy and calculated survival fractions. To gain functional insight, we chose SW837 and HT-29 for further experiments. Using γH2AX staining we evaluated DNA double strand repair after irradiation at 2 Gy and analyzed cell cycle changes before and after radiation. Furthermore, we studied Wnt/β-catenin pathway activity using the TOPFLASH/FOPFLASH reporter assay. Results: RNAi-mediated silencing of TCF7L2 led to a pronounced reduction in TCF7L2 protein levels. In radiation experiments we observed a highly significant radiosensitization in SW837 and SW480 SCCs, whereas no effect was observed in HT-29 SCCs. Well-fitting, we observed significantly more γH2AX foci 24h after radiation in SW837 SCCs compared to HT-29 SCCs, pointing to impaired DNA damage repair in the SCCs from SW837. Furthermore, in SW837 SCCs but not in HT-29 SCCs we noticed a change in the cell cycle distribution towards radiosensitive cell cycle phases before radiation and compromised cell cycle control after radiation. Finally, using the TOPFLASH/FOPFLASH reporter assay we found SW837 wild-type cells to show high Wnt/β-catenin pathway activity, while HT-29 wild-type cells only showed very low activity. Conclusion: TCF7L2 was found to be over-expressed in resistant rectal carcinomas, and its RNAi-mediated silencing caused a significant radiosensitization, mediated by DNA damage repair deficiencies and impaired cell cycle control. Interestingly, radiosensitization effetcts were only observed in cell lines showing Wnt/β-catenin pathway activity. Thus, we have uncovered a novel role of Wnt/β-catenin signaling for mediating resistance to multimodal cancer therapy. Moreover, these data suggest that TCF7L2 is a potential molecular target for sensitizing Wnt/β-catenin-dependent tumor cells to radiation. 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 2490. doi:10.1158/1538-7445.AM2011-2490
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-2490
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 8
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    The Biodistribution and Immune Suppressive Effects of Breast Cancer–Derived Exosomes
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 23 ( 2016-12-01), p. 6816-6827
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 23 ( 2016-12-01), p. 6816-6827
    Abstract: Small membranous secretions from tumor cells, termed exosomes, contribute significantly to intercellular communication and subsequent reprogramming of the tumor microenvironment. Here, we use optical imaging to determine that exogenously administered fluorescently labeled exosomes derived from highly metastatic murine breast cancer cells distributed predominantly to the lung of syngeneic mice, a frequent site of breast cancer metastasis. At the sites of accumulation, exosomes were taken up by CD45+ bone marrow–derived cells. Subsequent long-term conditioning of naïve mice with exosomes from highly metastatic breast cancer cells revealed the accumulation of myeloid-derived suppressor cells in the lung and liver. This favorable immune suppressive microenvironment was capable of promoting metastatic colonization in the lung and liver, an effect not observed from exosomes derived from nonmetastatic cells and liposome control vesicles. Furthermore, we determined that breast cancer exosomes directly suppressed T-cell proliferation and inhibited NK cell cytotoxicity, and hence likely suppressed the anticancer immune response in premetastatic organs. Together, our findings provide novel insight into the tissue-specific outcomes of breast cancer–derived exosome accumulation and their contribution to immune suppression and promotion of metastases. Cancer Res; 76(23); 6816–27. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-16-0868
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 9
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    Interferon-α Suppresses cAMP to Disarm Human Regulatory T Cells
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 18 ( 2013-09-15), p. 5647-5656
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 18 ( 2013-09-15), p. 5647-5656
    Abstract: IFN-α is an antineoplastic agent in the treatment of several solid and hematologic malignancies that exerts strong immune- and autoimmune-stimulating activity. However, the mechanisms of immune activation by IFN-α remain incompletely understood, particularly with regard to CD4+CD25highFoxp+ regulatory T cells (Treg). Here, we show that IFN-α deactivates the suppressive function of human Treg by downregulating their intracellular cAMP level. IFN-α–mediated Treg inactivation increased CD4+ effector T-cell activation and natural killer cell tumor cytotoxicity. Mechanistically, repression of cAMP in Treg was caused by IFN-α–induced MAP–ERK kinase (MEK)/extracellular signal-regulated kinase (ERK)–mediated phosphodiesterase 4 (PDE4) activation and accompanied by downregulation of IFN receptor (IFNAR)-2 and negative regulation of T-cell receptor signaling. IFN-α did not affect the anergic state, cytokine production, Foxp3 expression, or methylation state of the Treg-specific demethylated region (TSDR) within the FOXP3 locus associated with a stable imprinted phenotype of human Treg. Abrogated protection by IFN-α–treated Treg in a humanized mouse model of xenogeneic graft-versus-host disease confirmed IFN-α–dependent regulation of Treg activity in vivo. Collectively, the present study unravels Treg inactivation as a novel IFN-α activity that provides a conceivable explanation for the immune-promoting effect and induction of autoimmunity by IFN-α treatment in patients with cancer and suggests IFN-α for concomitant Treg blockade in the context of therapeutic vaccination against tumor antigens. Cancer Res; 73(18); 5647–56. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-12-3788
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 10
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    Abstract 3374: Large-scale single-cell whole transcriptomic analyses reveal distinct malignant phenotypes of CTCs from NSCLC patients
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 3374-3374
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 3374-3374
    Abstract: Circulating tumor cells (CTC) hold great promise for representation of intratumoral heterogeneity and increasing our understanding of resistance mechanisms. However, especially in non-small cell lung cancer (NSCLC), numbers of CTCs detected and isolatable from peripheral blood samples using standard EPCAM-based techniques are too low to perform robust multi-omics analyses. Recent data suggested that diagnostic leukapheresis (DLA) can be used to increase CTC numbers by enriching them from larger blood volumes. Here, we present single-cell RNA sequencing data (scRNAseq) from 3172 NSCLC CTCs isolated by DLA. Between 3.1 and 8.0 liters of blood volume was processed with DLA and mononuclated cells were collected from six stage IV NSCLC patients. A total of 80x108 cells (≈33% of the DLA) were used for magnetic depletion of CD31+, CD3+, CD16+, CD235a+ and CD45+ cells followed by FACS sorting for CD45 negativity. Sorted cells were subjected to scRNAseq analysis using 10X Genomics. CTC transcriptomes were identified by marker gene expression (Satija Lab, US and R package SingleR). Gene set enrichment analysis (GSEA) on hallmark gene sets were performed to compare CTC transcriptomes and sc transcriptomes from primary NSCLC tumors. Unsupervised dimensional reduction and clustering revealed 7 distinct CTC cluster. Inferred copy number variation (CNV) analyses confirmed greater CNV variability compared to hematopoietic cells and a high degree of heterogeneity consistent with tumor cells. Also, CTC transcriptomes showed significantly higher expression of cancer-associated genes like Cyclin D1 and metastasis-associated protein 2 compared to normal hematopoietic cells. CTC clustering was independent of patient or histology, thus indicating a potential function-based clustering. Pseudotime analyses of all scCTC transcriptomes revealed three principal CTC phenotypes: (i) epithelial-like (expression of E-Cadherin), highly proliferative (expression of KI67 and E2F targets pathway) and immune responsive (enriched for IL1B, Interferon-α/γ-response pathways), (ii) mesenchymal/invasive (expression of Vimentin, mTORC1, hypoxia and glycolysis pathways) and (iii) mesenchymal/cancer stem cell-like (enrichment of genes including ALDH1A3 and oxidative phosphorylation and adipogenesis pathways). Compared to a set of scRNAseq data from primary NSCLC tumors (n=46), GSEA revealed an enrichment of pathways involved in cell cycle, anti-apoptosis and invasion in CTCs suggesting higher malignant potential compared to tissue-resident NSCLC tumor cells. Performing CTC enrichment using DLAs resulted in generation of an unprecedented number of transcriptomes from individual CTCs derived from NSCLC patients. Our data should lead to a better understanding of the heterogeneity of blood circulating CTCs and their associated biology and may allow rational design of CTC-targeting drugs. Citation Format: Lisa-Marie Rieckmann, Michael Spohn, Ekaterina Selbuz, Claudia Schubert, David Agorku, Lisa Becker, Alina Borchers, Jenny Krause, Lisa Ruff, Sarina Heinemann, Franca Kobus, Jurek Hille, Andia Louisa Tehrany, Janna-Lisa Velthaus-Rusik, Sören Franzenburg, Petros Christopoulos, Hauke Winter, Michael Thomas, Sabine Riethdorf, Nicola Gagliani, Carsten Bokemeyer, Christian F. Krebs, Martin Sprick, Andreas Trumpp, Sven Peine, Olaf Hardt, Nikolas H. Stoecklein, Klaus Pantel, Philipp Rosenstiel, Sonja Loges, Melanie Janning. Large-scale single-cell whole transcriptomic analyses reveal distinct malignant phenotypes of CTCs from NSCLC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3374.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-3374
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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