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Dive into the research topics where Paola Capodieci is active.

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Featured researches published by Paola Capodieci.


Nature | 2001

Inactivation of the apoptosis effector Apaf-1 in malignant melanoma

Maria S. Soengas; Paola Capodieci; David Polsky M.D.; Jaume Mora; Manel Esteller; Ximena Opitz-Araya; Richard McCombie; James G. Herman; William L. Gerald; Yuri Lazebnik; Carlos Cordon-Cardo; Scott W. Lowe

Metastatic melanoma is a deadly cancer that fails to respond to conventional chemotherapy and is poorly understood at the molecular level. p53 mutations often occur in aggressive and chemoresistant cancers but are rarely observed in melanoma. Here we show that metastatic melanomas often lose Apaf-1, a cell-death effector that acts with cytochrome c and caspase-9 to mediate p53-dependent apoptosis. Loss of Apaf-1 expression is accompanied by allelic loss in metastatic melanomas, but can be recovered in melanoma cell lines by treatment with the methylation inhibitor 5-aza-2′-deoxycytidine (5aza2dC). Apaf-1-negative melanomas are invariably chemoresistant and are unable to execute a typical apoptotic programme in response to p53 activation. Restoring physiological levels of Apaf-1 through gene transfer or 5aza2dC treatment markedly enhances chemosensitivity and rescues the apoptotic defects associated with Apaf-1 loss. We conclude that Apaf-1 is inactivated in metastatic melanomas, which leads to defects in the execution of apoptotic cell death. Apaf-1 loss may contribute to the low frequency of p53 mutations observed in this highly chemoresistant tumour type.


American Journal of Pathology | 2003

Tumor Suppressor Role of KiSS-1 in Bladder Cancer: Loss of KiSS-1 Expression Is Associated with Bladder Cancer Progression and Clinical Outcome

Marta Sanchez-Carbayo; Paola Capodieci; Carlos Cordon-Cardo

The expression profiles of nine bladder cancer cell lines were compared against a pool containing equal total RNA quantities of each of them. Lower expression of KiSS-1 was revealed in cells derived from the most advanced bladder tumors. When comparing 15 primary bladder tumors versus a pool of four bladder cancer cell lines, lower transcript levels of KiSS-1 were observed in the invasive bladder carcinomas as compared to superficial tumors. KiSS-1 expression ratios provided prognostic information. The expression pattern of KiSS-1 transcripts was analyzed using in situ hybridization in nine bladder cancer cells, paired normal urothelium and bladder tumor samples (n = 25), and tissue microarrays of bladder tumors (n = 173). We observed complete loss of KiSS-1 in all invasive tumors under study as compared to their respective normal urothelium. The expression of KiSS-1 was found to be significantly associated with histopathological stage. Patients with lower KiSS-1 expression showed a direct correlation with overall survival in a subset of bladder tumors whose follow-up was available (n = 69). We did not observe any significant differential KiSS-1 expression along cell cycle by sorting analysis. A potential tumor suppressor role in bladder cancer was revealed for KiSS-1. Moreover, it showed predictive value by identifying patients with poor outcome.


Journal of Clinical Investigation | 2007

Improved prediction of prostate cancer recurrence through systems pathology

Carlos Cordon-Cardo; Angeliki Kotsianti; David Verbel; Mikhail Teverovskiy; Paola Capodieci; Stefan Hamann; Yusuf Jeffers; Mark Clayton; Faysal Elkhettabi; Faisal M. Khan; Marina Sapir; Valentina Bayer-Zubek; Yevgen Vengrenyuk; Stephen Fogarsi; Olivier Saidi; Victor E. Reuter; Howard I. Scher; Michael W. Kattan; Fernando J. Bianco; Thomas M. Wheeler; Gustavo Ayala; Peter T. Scardino; Michael J. Donovan

We have developed an integrated, multidisciplinary methodology, termed systems pathology, to generate highly accurate predictive tools for complex diseases, using prostate cancer for the prototype. To predict the recurrence of prostate cancer following radical prostatectomy, defined by rising serum prostate-specific antigen (PSA), we used machine learning to develop a model based on clinicopathologic variables, histologic tumor characteristics, and cell type-specific quantification of biomarkers. The initial study was based on a cohort of 323 patients and identified that high levels of the androgen receptor, as detected by immunohistochemistry, were associated with a reduced time to PSA recurrence. The model predicted recurrence with high accuracy, as indicated by a concordance index in the validation set of 0.82, sensitivity of 96%, and specificity of 72%. We extended this approach, employing quantitative multiplex immunofluorescence, on an expanded cohort of 682 patients. The model again predicted PSA recurrence with high accuracy, concordance index being 0.77, sensitivity of 77% and specificity of 72%. The androgen receptor was selected, along with 5 clinicopathologic features (seminal vesicle invasion, biopsy Gleason score, extracapsular extension, preoperative PSA, and dominant prostatectomy Gleason grade) as well as 2 histologic features (texture of epithelial nuclei and cytoplasm in tumor only regions). This robust platform has broad applications in patient diagnosis, treatment management, and prognostication.


Nature Genetics | 2004

Caenorhabditis elegans ABL-1 antagonizes p53-mediated germline apoptosis after ionizing irradiation.

Xinzhu Deng; E. Randal Hofmann; Alberto Villanueva; Oliver Hobert; Paola Capodieci; Darren R. Veach; Xianglei Yin; Luis Campodonico; Athanasios Glekas; Carlos Cordon-Cardo; Bayard D. Clarkson; William Bornmann; Zvi Fuks; Michael O. Hengartner; Richard Kolesnick

c-Abl, a conserved nonreceptor tyrosine kinase, integrates genotoxic stress responses, acting as a transducer of both pro- and antiapoptotic effector pathways. Nuclear c-Abl seems to interact with the p53 homolog p73 to elicit apoptosis. Although several observations suggest that cytoplasmic localization of c-Abl is required for antiapoptotic function, the signals that mediate its antiapoptotic effect are largely unknown. Here we show that worms carrying an abl-1 deletion allele, abl-1(ok171), are specifically hypersensitive to radiation-induced apoptosis in the Caenorhabditis elegans germ line. Our findings delineate an apoptotic pathway antagonized by ABL-1, which requires sequentially the cell cycle checkpoint genes clk-2, hus-1 and mrt-2; the C. elegans p53 homolog, cep-1; and the genes encoding the components of the conserved apoptotic machinery, ced-3, ced-9 and egl-1. ABL-1 does not antagonize germline apoptosis induced by the DNA-alkylating agent ethylnitrosourea. Furthermore, worms treated with the c-Abl inhibitor STI-571 (Gleevec; used in human cancer therapy), two newly synthesized STI-571 variants or PD166326 had a phenotype similar to that generated by abl-1(ok171). These studies indicate that ABL-1 distinguishes proapoptotic signals triggered by two different DNA-damaging agents and suggest that C. elegans might provide tissue models for development of anticancer drugs.


BJUI | 2010

Androgen receptor expression is associated with prostate cancer-specific survival in castrate patients with metastatic disease

Michael J. Donovan; Iman Osman; Faisal M. Khan; Yevgen Vengrenyuk; Paola Capodieci; Michael Koscuiszka; Aseem Anand; Carlos Cordon-Cardo; Jose Costa; Howard I. Scher

Study Type – Aetiology (case series)
 Level of Evidence 4


Nature Methods | 2005

Gene expression profiling in single cells within tissue.

Paola Capodieci; Michael J. Donovan; Heidi Buchinsky; Yusuf Jeffers; Carlos Cordon-Cardo; William L. Gerald; Jon Edelson; Shailesh M. Shenoy; Robert H. Singer

We developed a robust multiplex fluorescent in situ hybridization (FISH) technique in archival formalin-fixed, paraffin-embedded (FFPE) human tissue sections while preserving the microanatomical context. This identifies single-cell gene expression patterns by probing multiple, unique nascent RNA transcripts and yields predictive quantitative gene expression signatures.


Journal of Cellular Biochemistry | 2007

The spatial order of transcription in mammalian cells.

Jeffrey M. Levsky; Shailesh M. Shenoy; Jonathan R. Chubb; Charles B. Hall; Paola Capodieci; Robert H. Singer

We have previously developed technology for multiplexing probes for the detection of transcription of many genes simultaneously within single cells. This has allowed us to determine the spatial localization of multiple genes with respect to each other in the nucleus, and ultimately the expression profile of the cell with respect to surrounding cells in a tissue. Six parameters of transcriptional organization in individual cells from culture and tissue were used to characterize significant differences in intracellular and intercellular expression patterns while preserving cellular morphology and histological context. We found that, unlike yeast, mammalian expression is excluded from the periphery and in addition, a subtle but complex organization underlies the transcriptional activity of these cells, both intra‐ and intercellularly. The approach has sufficient spatial resolution to be applied to the detection of chromosomal translocations or the identification of cancer cells. J. Cell. Biochem. 102: 609–617, 2007.


international symposium on biomedical imaging | 2008

Automated localization and quantification of protein multiplexes via multispectral fluorescence imaging

Mikhail Teverovskiy; Yevgen Vengrenyuk; Ali Tabesh; Marina Sapir; Stephen Fogarasi; Ho-Yuen Pang; Faisal M. Khan; Stefan Hamann; Paola Capodieci; Mark Clayton; Robert Kim; Gerardo Fernandez; Ricardo Mesa-Tejada; Michael J. Donovan

We present a new system for automated localization and quantification of the expression of protein biomarkers in immunofluorescence (IF) microscopic images. The system includes a novel method for discriminating the biomarker signal from background, where signal may be the expression of any of the many biomarkers or counterstains used in IF. The method is based on supervised learning and represents the biomarker intensity threshold as a function of image background characteristics. The utility of the proposed system is demonstrated in predicting prostate cancer recurrence in patients undergoing prostatectomy. Specifically, features representing androgen receptor (AR) expression are shown to be statistically significantly associated with poor outcome in univariate analysis. AR features are also shown to be valuable for multivariate recurrence prediction.


Proceedings of the National Academy of Sciences of the United States of America | 2018

mTORC1 signaling suppresses Wnt/β-catenin signaling through DVL-dependent regulation of Wnt receptor FZD level

Hao Zeng; Bo Lu; Raffaella Zamponi; Zinger Yang; Kristie Wetzel; Joseph Loureiro; Sina Mohammadi; Martin Beibel; Sebastian Bergling; John S. Reece-Hoyes; Carsten Russ; Guglielmo Roma; Jan S. Tchorz; Paola Capodieci; Feng Cong

Significance The Wnt/β-catenin signaling pathway plays prominent roles during embryonic development and adult tissue homeostasis by maintaining somatic stem cell functions. The mammalian target of rapamycin complex 1 (mTORC1) signaling pathway has also been implicated in regulating stem cell functions in multiple tissue types. However, the crosstalk between these two pathways remains largely unclear. Herein, using in vitro cell lines, ex vivo organoids, and an in vivo mouse model, we made striking findings in support of a paradigm that mTORC1 signaling cell autonomously suppresses Wnt/β-catenin signaling through down-regulating the Wnt receptor FZD level to influence stem cell functions, with implications in the aging process. Wnt/β-catenin signaling plays pivotal roles in cell proliferation and tissue homeostasis by maintaining somatic stem cell functions. The mammalian target of rapamycin (mTOR) signaling functions as an integrative rheostat that orchestrates various cellular and metabolic activities that shape tissue homeostasis. Whether these two fundamental signaling pathways couple to exert physiological functions still remains mysterious. Using a genome-wide CRISPR-Cas9 screening, we discover that mTOR complex 1 (mTORC1) signaling suppresses canonical Wnt/β-catenin signaling. Deficiency in tuberous sclerosis complex 1/2 (TSC1/2), core negative regulators of mTORC1 activity, represses Wnt/β-catenin target gene expression, which can be rescued by RAD001. Mechanistically, mTORC1 signaling regulates the cell surface level of Wnt receptor Frizzled (FZD) in a Dishevelled (DVL)-dependent manner by influencing the association of DVL and clathrin AP-2 adaptor. Sustained mTORC1 activation impairs Wnt/β-catenin signaling and causes loss of stemness in intestinal organoids ex vivo and primitive intestinal progenitors in vivo. Wnt/β-catenin–dependent liver metabolic zonation gene expression program is also down-regulated by mTORC1 activation. Our study provides a paradigm that mTORC1 signaling cell autonomously regulates Wnt/β-catenin pathway to influence stem cell maintenance.


Science | 2001

Endothelial Apoptosis as the Primary Lesion Initiating Intestinal Radiation Damage in Mice

François Paris; Zvi Fuks; Anthony Kang; Paola Capodieci; Gloria Juan; Desiree Ehleiter; Adriana Haimovitz-Friedman; Carlos Cordon-Cardo; Richard Kolesnick

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Carlos Cordon-Cardo

Icahn School of Medicine at Mount Sinai

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Michael J. Donovan

Icahn School of Medicine at Mount Sinai

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David Verbel

Memorial Sloan Kettering Cancer Center

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Howard I. Scher

Memorial Sloan Kettering Cancer Center

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Faisal M. Khan

Icahn School of Medicine at Mount Sinai

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Iman Osman

Memorial Sloan Kettering Cancer Center

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Marija Drobnjak

Memorial Sloan Kettering Cancer Center

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Rosa Bernardi

Vita-Salute San Raffaele University

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Andrew Koff

Memorial Sloan Kettering Cancer Center

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