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Claudio Basilico - One of the best experts on this subject based on the ideXlab platform.

  • Sox2 is required for tumor development and cancer cell proliferation in osteosarcoma
    Oncogene, 2018
    Co-Authors: Giulia Maurizi, Alka Mansukhani, Narendra Verma, Abhilash Gadi, Claudio Basilico
    Abstract:

    The stem cell Transcription Factor Sox2 is highly expressed in many cancers where it is thought to mark cancer stem cells (CSCs). In osteosarcomas, the most common bone malignancy, high Sox2 expression marks and maintains a fraction of tumor-initiating cells that show all the properties of CSC. Knockdown of Sox2 expression abolishes tumorigenicity and suppresses the CSC phenotype. Here we show that, in a mouse model of osteosarcoma, osteoblast-specific Sox2 conditional knockout (CKO) causes a drastic reduction in the frequency and onset of tumors. The rare tumors detected in the Sox2 CKO animals were all Sox2 positive, indicating that they arose from cells that had escaped Sox2 deletion. Furthermore, Sox2 inactivation in cultured osteosarcoma cells by CRISPR/CAS technology leads to a loss of viability and proliferation of the entire cell population. Inactivation of the YAP gene, a major Hippo pathway effector which is a direct Sox2 target, causes similar results and YAP overexpression rescues cells from the lethality caused by Sox2 inactivation. These effects were osteosarcoma-specific, suggesting a mechanism of cell "addiction" to Sox2-initiated pathways. The requirement of Sox2 for osteosarcoma formation as well as for the survival of the tumor cells suggests that disruption of Sox2-initiated pathways could be an effective strategy for the treatment of osteosarcoma.

  • Sox2 antagonizes the hippo pathway to maintain stemness in cancer cells
    Nature Communications, 2015
    Co-Authors: Upal Basuroy, Alka Mansukhani, Sumru N Bayin, Kirk Rattanakorn, Eugenia Han, Dimitris G Placantonakis, Claudio Basilico
    Abstract:

    The repressive Hippo pathway has a profound tumour suppressive role in cancer by restraining the growth-promoting function of the Transcriptional coactivator, YAP. We previously showed that the stem cell Transcription Factor Sox2 maintains cancer stem cells (CSCs) in osteosarcomas. We now report that in these tumours, Sox2 antagonizes the Hippo pathway by direct repression of two Hippo activators, Nf2 (Merlin) and WWC1 (Kibra), leading to exaggerated YAP function. Repression of Nf2, WWC1 and high YAP expression marks the CSC fraction of the tumor population, while the more differentiated fraction has high Nf2, high WWC1 and reduced YAP expression. YAP depletion sharply reduces CSCs and tumorigenicity of osteosarcomas. Thus, Sox2 interferes with the tumour-suppressive Hippo pathway to maintain CSCs in osteosarcomas. This Sox2-Hippo axis is conserved in other Sox2-dependent cancers such as glioblastomas. Disruption of YAP Transcriptional activity could be a therapeutic strategy for Sox2-dependent tumours.

  • Sox2 maintains self renewal of tumor initiating cells in osteosarcomas
    Oncogene, 2012
    Co-Authors: Upal Basuroy, Alka Mansukhani, Eunjeong Seo, Lalitha Ramanathapuram, Timothy B Rapp, Jennifer A Perry, Stuart H Orkin, Claudio Basilico
    Abstract:

    Tumors are thought to be sustained by a reservoir of self-renewing cells, termed tumor initiating cells or cancer stem cells. Osteosarcomas are high-grade sarcomas derived from osteoblast progenitor cells and are the most common pediatric bone malignancy. In this report we show that the stem cell Transcription Factor Sox2 is highly expressed in human and murine osteosarcoma cell lines as well as in tumor samples. Osteosarcoma cells have increased ability to grow in suspension as osteospheres, that are greatly enriched in expression of Sox2 and the stem cell marker, Sca-1. Depletion of Sox2 by shRNAs in independent murine osteosarcoma-derived cells drastically reduces their transformed properties in vitro and their ability to form tumors. Sox2-depleted osteosarcoma cells can no longer form osteospheres, and differentiate into mature osteoblasts. Concomitantly, they exhibit decreased Sca-1 expression and upregulation of the Wnt signaling pathway. Thus, despite other mutations, these tumor cells maintain a proliferative requirement for Sox2. Our data indicate that Sox2 is required for osteosarcoma cell self-renewal, and that Sox2 antagonizes the pro-differentiation Wnt pathway, that can in turn reduce Sox2 expression. These studies define Sox2 as a survival Factor and a novel biomarker of self-renewal in osteosarcomas, and support a tumor suppressive role for the Wnt pathway in tumors of mesenchymal origin. Our findings could provide the basis for novel therapeutic strategies based on inhibiting Sox2 or enhancing Wnt signaling for the treatment of osteosarcomas.

  • The Transcription Factor Sox2 is required for osteoblast self-renewal.
    Cell death and differentiation, 2010
    Co-Authors: Upal Basu-roy, Davide Ambrosetti, Rebecca Favaro, Silvia K. Nicolis, Alka Mansukhani, Claudio Basilico
    Abstract:

    The development and maintenance of most tissues and organs require the presence of multipotent and unipotent stem cells that have the ability of self-renewal as well as of generating committed, further differentiated cell types. The Transcription Factor Sox2 is essential for embryonic development and maintains pluripotency and self-renewal in embryonic stem cells. It is expressed in immature osteoblasts/osteoprogenitors in vitro and in vivo and is induced by fibroblast growth Factor signaling, which stimulates osteoblast proliferation and inhibits differentiation. Sox2 overexpression can by itself inhibit osteoblast differentiation. To elucidate its function in the osteoblastic lineage, we generated mice with an osteoblast-specific, Cre-mediated knockout of Sox2. These mice are small and osteopenic, and mosaic for Sox2 inactivation. However, culturing calvarial osteoblasts from the mutant mice for 2–3 passages failed to yield any Sox2-null cells. Inactivation of the Sox2 gene by Cre-mediated excision in cultured osteoblasts showed that Sox2-null cells could not survive repeated passage in culture, could not form colonies, and arrested their growth with a senescent phenotype. In addition, expression of Sox2-specific shRNAs in independent osteoblastic cell lines suppressed their proliferative ability. Osteoblasts capable of forming ‘osteospheres’ are greatly enriched in Sox2 expression. These data identify a novel function for Sox2 in the maintenance of self-renewal in the osteoblastic lineage.

Yasuhiro Tsutani - One of the best experts on this subject based on the ideXlab platform.

Masae Tatematsu - One of the best experts on this subject based on the ideXlab platform.

  • down regulation of a gastric Transcription Factor Sox2 and ectopic expression of intestinal homeobox genes cdx1 and cdx2 inverse correlation during progression from gastric intestinal mixed to complete intestinal metaplasia
    Journal of Cancer Research and Clinical Oncology, 2004
    Co-Authors: Tetsuya Tsukamoto, Ken Ichi Inada, Harunari Tanaka, Tsutomu Mizoshita, Mami Mihara, Toshikazu Ushijima, Yoshitaka Yamamura, Shigeo Nakamura, Masae Tatematsu
    Abstract:

    Purpose The molecular mechanisms underlying the development of intestinal metaplasia (IM) of the human stomach have yet to be clarified in detail. Besides ectopic expression of intestinal Transcription Factors, Cdx1 and Cdx2, little information is available regarding other regulatory Factors. Hence, we here analyzed Sox2, a human homolog of a chicken gastric Transcription Factor, with reference to our new classification for gastric/intestinal (GI)-mixed type IM.

  • down regulation of a gastric Transcription Factor Sox2 and ectopic expression of intestinal homeobox genes cdx1 and cdx2 inverse correlation during progression from gastric intestinal mixed to complete intestinal metaplasia
    Journal of Cancer Research and Clinical Oncology, 2004
    Co-Authors: Tetsuya Tsukamoto, Ken Ichi Inada, Harunari Tanaka, Tsutomu Mizoshita, Mami Mihara, Toshikazu Ushijima, Yoshitaka Yamamura, Shigeo Nakamura, Masae Tatematsu
    Abstract:

    The molecular mechanisms underlying the development of intestinal metaplasia (IM) of the human stomach have yet to be clarified in detail. Besides ectopic expression of intestinal Transcription Factors, Cdx1 and Cdx2, little information is available regarding other regulatory Factors. Hence, we here analyzed Sox2, a human homolog of a chicken gastric Transcription Factor, with reference to our new classification for gastric/intestinal (GI)-mixed type IM. Twenty specimens of surgically resected antral mucosa were subjected to a gland isolation technique. Isolated glands were classified into gastric (G), GI-mixed, and solely intestinal (I) types according to Alcian blue and paradoxical concanavalin A staining and were quantified for mRNA levels of gastrointestinal markers. MUC5AC and MUC6 transcripts decreased with the progression of IM, while MUC2 and villin-1 were inversely correlated. Sox2 showed a gradual decrease from G, through GI, to the I type (G vs GI and GI vs I, P<0.01 and P<0.005, respectively). On the other hand, Cdx1 (G vs GI and GI vs I, P<0.0001 and P=0.337, respectively) and Cdx2 (G vs GI and GI vs I, P<0.0001 and P<0.05, respectively) appeared in IM. Immunohistochemical study confirmed decreased expression of Sox2 and ectopic emergence of Cdx2 protein in IM glands. Down-regulation of Sox2, besides ectopic expression of Cdx genes, may be important Factors for the development of IM.

Giancarlo Ciccioli - One of the best experts on this subject based on the ideXlab platform.

  • op0012 expression of the pluripotency Transcription Factor Sox2 in primary breast cancers correlation with clinicopathological features and recurrence
    European Journal of Cancer, 2015
    Co-Authors: Barbara Pistilli, Giovanni Benedetti, Mauro Finicelli, Tiziana Squillaro, Andrea Marcellusi, Tommasina Biscotti, Alfredo Santinelli, Paola Mariani, Paolo Decembrini, Giancarlo Ciccioli
    Abstract:

    Background Sox2 is one of the pluripotency Transcription Factors expressed by stem cells, playing a central role in maintenance of stemness and overexpressed in a variety of solid tumours. In breast cancer, Sox2 expression has mainly been reported in the basal-like subtype. We evaluated a heterogenous group of breast cancer tissues to determine whether the expression of Sox2 and other pluripotency Transcription Factors correlated with clinicopathological Factors and recurrence. Methods 140 primary invasive breast cancer specimens were collected. mRNA expression for Sox2, OCT4, NANOG, and GDF3 genes was assessed by RT-PCR. Immunohistochemistry was done for Sox2. Correlations with molecular subtypes, menopausal status, grading, ER, PR, ki67 (⩽20%), HER2, T-size, and node status were evaluated. Association of Sox2 expression and disease-free survival was estimated by univariate and multivariate analysis (p ⩽ 0.05). Findings In 117 samples assessable by RT-PCR we found the following correlations: NANOG and grade 2, GDF3 and node-negative, Sox2 and higher ki67 (p = 0.019, p = 0.029, p = 0.035, respectively). At univariate analysis of disease-free survival, Sox2 expression (hazard ratio (HR) 2.36; p = 0.002), ki67 (HR 2.19; p = 0.028), T-size ⩾1 (HR 2.06; p = 2.011), node-status (HR 2.21; p = 0.014); ER/PR (HR 0.58/HR 0.59, p = 0.065/p = 0.068) were statistically significant. At multivariate analysis, Sox2 (HR 2.99; 95% confidence interval (CI) 1.41–6.30; p = 0.004), node-status (HR 2.44; 95% CI 1.25–4.76; p = 0.009), and T-size ⩾1 (HR 1.77; 95% CI 0.99–3.13; p = 0.051) were associated with increased risk of recurrence. An earlier recurrence was observed in Sox2 + (median 34.9 months; 95% CI 7.5–62.2) than Sox2- patients (median: 60.3 months; 95% CI 32.6–88.1; p = 0.017); overall survival was shorter in Sox2 + patients than in those who were SOX-(68.2 months, 95% CI 63.7–151.4 versus 145.3 months, 95% CI: 80.5–210.2) although this was not significant (p = 0.104). IHC showed Sox2 protein expression in all of 11 samples; no expression was noted in 20 randomly selected Sox2- samples. Interpretation Our analysis confirms that expression of pluripotency Transcription Factors correlates with specific clinicopathological Factors (grade, node-status, and ki67). Sox2 expression was associated with an increased risk of recurrence, irrespective of other clinicopathological Factors.

  • abstract p2 06 05 expression of the pluripotency Transcription Factor Sox2 in primary breast cancers bcs correlation with clinicopathological features cpfs and recurrence
    Cancer Research, 2015
    Co-Authors: Barbara Pistilli, Giovanni Benedetti, Mauro Finicelli, Tiziana Squillaro, Andrea Marcellusi, Tommasina Biscotti, Alfredo Santinelli, Paola Mariani, Paolo Decembrini, Giancarlo Ciccioli
    Abstract:

    BACKGROUND Sox2 is one of the pluripotency Transcription Factors expressed by stem cells, which plays a central role in controlling the expression of genes implicated in embryonic development and stemness manteinance. Key regulators of embryonic stem cell (ESC) identity, such as NANOG, Sox2, OCT4 and GDF3 resulted overexpressed in a variety of solid tumors with a possible role in cancer progression and prognosis. Sox2 expression has mainly been reported in basal-like BC subtype, suggesting a role in conferring a less differentiated phenotype. In our analysis we evaluated a heterogenous group of BC tissues to determine whether the expression of ESC-regulating genes correlated with CPfs and recurrence. METHODS 140 primary invasive BC specimens were collected from 137 female patients who underwent surgery. mRNA expression for Sox2, OCT4, NANOG, GDF3 genes was assessed by RT-PCR. Immunoistochemistry (IHC) was performed for Sox2 with mouse monoclonal antibody (1:50, Y17, Santa Cruz Biotechnology, USA). Correlations with molecular subtypes, menopausal status, grading, ER, PR, ki67 (≤ 20% and > 20%), HER2, T-size and node status were evaluated by Fisher9s exact test and χ2 test. Association of ESC-genes, CPfs and DFS was estimated by univariate and multivariate Cox-regression analysis (p≤ 0.05). Survival analysis (DFS and OS) were calculated by Kaplan-Meier curves and compared by log-rank test. RESULTS In 117 samples assessable by RT-PCR the genes resulted expressed as follows: NANOG=52 (44.5%), Sox2=11 (9.4%), GDF3=9 (7.2%), OCT-4=0. Correlation of mRNA gene expression with CPfs was statistically significant between NANOG and grade 2, GDF3 and node-negative status, Sox2 and higher ki67 (p=0.019, p=0.029, p= 0.035, respectively). Six out of 11 Sox2+ tumors were HER2+ (data not statistically significant); in the remaining 5 samples the fluorescence in situ hybridization was performed but no HER2 amplification was detected. At univariate analysis of DFS, Sox2 expression (HR=2,36; p=0.002), ki67 (HR= 2,19; p=0,028), T-size >1 (HR=2,06; p=2.011), node-status (HR=2,21; p= 0.014); ER/PR(HR=0,58/HR=0,59, p=0.065/p=0.068) resulted statistically significant. At multivariate analysis, Sox2 (HR=2,99; 95% CI 1,41-6,30; p=0.004), node-status (HR=2,44; 95%CI 1,25-4,76; p=0.009) and T-size >1 (HR=1,77; 95% CI=0,99-3,13; p=0.051) were independently associated with increased risk of recurrence. An earlier recurrence was observed in Sox2+ patients (median 34.9 months; 95% CI: 7.5-62.2) than Sox2- patients (median: 60.3 months; 95% CI: 32.6-88.1) (p=0.017); OS resulted shorter in Sox2+ (68.2 months 95%CI: 63.7-151.4 vs 145.3 months 95% CI: 80.5-210.2) albeit not statistically significant (p=0.104). IHC analysis showed a positive score for Sox2 protein expression in all of 11 samples with Sox2 mRNA amplification; Sox2+ protein was not detected in 20 samples randomly selected among the tissues not expressing Sox2 mRNA. CONCLUSIONS Our analysis confirm that ESC-regulating genes correlate with specific CPfs (grading, node-status and ki67). Notably, Sox2 resulted to be an independent prognostic Factor, as it was associated with a risk of recurrence increased by 3 times, irrespective of other CPfs. Citation Format: Barbara Pistilli, Giovanni Benedetti, Mauro Finicelli, Tiziana Squillaro, Andrea Marcellusi, Tommasina Biscotti, Alfredo Santinelli, Paola Mariani, Paolo Decembrini, Giancarlo Ciccioli, Luciano Latini, Antonio Giordano, Umberto Galderisi. Expression of the pluripotency Transcription Factor Sox2 in primary breast cancers (BCs): Correlation with clinicopathological features (CPfs) and recurrence [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-06-05.

Angie Rizzino - One of the best experts on this subject based on the ideXlab platform.

  • determination of protein interactome of Transcription Factor Sox2 in embryonic stem cells engineered for inducible expression of four reprogramming Factors
    Journal of Biological Chemistry, 2012
    Co-Authors: Zhiguang Gao, Jesse L Cox, Joshua M Gilmore, Briana D Ormsbee, Sunil K Mallanna, Michael P Washburn, Angie Rizzino
    Abstract:

    Unbiased proteomic screens provide a powerful tool for defining protein-protein interaction networks. Previous studies employed multidimensional protein identification technology to identify the Sox2-interactome in embryonic stem cells (ESC) undergoing differentiation in response to a small increase in the expression of epitope-tagged Sox2. Thus far the Sox2-interactome in ESC has not been determined. To identify the Sox2-interactome in ESC, we engineered ESC for inducible expression of different combinations of epitope-tagged Sox2 along with Oct4, Klf4, and c-Myc. Epitope-tagged Sox2 was used to circumvent the lack of suitable Sox2 antibodies needed to perform an unbiased proteomic screen of Sox2-associated proteins. Although i-OS-ESC differentiate when both Oct4 and Sox2 are elevated, i-OSKM-ESC do not differentiate even when the levels of the four Transcription Factors are coordinately elevated ∼2-3-fold. Our findings with i-OS-ESC and i-OSKM-ESC provide new insights into the reasons why ESC undergo differentiation when Sox2 and Oct4 are elevated in ESC. Importantly, the use of i-OSKM-ESC enabled us to identify the Sox2-interactome in undifferentiated ESC. Using multidimensional protein identification technology, we identified >70 proteins that associate with Sox2 in ESC. We extended these findings by testing the function of the Sox2-assoicated protein Smarcd1 and demonstrate that knockdown of Smarcd1 disrupts the self-renewal of ESC and induces their differentiation. Together, our work provides the first description of the Sox2-interactome in ESC and indicates that Sox2 along with other master regulators is part of a highly integrated protein-protein interaction landscape in ESC.

  • small increases in the level of Sox2 trigger the differentiation of mouse embryonic stem cells
    Stem Cells, 2008
    Co-Authors: Briana D Ormsbee, Angie Rizzino, Janel L Kopp, Michelle Desler
    Abstract:

    Previous studies have demonstrated that the Transcription Factor Sox2 is essential during the early stages of development. Furthermore, decreasing the expression of Sox2 severely interferes with the self-renewal and pluripotency of embryonic stem (ES) cells. Other studies have shown that Sox2, in conjunction with the Transcription Factor Oct-3/4, stimulates its own Transcription as well as the expression of a growing list of genes (Sox2:Oct-3/4 target genes) that require the cooperative action of Sox2 and Oct-3/4. Remarkably, recent studies have shown that overexpression of Sox2 decreases expression of its own gene, as well as four other Sox2:Oct-3/4 target genes (Oct-3/4, Nanog, Fgf-4, and Utf1). This finding led to the prediction that overexpression of Sox2 in ES cells would trigger their differentiation. In the current study, we initially engineered mouse ES cells for inducible overexpression of Sox2. Using this model system, we demonstrate that small increases (twofold or less) in Sox2 protein trigger the differentiation of ES cells into cells that exhibit markers for a wide range of differentiated cell types, including neuroectoderm, mesoderm, and trophectoderm but not endoderm. We also demonstrate that elevating the levels of Sox2 quickly downregulates several developmentally regulated genes, including Nanog, and a newly identified Sox2:Oct-3/4 target gene, Lefty1. Together, these data argue that the self-renewal of ES cells requires that Sox2 levels be maintained within narrow limits. Thus, Sox2 appears to function as a molecular rheostat that controls the expression of a critical set of embryonic genes, as well as the self-renewal and differentiation of ES cells.