149 results on '"Dotto GP"'
Search Results
2. ANKRD1 is a mesenchymal-specific driver of cancer-associated fibroblast activation bridging androgen receptor loss to AP-1 activation.
- Author
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Mazzeo L, Ghosh S, Di Cicco E, Isma J, Tavernari D, Samarkina A, Ostano P, Youssef MK, Simon C, and Dotto GP
- Subjects
- Humans, Fibroblasts metabolism, Muscle Proteins metabolism, Nuclear Proteins genetics, Nuclear Proteins metabolism, Receptors, Androgen genetics, Receptors, Androgen metabolism, Repressor Proteins genetics, Repressor Proteins metabolism, Transcription Factor AP-1 genetics, Transcription Factor AP-1 metabolism, Tumor Microenvironment, Cancer-Associated Fibroblasts metabolism, Skin Neoplasms pathology
- Abstract
There are significant commonalities among several pathologies involving fibroblasts, ranging from auto-immune diseases to fibrosis and cancer. Early steps in cancer development and progression are closely linked to fibroblast senescence and transformation into tumor-promoting cancer-associated fibroblasts (CAFs), suppressed by the androgen receptor (AR). Here, we identify ANKRD1 as a mesenchymal-specific transcriptional coregulator under direct AR negative control in human dermal fibroblasts (HDFs) and a key driver of CAF conversion, independent of cellular senescence. ANKRD1 expression in CAFs is associated with poor survival in HNSCC, lung, and cervical SCC patients, and controls a specific gene expression program of myofibroblast CAFs (my-CAFs). ANKRD1 binds to the regulatory region of my-CAF effector genes in concert with AP-1 transcription factors, and promotes c-JUN and FOS association. Targeting ANKRD1 disrupts AP-1 complex formation, reverses CAF activation, and blocks the pro-tumorigenic properties of CAFs in an orthotopic skin cancer model. ANKRD1 thus represents a target for fibroblast-directed therapy in cancer and potentially beyond., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
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3. Androgen receptor is a determinant of melanoma targeted drug resistance.
- Author
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Samarkina A, Youssef MK, Ostano P, Ghosh S, Ma M, Tassone B, Proust T, Chiorino G, Levesque MP, Goruppi S, and Dotto GP
- Subjects
- Humans, CD8-Positive T-Lymphocytes metabolism, Receptors, Androgen genetics, Drug Resistance, Neoplasm genetics, Neoplasm Recurrence, Local drug therapy, Mitogen-Activated Protein Kinase Kinases, Carcinogenesis, Protein Kinase Inhibitors pharmacology, Cell Line, Tumor, Proto-Oncogene Proteins B-raf metabolism, Melanoma drug therapy, Melanoma genetics, Melanoma metabolism
- Abstract
Melanoma provides a primary benchmark for targeted drug therapy. Most melanomas with BRAF
V600 mutations regress in response to BRAF/MEK inhibitors (BRAFi/MEKi). However, nearly all relapse within the first two years, and there is a connection between BRAFi/MEKi-resistance and poor response to immune checkpoint therapy. We reported that androgen receptor (AR) activity is required for melanoma cell proliferation and tumorigenesis. We show here that AR expression is markedly increased in BRAFi-resistant melanoma cells, and in sensitive cells soon after BRAFi exposure. Increased AR expression is sufficient to render melanoma cells BRAFi-resistant, eliciting transcriptional changes of BRAFi-resistant subpopulations, including elevated EGFR and SERPINE1 expression, of likely clinical significance. Inhibition of AR expression or activity blunts changes in gene expression and suppresses proliferation and tumorigenesis of BRAFi-resistant melanoma cells, promoting clusters of CD8+ T cells infiltration and cancer cells killing. Our findings point to targeting AR as possible co-therapeutical approach in melanoma treatment., (© 2023. Springer Nature Limited.)- Published
- 2023
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4. Nuclear lamin A/C phosphorylation by loss of Androgen Receptor is a global determinant of cancer-associated fibroblast activation.
- Author
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Ghosh S, Isma J, Mazzeo L, Toniolo A, Simon C, and Dotto GP
- Abstract
Alterations of nuclear structure and function, and associated impact on gene transcription, are a hallmark of cancer cells. Little is known of these alterations in Cancer-Associated Fibroblasts (CAFs), a key component of the tumor stroma. Here we show that loss of androgen receptor (AR), which triggers early steps of CAF activation in human dermal fibroblasts (HDFs), leads to nuclear membrane alterations and increased micronuclei formation, which are unlinked from induction of cellular senescence. Similar alterations occur in fully established CAFs, which are overcome by restored AR function. AR associates with nuclear lamin A/C and loss of AR results in a substantially increased lamin A/C nucleoplasmic redistribution. Mechanistically, AR functions as a bridge between lamin A/C with the protein phosphatase PPP1. In parallel with a decreased lamin-PPP1 association, AR loss results in a marked increase of lamin A/C phosphorylation at Ser 301, which is also a feature of CAFs. Phosphorylated lamin A/C at Ser 301 binds to the transcription promoter regulatory region of several CAF effector genes, which are upregulated due to the loss of AR. More directly, expression of a lamin A/C Ser301 phosphomimetic mutant alone is sufficient to convert normal fibroblasts into tumor-promoting CAFs of the myofibroblast subtype, without an impact on senescence. These findings highlight the pivotal role of the AR-lamin A/C-PPP1 axis and lamin A/C phosphorylation at Ser 301 in driving CAF activation., Competing Interests: Declaration of interests The Authors declare that there are no competing financial interests
- Published
- 2023
- Full Text
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5. Pre-cancer: From diagnosis to intervention opportunities.
- Author
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Hwang ES, Reading J, Yu J, Dotto GP, Grady WM, Czerniak B, and Serrano M
- Subjects
- Humans, Carcinogenesis, Tumor Microenvironment, Neoplasms diagnosis, Neoplasms therapy, Neoplasms metabolism
- Abstract
The multi-step process of carcinogenesis implies the existence of pre-malignant yet altered states that involve both the potentially carcinogenic cell as well as its surrounding microenvironment. Experts discuss some tumor types for which clear pre-cancerous stages have been identified and mention key biological alterations used for diagnosis and intervention strategies., Competing Interests: Declaration of interests G.P.D. has filed the following patents: Methods and compositions for preventing skin damage, patent # US 7,192,770; In vivo screening array, patent # US 7,202,392; Methods and compositions for Reducing skin damage (Notch), patent # 8,114,422; and Methods and compositions for the treatment of cancer, patent # US10188747B2, WO2015130477A1. W.M.G. is a scientific advisory board member for Freenome, Natera, Guardant Health, and SEngine and consultant for DiaCarta, Nephron, Guidepoint, and GLG. W.M.G. is an investigator in a clinical trial sponsored by Janssen Pharmaceuticals and receives research support from Tempus and LucidDx., (Copyright © 2023. Published by Elsevier Inc.)
- Published
- 2023
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6. Mesenchymal cells in health and disease.
- Author
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Koliaraki V, Dotto GP, Buckley CD, and Kollias G
- Subjects
- Mesenchymal Stem Cells
- Published
- 2022
- Full Text
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7. Sphingolipids control dermal fibroblast heterogeneity.
- Author
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Capolupo L, Khven I, Lederer AR, Mazzeo L, Glousker G, Ho S, Russo F, Montoya JP, Bhandari DR, Bowman AP, Ellis SR, Guiet R, Burri O, Detzner J, Muthing J, Homicsko K, Kuonen F, Gilliet M, Spengler B, Heeren RMA, Dotto GP, La Manno G, and D'Angelo G
- Subjects
- Humans, Lipidomics methods, Metabolic Networks and Pathways, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization methods, Transcriptome, Fibroblasts chemistry, Fibroblasts classification, Fibroblasts metabolism, Skin chemistry, Skin metabolism, Sphingolipids analysis, Sphingolipids metabolism
- Abstract
Human cells produce thousands of lipids that change during cell differentiation and can vary across individual cells of the same type. However, we are only starting to characterize the function of these cell-to-cell differences in lipid composition. Here, we measured the lipidomes and transcriptomes of individual human dermal fibroblasts by coupling high-resolution mass spectrometry imaging with single-cell transcriptomics. We found that the cell-to-cell variations of specific lipid metabolic pathways contribute to the establishment of cell states involved in the organization of skin architecture. Sphingolipid composition is shown to define fibroblast subpopulations, with sphingolipid metabolic rewiring driving cell-state transitions. Therefore, cell-to-cell lipid heterogeneity affects the determination of cell states, adding a new regulatory component to the self-organization of multicellular systems.
- Published
- 2022
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8. HSD17B7 gene in self-renewal and oncogenicity of keratinocytes from Black versus White populations.
- Author
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Xu X, Tassone B, Ostano P, Katarkar A, Proust T, Joseph JM, Riganti C, Chiorino G, Kutalik Z, Lefort K, and Dotto GP
- Subjects
- Cell Proliferation, Humans, Keratinocytes, Oncogenes, Carcinoma, Squamous Cell
- Abstract
Human populations of Black African ancestry have a relatively high risk of aggressive cancer types, including keratinocyte-derived squamous cell carcinomas (SCCs). We show that primary keratinocytes (HKCs) from Black African (Black) versus White Caucasian (White) individuals have on average higher oncogenic and self-renewal potential, which are inversely related to mitochondrial electron transfer chain activity and ATP and ROS production. HSD17B7 is the top-ranked differentially expressed gene in HKCs and Head/Neck SCCs from individuals of Black African versus Caucasian ancestries, with several ancestry-specific eQTLs linked to its expression. Mirroring the differences between Black and White HKCs, modulation of the gene, coding for an enzyme involved in sex steroid and cholesterol biosynthesis, determines HKC and SCC cell proliferation and oncogenicity as well as mitochondrial OXPHOS activity. Overall, the findings point to a targetable determinant of cancer susceptibility among different human populations, amenable to prevention and management of the disease., (© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2021
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9. Flash forward genetics: new twists in transcription across evolutionary boundaries.
- Author
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Dotto GP and Missero C
- Subjects
- Animals, Biological Evolution, Gene Expression Regulation, Mice, Mice, Nude, Forkhead Transcription Factors genetics, Forkhead Transcription Factors metabolism, Hair Follicle metabolism
- Abstract
"Flash forward genetics" refers to a genetic approach based on the functional interaction of a given factor with unknown partner(s) converging on shared targets across evolutionary boundaries. A study by Li et al (2021), published in this issue of EMBO Reports, illustrates the innovative potential of the approach. The authors applied it to identify interacting factors for FOXN1, a mammalian transcription factor with a highly specialized function in hair follicle morphogenesis and thymus. The authors express FOXN1 in the Drosophila eye to perform an unbiased genetic screen in a totally heterologous system. In a remarkable tour de force, the authors identify and characterize a factor so far known for its ubiquitous function in transcription elongation, AFF4. Li et al show that AFF4 plays also a specific role in hair follicle and thymus development in the mouse overlapping with that of FOXN1., (© 2021 The Authors.)
- Published
- 2021
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10. Sustained androgen receptor signaling is a determinant of melanoma cell growth potential and tumorigenesis.
- Author
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Ma M, Ghosh S, Tavernari D, Katarkar A, Clocchiatti A, Mazzeo L, Samarkina A, Epiney J, Yu YR, Ho PC, Levesque MP, Özdemir BC, Ciriello G, Dummer R, and Dotto GP
- Subjects
- Animals, Carcinogenesis pathology, Cell Line, Tumor, DNA Damage genetics, DNA Repair genetics, Down-Regulation genetics, Female, Gene Expression Regulation, Neoplastic genetics, Humans, Male, Melanoma pathology, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, SCID, RNA Polymerase II genetics, Carcinogenesis genetics, Cell Proliferation genetics, Melanoma genetics, Receptors, Androgen genetics, Signal Transduction genetics
- Abstract
Melanoma susceptibility differs significantly in male versus female populations. Low levels of androgen receptor (AR) in melanocytes of the two sexes are accompanied by heterogeneous expression at various stages of the disease. Irrespective of expression levels, genetic and pharmacological suppression of AR activity in melanoma cells blunts proliferation and induces senescence, while increased AR expression or activation exert opposite effects. AR down-modulation elicits a shared gene expression signature associated with better patient survival, related to interferon and cytokine signaling and DNA damage/repair. AR loss leads to dsDNA breakage, cytoplasmic leakage, and STING activation, with AR anchoring the DNA repair proteins Ku70/Ku80 to RNA Pol II and preventing RNA Pol II-associated DNA damage. AR down-modulation or pharmacological inhibition suppresses melanomagenesis, with increased intratumoral infiltration of macrophages and, in an immune-competent mouse model, cytotoxic T cells. AR provides an attractive target for improved management of melanoma independent of patient sex., Competing Interests: Disclosures: R. Dummer had intermittent, project-focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, and Alligator outside the submitted work. No other disclosures were reported., (© 2020 Ma et al.)
- Published
- 2021
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11. Phenformin Promotes Keratinocyte Differentiation via the Calcineurin/NFAT Pathway.
- Author
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Zhou Q, Kim SH, Pérez-Lorenzo R, Liu C, Huang M, Dotto GP, Zheng B, and Wu X
- Subjects
- Animals, Cell Differentiation, Humans, Hypoglycemic Agents pharmacology, Keratinocytes drug effects, Keratinocytes metabolism, Melanoma metabolism, Melanoma pathology, Mice, Neoplasms, Experimental, Signal Transduction, Skin metabolism, Skin Neoplasms metabolism, Skin Neoplasms pathology, Calcineurin metabolism, Keratinocytes pathology, Melanoma drug therapy, Nitrofurans metabolism, Phenformin pharmacology, Skin pathology, Skin Neoplasms drug therapy
- Abstract
Phenformin is a drug in the biguanide class that was previously used to treat type 2 diabetes. We have reported the antitumor activities of phenformin to enhance the efficacy of BRAF-MAPK kinase-extracellular signal-regulated kinase pathway inhibition and to inhibit myeloid-derived suppressor cells in various melanoma models. Here we demonstrate that phenformin suppresses tumor growth and promotes keratinocyte differentiation in the 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate two-stage skin carcinogenesis mouse model. Moreover, phenformin enhances the suspension-induced differentiation of mouse and human keratinocytes. Mechanistically, phenformin induces the nuclear translocation of NFATc1 in keratinocytes in an AMPK-dependent manner. Pharmacologic or genetic inhibition of calcineurin and NFAT signaling reverses the effects of phenformin on keratinocyte differentiation. Taken together, our study reveals an antitumor activity of phenformin to promote keratinocyte differentiation that warrants future translational efforts to repurpose phenformin for the treatment of cutaneous squamous cell carcinomas., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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12. Visualizing cellular heterogeneity by quantifying the dynamics of MAPK activity in live mammalian cells with synthetic fluorescent biosensors.
- Author
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Ma M, Bordignon P, Dotto GP, and Pelet S
- Abstract
Mitogen-Activated Protein Kinases (MAPKs) control a wide array of cellular functions by transducing extracellular information into defined biological responses. In order to understand how these pathways are regulated, dynamic single cell measurements are highly needed. Fluorescence microscopy is well suited to perform these measurements. However, more dynamic and sensitive biosensors that allow the quantification of signaling activity in living mammalian cells are required. We have engineered a synthetic fluorescent substrate for human MAPKs (ERK, JNK and p38) that relocates from the nucleus to the cytoplasm when phosphorylated by the kinases. We demonstrate that this reporter displays an improved response compared to other relocation biosensors. This assay allows to monitor the heterogeneity in the MAPK response in a population of isogenic cells, revealing pulses of ERK activity upon a physiological EGFR stimulation. We show applicability of this approach to the analysis of multiple cancer cell lines and primary cells as well as its application in vivo to developing tumors. Using this ERK biosensor, dynamic single cell measurements with high temporal resolution can be obtained. These MAPK reporters can be widely applied to the analysis of molecular mechanisms of MAPK signaling in healthy and diseased state, in cell culture assays or in vivo ., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors.)
- Published
- 2020
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13. NOTCH1 gene amplification promotes expansion of Cancer Associated Fibroblast populations in human skin.
- Author
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Katarkar A, Bottoni G, Clocchiatti A, Goruppi S, Bordignon P, Lazzaroni F, Gregnanin I, Ostano P, Neel V, and Dotto GP
- Subjects
- Animals, DNA Damage, Female, Forkhead Box Protein O3 genetics, Forkhead Box Protein O3 metabolism, Humans, Mice, Mice, SCID, Receptor, Notch1 genetics, Skin metabolism, Skin Neoplasms genetics, Cancer-Associated Fibroblasts metabolism, Gene Amplification, Receptor, Notch1 metabolism, Skin Neoplasms metabolism
- Abstract
Cancer associated fibroblasts (CAFs) are a key component of the tumor microenvironment. Genomic alterations in these cells remain a point of contention. We report that CAFs from skin squamous cell carcinomas (SCCs) display chromosomal alterations, with heterogeneous NOTCH1 gene amplification and overexpression that also occur, to a lesser extent, in dermal fibroblasts of apparently unaffected skin. The fraction of the latter cells harboring NOTCH1 amplification is expanded by chronic UVA exposure, to which CAFs are resistant. The advantage conferred by NOTCH1 amplification and overexpression can be explained by NOTCH1 ability to block the DNA damage response (DDR) and ensuing growth arrest through suppression of ATM-FOXO3a association and downstream signaling cascade. In an orthotopic model of skin SCC, genetic or pharmacological inhibition of NOTCH1 activity suppresses cancer/stromal cells expansion. Here we show that NOTCH1 gene amplification and increased expression in CAFs are an attractive target for stroma-focused anti-cancer intervention.
- Published
- 2020
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14. Response by the author.
- Author
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Dotto GP
- Subjects
- Thermodynamics, Authorship
- Published
- 2020
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15. To be or not to be: The second law of thermodynamics and the flow of life and death.
- Author
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Dotto GP
- Subjects
- Thermodynamics
- Abstract
Hamlet's question is the artist's expression of the meaning of life. The second law of thermodynamics is the physicist's equivalent., (© 2020 The Author. Published under the terms of the CC BY 4.0 license.)
- Published
- 2020
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16. Conjectures, refutations and the search for truths: Science, symbolic truths and the devil.
- Author
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Dotto GP
- Abstract
In times of fake news, post-truths and post-science, the principles of science can inform all kinds of inquiries into the true nature of reality., (© 2020 The Author. Published under the terms of the CC BY 4.0 license.)
- Published
- 2020
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17. Gender medicine and oncology: report and consensus of an ESMO workshop.
- Author
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Wagner AD, Oertelt-Prigione S, Adjei A, Buclin T, Cristina V, Csajka C, Coukos G, Dafni U, Dotto GP, Ducreux M, Fellay J, Haanen J, Hocquelet A, Klinge I, Lemmens V, Letsch A, Mauer M, Moehler M, Peters S, and Özdemir BC
- Subjects
- Body Composition, Decision Making, Female, Humans, Male, Neoplasms genetics, Neoplasms pathology, Physicians, Treatment Outcome, Medical Oncology trends, Neoplasms epidemiology, Neoplasms therapy, Sex Characteristics
- Abstract
Background: The importance of sex and gender as modulators of disease biology and treatment outcomes is well known in other disciplines of medicine, such as cardiology, but remains an undervalued issue in oncology. Considering the increasing evidence for their relevance, European Society for Medical Oncology decided to address this topic and organized a multidisciplinary workshop in Lausanne, Switzerland, on 30 November and 1 December 2018., Design: Twenty invited faculty members and 40 selected physicians/scientists participated. Relevant content was presented by faculty members on the basis of a literature review conducted by each speaker. Following a moderated consensus session, the final consensus statements are reported here., Results: Clinically relevant sex differences include tumour biology, immune system activity, body composition and drug disposition and effects. The main differences between male and female cells are sex chromosomes and the level of sexual hormones they are exposed to. They influence both local and systemic determinants of carcinogenesis. Their effect on carcinogenesis in non-reproductive organs is largely unknown. Recent evidence also suggests differences in tumour biology and molecular markers. Regarding body composition, the difference in metabolically active, fat-free body mass is one of the most prominent: in a man and a woman of equal weight and height, it accounts for 80% of the man's and 65% of the woman's body mass, and is not taken into account in body-surface area based dosing of chemotherapy., Conclusion: Sex differences in cancer biology and treatment deserve more attention and systematic investigation. Interventional clinical trials evaluating sex-specific dosing regimens are necessary to improve the balance between efficacy and toxicity for drugs with significant pharmacokinetic differences. Especially in diseases or disease subgroups with significant differences in epidemiology or outcomes, men and women with non-sex-related cancers should be considered as biologically distinct groups of patients, for whom specific treatment approaches merit consideration., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2019
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18. Dualism of FGF and TGF-β Signaling in Heterogeneous Cancer-Associated Fibroblast Activation with ETV1 as a Critical Determinant.
- Author
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Bordignon P, Bottoni G, Xu X, Popescu AS, Truan Z, Guenova E, Kofler L, Jafari P, Ostano P, Röcken M, Neel V, and Dotto GP
- Subjects
- Animals, Carcinoma, Squamous Cell pathology, Cells, Cultured, Child, Preschool, Epithelial-Mesenchymal Transition, Female, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Skin Neoplasms pathology, Cancer-Associated Fibroblasts metabolism, Carcinoma, Squamous Cell metabolism, DNA-Binding Proteins metabolism, Fibroblast Growth Factors metabolism, Signal Transduction, Skin Neoplasms metabolism, Transcription Factors metabolism, Transforming Growth Factor beta metabolism
- Abstract
Heterogeneity of cancer-associated fibroblasts (CAFs) can result from activation of distinct signaling pathways. We show that in primary human dermal fibroblasts (HDFs), fibroblast growth factor (FGF) and transforming growth factor β (TGF-β) signaling oppositely modulate multiple CAF effector genes. Genetic abrogation or pharmacological inhibition of either pathway results in induction of genes responsive to the other, with the ETV1 transcription factor mediating the FGF effects. Duality of FGF/TGF-β signaling and differential ETV1 expression occur in multiple CAF strains and fibroblasts of desmoplastic versus non-desmoplastic skin squamous cell carcinomas (SCCs). Functionally, HDFs with opposite TGF-β versus FGF modulation converge on promoting cancer cell proliferation. However, HDFs with increased TGF-β signaling enhance invasive properties and epithelial-mesenchymal transition (EMT) of SCC cells, whereas HDFs with increased FGF signaling promote macrophage infiltration. The findings point to a duality of FGF versus TGF-β signaling in distinct CAF populations that promote cancer development through modulation of different processes., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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19. Sex Hormones and Anticancer Immunity.
- Author
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Özdemir BC and Dotto GP
- Subjects
- Breast Neoplasms metabolism, Breast Neoplasms therapy, Female, Humans, Immunotherapy methods, Male, Prostatic Neoplasms metabolism, Prostatic Neoplasms therapy, Antineoplastic Agents, Hormonal therapeutic use, B7-H1 Antigen antagonists & inhibitors, Breast Neoplasms immunology, Gonadal Steroid Hormones immunology, Immunity, Cellular, Prostatic Neoplasms immunology, Tumor Microenvironment immunology
- Abstract
The impact of sex hormones on anticancer immunity deserves attention due to the importance of the immune system in cancer therapy and the recognition of sex differences in immunity. Cancer is ultimately the result of failed immune surveillance, and the diverging effects of male and female sex hormones on anticancer immunity could contribute to the higher cancer incidence and poorer outcome in men. Estrogens and androgens affect the number and function of immune cells, an effect that depends on cell type, tumor microenvironment, and the age and reproductive status of the individual. Despite the recent progress in immuno-oncology, our current understanding of the interplay between sex hormones and anticancer immune responses is in its infancy. In this review, we will focus on the impact of sex hormones on anticancer immunity and immunotherapy. We will discuss the potential role of the changing hormone levels in anticancer immunity during aging and in the context of menopausal hormone therapies and oral contraception. We will review emerging data on sex differences in PD-L1 expression and potential biomarkers predictive for the efficacy of immune checkpoint inhibitors such as the microbiome and consider ongoing clinical trials evaluating the potential impact of hormone deprivation therapies to increase response to immune checkpoint inhibitors in breast and prostate cancer. Finally, we will point to areas of future research., (©2019 American Association for Cancer Research.)
- Published
- 2019
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20. Retraction Notice to: RhoE Is a Pro-Survival p53 Target Gene that Inhibits ROCK I-Mediated Apoptosis in Response to Genotoxic Stress.
- Author
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Ongusaha PP, Kim HG, Boswell SA, Ridley AJ, Der CJ, Dotto GP, Kim YB, Aaronson SA, and Lee SW
- Published
- 2019
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21. Gender and sex-time to bridge the gap.
- Author
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Dotto GP
- Subjects
- Brain growth & development, Chromosomes, Human, Y genetics, Female, Health, Hormones metabolism, Humans, Male, Sex Factors, Sex Characteristics
- Published
- 2019
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22. A role for stromal autophagy in cancer-associated fibroblast activation.
- Author
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Goruppi S, Clocchiatti A, and Dotto GP
- Subjects
- Fibroblasts, Humans, Signal Transduction, Tumor Microenvironment, Autophagy, Cancer-Associated Fibroblasts, Carcinoma, Squamous Cell
- Abstract
In the tumor stroma, cancer-associated fibroblasts (CAFs) affect all aspects of tumor evolution. Whereas several programs leading to CAF activation have been elucidated, little is known about the impact of the microenvironment on the turnover of key CAF regulators. RBPJ/CSL is a transcriptional repressor that mediates NOTCH signaling and its down-modulation activates the gene expression program(s) leading to stromal senescence and CAF activation. We overview our evidence that conditions increasing macroautophagy/autophagy, as often found in the stroma of tumors, cause the down-modulation of the RBPJ protein. This event requires the autophagic machinery and is functionally relevant because it is associated with an increase of CAF effector gene expression. The mechanism involves the direct association with the autophagy receptor SQSTM1/p62, which is required for RBPJ down-modulation. As a reflection of increased autophagy in the stroma, both the RBPJ and SQSTM1 proteins are down-modulated in Squamous Cell Carcinoma (SCC) patient-derived CAFs. Increasing RBPJ cellular levels stabilizes SQSTM1 and down-modulates the autophagic process. Our findings identify an autophagy-initiated mechanism for RBPJ down-modulation leading to increased CAF gene expression.
- Published
- 2019
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23. Androgen receptor functions as transcriptional repressor of cancer-associated fibroblast activation.
- Author
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Clocchiatti A, Ghosh S, Procopio MG, Mazzeo L, Bordignon P, Ostano P, Goruppi S, Bottoni G, Katarkar A, Levesque M, Kölblinger P, Dummer R, Neel V, Özdemir BC, and Dotto GP
- Subjects
- Animals, Cancer-Associated Fibroblasts pathology, Cell Line, Tumor, Female, Humans, Mice, Mice, Inbred NOD, Neoplasm Proteins genetics, Receptors, Androgen genetics, Repressor Proteins genetics, Skin Neoplasms genetics, Skin Neoplasms pathology, Cancer-Associated Fibroblasts metabolism, Neoplasm Proteins metabolism, Receptors, Androgen metabolism, Repressor Proteins metabolism, Skin Neoplasms metabolism, Transcriptional Activation
- Abstract
The aging-associated increase of cancer risk is linked with stromal fibroblast senescence and concomitant cancer-associated fibroblast (CAF) activation. Surprisingly little is known about the role of androgen receptor (AR) signaling in this context. We have found downmodulated AR expression in dermal fibroblasts underlying premalignant skin cancer lesions (actinic keratoses and dysplastic nevi) as well as in CAFs from the 3 major skin cancer types, squamous cell carcinomas (SCCs), basal cell carcinomas, and melanomas. Functionally, decreased AR expression in primary human dermal fibroblasts (HDFs) from multiple individuals induced early steps of CAF activation, and in an orthotopic skin cancer model, AR loss in HDFs enhanced tumorigenicity of SCC and melanoma cells. Forming a complex, AR converged with CSL/RBP-Jκ in transcriptional repression of key CAF effector genes. AR and CSL were positive determinants of each other's expression, with BET inhibitors, which counteract the effects of decreased CSL, restoring AR expression and activity in CAFs. Increased AR expression in these cells overcame the consequences of CSL loss and was by itself sufficient to block the growth and tumor-enhancing effects of CAFs on neighboring cancer cells. As such, the findings establish AR as a target for stroma-focused cancer chemoprevention and treatment.
- Published
- 2018
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24. Autophagy Controls CSL/RBPJκ Stability through a p62/SQSTM1-Dependent Mechanism.
- Author
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Goruppi S, Jo SH, Laszlo C, Clocchiatti A, Neel V, and Dotto GP
- Subjects
- Animals, Cell Line, Cells, Cultured, Down-Regulation, Fibroblasts metabolism, Humans, Immunoglobulin J Recombination Signal Sequence-Binding Protein genetics, Mice, Protein Binding, Protein Stability, Sequestosome-1 Protein genetics, Signal Transduction, Autophagy, Immunoglobulin J Recombination Signal Sequence-Binding Protein metabolism, Sequestosome-1 Protein metabolism, Skin Neoplasms metabolism
- Abstract
Cancer-associated fibroblasts (CAFs) are important at all tumor stages. CSL/RBPJκ suppresses the gene expression program leading to CAF activation and associated metabolic reprogramming, as well as autophagy. Little is known about CSL protein turnover, especially in the tumor microenvironment. We report that, in human dermal fibroblasts (HDFs), conditions inducing autophagy-often found in tumor stroma-down-regulate CSL protein levels but do not affect its mRNA levels. Genetic or pharmacologic targeting of the autophagic machinery blocks CSL down-modulation. Mechanistically, endogenous CSL associates with the autophagy and signaling adaptor p62/SQSTM1, which is required for CSL down-modulation by autophagy. This is functionally significant, because both CSL and p62 levels are lower in skin cancer-derived CAFs, in which autophagy is increased. Increasing cellular CSL levels stabilizes p62 and down-modulates the autophagic process. We reveal here an autophagy-initiated mechanism for CSL down-modulation, which could be targeted for stroma-focused cancer prevention and treatment., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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25. Sex Differences in Efficacy and Toxicity of Systemic Treatments: An Undervalued Issue in the Era of Precision Oncology.
- Author
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Özdemir BC, Csajka C, Dotto GP, and Wagner AD
- Subjects
- Female, Humans, Male, Medical Oncology, Antineoplastic Agents adverse effects, Precision Medicine, Sex Characteristics
- Published
- 2018
- Full Text
- View/download PDF
26. Notch-effector CSL promotes squamous cell carcinoma by repressing histone demethylase KDM6B.
- Author
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Al Labban D, Jo SH, Ostano P, Saglietti C, Bongiovanni M, Panizzon R, and Dotto GP
- Subjects
- Animals, Biomarkers, Tumor genetics, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell pathology, Cell Line, Tumor, Humans, Immunoglobulin J Recombination Signal Sequence-Binding Protein genetics, Jumonji Domain-Containing Histone Demethylases genetics, Keratinocytes metabolism, Keratinocytes pathology, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasm Proteins genetics, Neoplasms, Experimental genetics, Neoplasms, Experimental pathology, Receptors, Notch genetics, Receptors, Notch metabolism, Biomarkers, Tumor metabolism, Carcinoma, Squamous Cell metabolism, Immunoglobulin J Recombination Signal Sequence-Binding Protein metabolism, Jumonji Domain-Containing Histone Demethylases metabolism, Neoplasm Proteins metabolism, Neoplasms, Experimental metabolism, Signal Transduction
- Abstract
Notch 1/2 genes play tumor-suppressing functions in squamous cell carcinoma (SCC), a very common malignancy in skin and internal organs. In contrast with Notch, we show that the transcription factor CSL (also known as RBP-Jκ), a key effector of canonical Notch signaling endowed with intrinsic transcription-repressive functions, plays a tumor-promoting function in SCC development. Expression of this gene decreased in upper epidermal layers and human keratinocytes (HKCs) undergoing differentiation, while it increased in premalignant and malignant SCC lesions from skin, head/neck, and lung. Increased CSL levels enhanced the proliferative potential of HKCs and SCC cells, while silencing of CSL induced growth arrest and apoptosis. In vivo, SCC cells with increased CSL levels gave rise to rapidly expanding tumors, while cells with silenced CSL formed smaller and more differentiated tumors with enhanced inflammatory infiltrate. Global transcriptomic analysis of HKCs and SCC cells with silenced CSL revealed major modulation of apoptotic, cell-cycle, and proinflammatory genes. We also show that the histone demethylase KDM6B is a direct CSL-negative target, with inverse roles of CSL in HKC and SCC proliferative capacity, tumorigenesis, and tumor-associated inflammatory reaction. CSL/KDM6B protein expression could be used as a biomarker of SCC development and indicator of cancer treatment.
- Published
- 2018
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27. miR-181a decelerates proliferation in cutaneous squamous cell carcinoma by targeting the proto-oncogene KRAS.
- Author
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Neu J, Dziunycz PJ, Dzung A, Lefort K, Falke M, Denzler R, Freiberger SN, Iotzova-Weiss G, Kuzmanov A, Levesque MP, Dotto GP, and Hofbauer GFL
- Subjects
- Animals, Apoptosis, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell metabolism, Cell Differentiation, Cell Movement, Female, Humans, Mice, Mice, Nude, Proto-Oncogene Mas, Proto-Oncogene Proteins p21(ras) genetics, Signal Transduction, Skin metabolism, Skin Neoplasms genetics, Skin Neoplasms metabolism, Carcinoma, Squamous Cell pathology, Cell Proliferation, Gene Expression Regulation, Neoplastic, MicroRNAs genetics, Proto-Oncogene Proteins p21(ras) metabolism, Skin pathology, Skin Neoplasms pathology
- Abstract
Cutaneous squamous cell carcinoma (SCC) is the second most common human skin cancer with a rapidly increasing incidence among the Caucasian population. Among the many regulators, responsible for cancer progression and growth, microRNAs (miRNA) are generally accepted as key players by now. In our current study we found that microRNA-181a (miR-181a) shows low abundance in SCC compared to normal epidermal skin. In vitro, miRNA downregulation in normal primary keratinocytes induced increased proliferation, while in vivo miR-181a downregulation in HaCaT normal keratinocytes showed tumor-like growth increase up to 50%. Inversely, upregulation of these miRNAs in cancer cells lead to reduced cellular proliferation and induction of apoptosis in vitro. An in vivo therapeutic model with induced miR-181a expression in SCC13 cancer cells reduced tumor formation in mice by 80%. Modulation of miR-181a levels showed an inverse correlation with the proto-oncogene KRAS both on mRNA and protein level by direct interaction. Knockdown of KRAS mimicked the anti-proliferative effects of miR-181a overexpression in patient-derived SCC cells and abolished the enhanced viability of HaCaT cells following miR-181a knockdown. Furthermore, phospho-ERK levels correlated with KRAS levels, suggesting that the observed effects were mediated via the MAPK signaling pathway. miR-181a seemed regulated during keratinocyte differentiation probably in order to amplify the tumor suppressive character of differentiation. Taken together, miR-181a plays a crucial tumor suppressive role in SCC by targeting KRAS and could be a promising candidate for a miRNA based therapy.
- Published
- 2017
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28. The ULK3 Kinase Is Critical for Convergent Control of Cancer-Associated Fibroblast Activation by CSL and GLI.
- Author
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Goruppi S, Procopio MG, Jo S, Clocchiatti A, Neel V, and Dotto GP
- Subjects
- Animals, Autophagy physiology, Female, Fluorescent Antibody Technique, Humans, Immunoglobulin J Recombination Signal Sequence-Binding Protein metabolism, Mice, Protein Serine-Threonine Kinases genetics, Signal Transduction genetics, Zinc Finger Protein GLI1 genetics, Cancer-Associated Fibroblasts metabolism, Fibroblasts metabolism, Protein Serine-Threonine Kinases metabolism, Signal Transduction physiology, Zinc Finger Protein GLI1 metabolism
- Abstract
The connection between signaling pathways activating cancer-associated fibroblasts (CAFs) remains to be determined. Metabolic alterations linked to autophagy have also been implicated in CAF activation. CSL/RBPJ, a transcriptional repressor that mediates Notch signaling, suppresses the gene expression program(s), leading to stromal senescence and CAF activation. Deregulated GLI signaling can also contribute to CAF conversion. Here, we report that compromised CSL function depends on GLI activation for conversion of human dermal fibroblasts into CAFs, separately from cellular senescence. Decreased CSL upregulates the expression of the ULK3 kinase, which binds and activates GLI2. Increased ULK3 also induces autophagy, which is unlinked from GLI and CAF activation. ULK3 upregulation occurs in the CAFs of several tumor types, and ULK3 silencing suppresses the tumor-enhancing properties of these cells. Thus, ULK3 links two key signaling pathways involved in CAF conversion and is an attractive target for stroma-focused anti-cancer intervention., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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29. Convergent roles of ATF3 and CSL in chromatin control of cancer-associated fibroblast activation.
- Author
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Kim DE, Procopio MG, Ghosh S, Jo SH, Goruppi S, Magliozzi F, Bordignon P, Neel V, Angelino P, and Dotto GP
- Subjects
- Animals, Carcinoma, Squamous Cell physiopathology, Keratinocytes physiology, Mice, Mice, Inbred C57BL, Mice, Knockout, Skin Neoplasms physiopathology, Activating Transcription Factor 3 physiology, Cancer-Associated Fibroblasts physiology, Chromatin physiology, Muscle Proteins physiology
- Abstract
Cancer-associated fibroblasts (CAFs) are important for tumor initiation and promotion. CSL, a transcriptional repressor and Notch mediator, suppresses CAF activation. Like CSL, ATF3, a stress-responsive transcriptional repressor, is down-modulated in skin cancer stromal cells, and Atf3 knockout mice develop aggressive chemically induced skin tumors with enhanced CAF activation. Even at low basal levels, ATF3 converges with CSL in global chromatin control, binding to few genomic sites at a large distance from target genes. Consistent with this mode of regulation, deletion of one such site 2 Mb upstream of IL6 induces expression of the gene. Observed changes are of translational significance, as bromodomain and extra-terminal (BET) inhibitors, unlinking activated chromatin from basic transcription, counteract the effects of ATF3 or CSL loss on global gene expression and suppress CAF tumor-promoting properties in an in vivo model of squamous cancer-stromal cell expansion. Thus, ATF3 converges with CSL in negative control of CAF activation with epigenetic changes amenable to cancer- and stroma-focused intervention., (© 2017 Kim et al.)
- Published
- 2017
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30. CYFIP1 is directly controlled by NOTCH1 and down-regulated in cutaneous squamous cell carcinoma.
- Author
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Dziunycz PJ, Neu J, Lefort K, Djerbi N, Freiberger SN, Iotzova-Weiss G, French LE, Dotto GP, and Hofbauer GF
- Subjects
- Adaptor Proteins, Signal Transducing antagonists & inhibitors, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell metabolism, Cell Differentiation, Cell Line, Cell Movement drug effects, Chromatin Immunoprecipitation, Humans, Keratinocytes cytology, Keratinocytes metabolism, Promoter Regions, Genetic, Protein Binding, RNA Interference, RNA, Small Interfering metabolism, Signal Transduction drug effects, Skin Neoplasms genetics, Skin Neoplasms metabolism, Tamoxifen pharmacology, Transcription Factor HES-1 metabolism, Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Carcinoma, Squamous Cell physiopathology, Down-Regulation, Receptor, Notch1 metabolism, Skin Neoplasms physiopathology
- Abstract
Squamous cell carcinoma of the skin (SCC) represents one of the most common cancers in the general population and is associated with a substantial risk of metastasis. Previous work uncovered the functional role of CYFIP1 in epithelial tumors as an invasion inhibitor. It was down-regulated in some cancers and correlated with the metastatic properties of these malignant cells. We investigated its role and expression mechanisms in SCC. We analyzed the expression of CYFIP1 in patient derived SCC, primary keratinocytes and SCC cell lines, and correlated it to the differentiation and NOTCH1 levels. We analyzed the effects of Notch1 manipulation on CYFIP1 expression and confirmed the biding of Notch1 to the CYFIP1 promoter. CYFIP1 expression was down-regulated in SCC and correlated inversely with histological differentiation of tumors. As keratinocyte differentiation depends on Notch1 signaling, we investigated the influence of Notch1 on CYFIP1 expression. CYFIP1 mRNA was highly increased in human Notch1-overexpressing keratinocytes. Further manipulation of the Notch1 pathway in keratinocytes impacted CYFIP1 levels and chromatin immunoprecipitation assay confirmed the direct binding of Notch1 to the CYFIP1 promoter. CYFIP1 may be a link between loss of differentiation and invasive potential in malignant keratinocytes of cutaneous squamous cell carcinoma.
- Published
- 2017
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31. Racial Differences in Cancer Susceptibility and Survival: More Than the Color of the Skin?
- Author
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Özdemir BC and Dotto GP
- Subjects
- Asian genetics, Healthcare Disparities, Hispanic or Latino genetics, Humans, Neoplasms pathology, Social Class, White People genetics, Genetic Predisposition to Disease, Neoplasms epidemiology, Neoplasms genetics, Racial Groups genetics
- Abstract
Epidemiological studies point to race as a determining factor in cancer susceptibility. In US registries recording cancer incidence and survival by race (distinguishing 'black versus white'), individuals of African ancestry have a globally increased risk of malignancies compared with Caucasians and Asian Americans. Differences in socioeconomic status and health-care access play a key role. However, the lesser disease susceptibility of Hispanic populations with comparable lifestyles and socioeconomic status as African Americans (Hispanic paradox) points to the concomitant importance of genetic determinants. Here, we overview the molecular basis of racial disparity in cancer susceptibility ranging from genetic polymorphisms and cancer-driver gene mutations to obesity, chronic inflammation, and immune responses. We discuss implications for race-adapted cancer screening programs and clinical trials to reduce disparities in cancer burden., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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32. PDCD4 is a CSL associated protein with a transcription repressive function in cancer associated fibroblast activation.
- Author
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Jo SH, Kim DE, Clocchiatti A, and Dotto GP
- Subjects
- Animals, Apoptosis Regulatory Proteins genetics, Cancer-Associated Fibroblasts metabolism, Carcinoma, Squamous Cell genetics, Cell Line, Tumor, Cellular Senescence, Down-Regulation, HEK293 Cells, HeLa Cells, Humans, Keratosis, Actinic genetics, Mice, Mice, SCID, Protein Binding, RNA, Small Interfering genetics, RNA-Binding Proteins genetics, Signal Transduction, Skin Neoplasms genetics, Transcription, Genetic, Xenograft Model Antitumor Assays, Apoptosis Regulatory Proteins metabolism, Cancer-Associated Fibroblasts immunology, Carcinoma, Squamous Cell metabolism, Immunoglobulin J Recombination Signal Sequence-Binding Protein metabolism, Keratosis, Actinic metabolism, RNA-Binding Proteins metabolism, Skin Neoplasms metabolism
- Abstract
The Notch/CSL pathway plays an important role in skin homeostasis and carcinogenesis. CSL, the key effector of canonical Notch signaling endowed with an intrinsic transcription repressive function, suppresses stromal fibroblast senescence and Cancer Associated Fibroblast (CAF) activation through direct down-modulation of key effector genes. Interacting proteins that participate with CSL in this context are as yet to be identified. We report here that Programmed Cell Death 4 (PDCD4), a nuclear/cytoplasmic shuttling protein with multiple functions, associates with CSL and plays a similar role in suppressing dermal fibroblast senescence and CAF activation. Like CSL, PDCD4 is down-regulated in stromal fibroblasts of premalignant skin actinic keratosis (AKs) lesions and squamous cell carcinoma (SCC). While devoid of intrinsic DNA binding capability, PDCD4 is present at CSL binding sites of CAF marker genes as well as canonical Notch/CSL targets and suppresses expression of these genes in a fibroblast-specific manner. Thus, we propose that PDCD4 is part of the CSL repressive complex involved in negative control of stromal fibroblasts conversion into CAFs.
- Published
- 2016
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33. RhoE Is a Pro-Survival p53 Target Gene that Inhibits ROCK I-Mediated Apoptosis in Response to Genotoxic Stress.
- Author
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Ongusaha PP, Kim HG, Boswell SA, Ridley AJ, Der CJ, Dotto GP, Kim YB, Aaronson SA, and Lee SW
- Published
- 2016
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34. Dual tumor suppressing and promoting function of Notch1 signaling in human prostate cancer.
- Author
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Lefort K, Ostano P, Mello-Grand M, Calpini V, Scatolini M, Farsetti A, Dotto GP, and Chiorino G
- Subjects
- Aged, Carcinogenesis, Cell Differentiation physiology, Cell Line, Tumor, Cell Proliferation physiology, Genes, Tumor Suppressor, Humans, Male, Middle Aged, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Receptor, Notch1 genetics, Signal Transduction, Prostatic Neoplasms metabolism, Receptor, Notch1 metabolism
- Abstract
Adenocarcinomas of the prostate arise as multifocal heterogeneous lesions as the likely result of genetic and epigenetic alterations and deranged cell-cell communication. Notch signaling is an important form of intercellular communication with a role in growth/differentiation control and tumorigenesis. Contrasting reports exist in the literature on the role of this pathway in prostate cancer (PCa) development. We show here that i) compared to normal prostate tissue, Notch1 expression is significantly reduced in a substantial fraction of human PCas while it is unaffected or even increased in others; ii) acute Notch activation both inhibits and induces process networks associated with prostatic neoplasms; iii) down-modulation of Notch1 expression and activity in immortalized normal prostate epithelial cells increases their proliferation potential, while increased Notch1 activity in PCa cells suppresses growth and tumorigenicity through a Smad3-dependent mechanism involving p21WAF1/CIP1; iv) prostate cancer cells resistant to Notch growth inhibitory effects retain Notch1-induced upregulation of pro-oncogenic genes, like EPAS1 and CXCL6, also overexpressed in human PCas with high Notch1 levels. Taken together, these results reconcile conflicting data on the role of Notch1 in prostate cancer., Competing Interests: The authors declare that no conflicting financial interests exist.
- Published
- 2016
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35. Negative control of CSL gene transcription by stress/DNA damage response and p53.
- Author
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Menietti E, Xu X, Ostano P, Joseph JM, Lefort K, and Dotto GP
- Subjects
- Cell Line, Dermis cytology, Fibroblasts metabolism, Humans, Immunoglobulin J Recombination Signal Sequence-Binding Protein metabolism, Male, Mutagens toxicity, Oxidative Stress drug effects, Receptors, Notch metabolism, Signal Transduction genetics, DNA Damage genetics, Immunoglobulin J Recombination Signal Sequence-Binding Protein genetics, Oxidative Stress genetics, Transcription, Genetic, Tumor Suppressor Protein p53 metabolism
- Abstract
CSL is a key transcriptional repressor and mediator of Notch signaling. Despite wide interest in CSL, mechanisms responsible for its own regulation are little studied. CSL down-modulation in human dermal fibroblasts (HDFs) leads to conversion into cancer associated fibroblasts (CAF), promoting keratinocyte tumors. We show here that CSL transcript levels differ among HDF strains from different individuals, with negative correlation with genes involved in DNA damage/repair. CSL expression is negatively regulated by stress/DNA damage caused by UVA, Reactive Oxygen Species (ROS), smoke extract, and doxorubicin treatment. P53, a key effector of the DNA damage response, negatively controls CSL gene transcription, through suppression of CSL promoter activity and, indirectly, by increased p21 expression. CSL was previously shown to bind p53 suppressing its activity. The present findings indicate that p53, in turn, decreases CSL expression, which can serve to enhance p53 activity in acute DNA damage response of cells.
- Published
- 2016
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36. Squamous Cell Cancers: A Unified Perspective on Biology and Genetics.
- Author
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Dotto GP and Rustgi AK
- Subjects
- Alcohol Drinking adverse effects, Carcinoma, Squamous Cell etiology, Carcinoma, Squamous Cell therapy, Humans, Infections complications, Models, Genetic, Smoking adverse effects, Ultraviolet Rays adverse effects, Carcinoma, Squamous Cell genetics, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease genetics, Mutation
- Abstract
Squamous cell carcinomas (SCCs) represent the most frequent human solid tumors and are a major cause of cancer mortality. These highly heterogeneous tumors arise from closely interconnected epithelial cell populations with intrinsic self-renewal potential inversely related to the stratified differentiation program. SCCs can also originate from simple or pseudo-stratified epithelia through activation of quiescent cells and/or a switch in cell-fate determination. Here, we focus on specific determinants implicated in the development of SCCs by recent large-scale genomic, genetic, and epigenetic studies, and complementary functional analysis. The evidence indicates that SCCs from various body sites, while clinically treated as separate entities, have common determinants, pointing to a unified perspective of the disease and potential new avenues for prevention and treatment., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
37. Sexual dimorphism in cancer.
- Author
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Clocchiatti A, Cora E, Zhang Y, and Dotto GP
- Subjects
- Female, Gonadal Steroid Hormones metabolism, Humans, Male, Signal Transduction, Neoplasms physiopathology, Sex Characteristics
- Abstract
The incidence of many types of cancer arising in organs with non-reproductive functions is significantly higher in male populations than in female populations, with associated differences in survival. Occupational and/or behavioural factors are well-known underlying determinants. However, cellular and molecular differences between the two sexes are also likely to be important. In this Opinion article, we focus on the complex interplay that sex hormones and sex chromosomes can have in intrinsic control of cancer-initiating cell populations, the tumour microenvironment and systemic determinants of cancer development, such as the immune system and metabolism. A better appreciation of these differences between the two sexes could be of substantial value for cancer prevention as well as treatment.
- Published
- 2016
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- View/download PDF
38. CSL-p53: From senescence to CAF activation.
- Author
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Procopio MG, Laszlo C, and Dotto GP
- Subjects
- Cancer-Associated Fibroblasts pathology, Cell Cycle genetics, Cellular Senescence genetics, Epigenesis, Genetic genetics, Humans, Neoplasms pathology, Cancer-Associated Fibroblasts metabolism, Immunoglobulin J Recombination Signal Sequence-Binding Protein genetics, Neoplasms genetics, Tumor Suppressor Protein p53 genetics
- Published
- 2016
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- View/download PDF
39. Corrigendum: Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation.
- Author
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Procopio MG, Laszlo C, Al Labban D, Kim DE, Bordignon P, Jo SH, Goruppi S, Menietti E, Ostano P, Ala U, Provero P, Hoetzenecker W, Neel V, Kilarski WW, Swartz MA, Brisken C, Lefort K, and Dotto GP
- Published
- 2015
- Full Text
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40. Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation.
- Author
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Procopio MG, Laszlo C, Al Labban D, Kim DE, Bordignon P, Jo SH, Goruppi S, Menietti E, Ostano P, Ala U, Provero P, Hoetzenecker W, Neel V, Kilarski WW, Swartz MA, Brisken C, Lefort K, and Dotto GP
- Subjects
- Animals, Carcinoma, Squamous Cell pathology, Cell Line, Tumor, Cellular Senescence, Down-Regulation, Gene Expression Regulation, Neoplastic, Humans, Immunoglobulin J Recombination Signal Sequence-Binding Protein genetics, Mice, Receptors, Fibroblast Growth Factor metabolism, Signal Transduction, Skin Neoplasms pathology, Tumor Suppressor Protein p53 genetics, Carcinoma, Squamous Cell metabolism, Fibroblasts physiology, Immunoglobulin J Recombination Signal Sequence-Binding Protein metabolism, Skin Neoplasms metabolism, Tumor Suppressor Protein p53 metabolism
- Abstract
Stromal fibroblast senescence has been linked to ageing-associated cancer risk. However, density and proliferation of cancer-associated fibroblasts (CAFs) are frequently increased. Loss or downmodulation of the Notch effector CSL (also known as RBP-Jκ) in dermal fibroblasts is sufficient for CAF activation and ensuing keratinocyte-derived tumours. We report that CSL silencing induces senescence of primary fibroblasts from dermis, oral mucosa, breast and lung. CSL functions in these cells as a direct repressor of multiple senescence- and CAF-effector genes. It also physically interacts with p53, repressing its activity. CSL is downmodulated in stromal fibroblasts of premalignant skin actinic keratosis lesions and squamous cell carcinomas, whereas p53 expression and function are downmodulated only in the latter, with paracrine FGF signalling as the probable culprit. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances expression of CAF effectors and promotes stromal and cancer cell expansion. The findings support a CAF activation-stromal co-evolution model under convergent CSL-p53 control.
- Published
- 2015
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41. A novel Nrf2-miR-29-desmocollin-2 axis regulates desmosome function in keratinocytes.
- Author
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Kurinna S, Schäfer M, Ostano P, Karouzakis E, Chiorino G, Bloch W, Bachmann A, Gay S, Garrod D, Lefort K, Dotto GP, Beer HD, and Werner S
- Subjects
- Animals, Base Sequence, Cell Line, Tumor, Chromatin Immunoprecipitation, CpG Islands, DNA Methylation, Gene Expression Regulation, Gene Silencing, Homeostasis, Humans, Membrane Glycoproteins metabolism, Mice, Mice, Transgenic, Molecular Sequence Data, Skin metabolism, Desmocollins metabolism, Desmosomes metabolism, Keratinocytes cytology, MicroRNAs metabolism, NF-E2-Related Factor 2 metabolism
- Abstract
The Nrf2 transcription factor controls the expression of genes involved in the antioxidant defense system. Here, we identified Nrf2 as a novel regulator of desmosomes in the epidermis through the regulation of microRNAs. On Nrf2 activation, expression of miR-29a and miR-29b increases in cultured human keratinocytes and in mouse epidermis. Chromatin immunoprecipitation identified the Mir29ab1 and Mir29b2c genes as direct Nrf2 targets in keratinocytes. While binding of Nrf2 to the Mir29ab1 gene activates expression of miR-29a and -b, the Mir29b2c gene is silenced by DNA methylation. We identified desmocollin-2 (Dsc2) as a major target of Nrf2-induced miR-29s. This is functionally important, since Nrf2 activation in keratinocytes of transgenic mice causes structural alterations of epidermal desmosomes. Furthermore, the overexpression of miR-29a/b or knockdown of Dsc2 impairs the formation of hyper-adhesive desmosomes in keratinocytes, whereas Dsc2 overexpression has the opposite effect. These results demonstrate that a novel Nrf2-miR-29-Dsc2 axis controls desmosome function and cutaneous homeostasis.
- Published
- 2014
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42. The oncogene ATF3 is potentiated by cyclosporine A and ultraviolet light A.
- Author
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Dziunycz PJ, Lefort K, Wu X, Freiberger SN, Neu J, Djerbi N, Iotzowa-Weiss G, French LE, Dotto GP, and Hofbauer GFL
- Subjects
- Carcinoma, Squamous Cell etiology, Carcinoma, Squamous Cell pathology, Humans, Immunosuppressive Agents pharmacology, Keratinocytes cytology, Keratinocytes physiology, Keratinocytes radiation effects, NF-E2-Related Factor 2 metabolism, Neoplasms, Radiation-Induced pathology, Organ Culture Techniques, Organ Transplantation adverse effects, Primary Cell Culture, Reactive Oxygen Species metabolism, Skin pathology, Skin radiation effects, Skin Neoplasms etiology, Skin Neoplasms pathology, Tumor Cells, Cultured, Activating Transcription Factor 3 genetics, Carcinoma, Squamous Cell genetics, Cyclosporine pharmacology, Neoplasms, Radiation-Induced genetics, Skin Neoplasms genetics, Ultraviolet Rays adverse effects
- Abstract
Cutaneous squamous cell carcinoma (SCC) represents the most important cutaneous complication following organ transplantation. It develops mostly on sun-exposed areas. A recent study showed the role of activating transcription factor 3 (ATF3) in SCC development following treatment with calcineurin inhibitors. It has been reported that ATF3, which may act as an oncogene, is under negative calcineurin/nuclear factor of activated T cells (NFAT) control and is upregulated by calcineurin inhibitors. Still, these findings do not fully explain the preferential appearance of SCC on chronically sun-damaged skin. We analyzed the influence of UV radiation on ATF3 expression and its potential role in SCC development. We found that ATF3 is a specifically induced AP1 member in SCC of transplanted patients. Its expression was strongly potentiated by combination of cyclosporine A and UVA treatment. UVA induced ATF3 expression through reactive oxygen species-mediated nuclear factor erythroid 2-related factor 2 (NRF2) activation independently of calcineurin/NFAT inhibition. Activated NRF2 directly binds to ATF3 promoter, thus inducing its expression. These results demonstrate two mechanisms that independently induce and, when combined together, potentiate the expression of ATF3, which may then force SCC development. Taking into account the previously defined role of ATF3 in the SCC development, these findings may provide an explanation and a mechanism for the frequently observed burden on SCCs on sun-exposed areas of the skin in organ transplant recipients treated by calcineurin inhibitors.
- Published
- 2014
- Full Text
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43. Multifactorial ERβ and NOTCH1 control of squamous differentiation and cancer.
- Author
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Brooks YS, Ostano P, Jo SH, Dai J, Getsios S, Dziunycz P, Hofbauer GF, Cerveny K, Chiorino G, Lefort K, and Dotto GP
- Subjects
- Animals, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell pathology, Cell Line, Tumor, Estrogen Receptor beta genetics, Female, Genetic Loci, Head and Neck Neoplasms genetics, Head and Neck Neoplasms pathology, Heterografts, Humans, Lung Neoplasms genetics, Lung Neoplasms pathology, Male, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasm Proteins genetics, Neoplasm Transplantation, RNA Polymerase II genetics, RNA Polymerase II metabolism, Receptor, Notch1 genetics, Transcription, Genetic genetics, Carcinoma, Squamous Cell metabolism, Cell Differentiation, Estrogen Receptor beta metabolism, Gene Expression Regulation, Neoplastic, Head and Neck Neoplasms metabolism, Lung Neoplasms metabolism, Neoplasm Proteins metabolism, Receptor, Notch1 biosynthesis
- Abstract
Downmodulation or loss-of-function mutations of the gene encoding NOTCH1 are associated with dysfunctional squamous cell differentiation and development of squamous cell carcinoma (SCC) in skin and internal organs. While NOTCH1 receptor activation has been well characterized, little is known about how NOTCH1 gene transcription is regulated. Using bioinformatics and functional screening approaches, we identified several regulators of the NOTCH1 gene in keratinocytes, with the transcription factors DLX5 and EGR3 and estrogen receptor β (ERβ) directly controlling its expression in differentiation. DLX5 and ERG3 are required for RNA polymerase II (PolII) recruitment to the NOTCH1 locus, while ERβ controls NOTCH1 transcription through RNA PolII pause release. Expression of several identified NOTCH1 regulators, including ERβ, is frequently compromised in skin, head and neck, and lung SCCs and SCC-derived cell lines. Furthermore, a keratinocyte ERβ-dependent program of gene expression is subverted in SCCs from various body sites, and there are consistent differences in mutation and gene-expression signatures of head and neck and lung SCCs in female versus male patients. Experimentally increased ERβ expression or treatment with ERβ agonists inhibited proliferation of SCC cells and promoted NOTCH1 expression and squamous differentiation both in vitro and in mouse xenotransplants. Our data identify a link between transcriptional control of NOTCH1 expression and the estrogen response in keratinocytes, with implications for differentiation therapy of squamous cancer.
- Published
- 2014
- Full Text
- View/download PDF
44. Small GTPase RhoE/Rnd3 is a critical regulator of Notch1 signaling.
- Author
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Zhu Z, Todorova K, Lee KK, Wang J, Kwon E, Kehayov I, Kim HG, Kolev V, Dotto GP, Lee SW, and Mandinova A
- Subjects
- Active Transport, Cell Nucleus, Animals, Carcinoma, Squamous Cell chemistry, Cell Differentiation, Cells, Cultured, Female, Humans, Keratinocytes metabolism, Mice, Receptor, Notch1 analysis, Skin Neoplasms pathology, rho GTP-Binding Proteins analysis, rho GTP-Binding Proteins genetics, Carcinoma, Squamous Cell pathology, Receptor, Notch1 physiology, Signal Transduction physiology, rho GTP-Binding Proteins physiology
- Abstract
Aberrations of Notch signaling have been implicated in a variety of human cancers. Oncogenic mutations in NOTCH1 are common in human T-cell leukemia and lymphomas. However, loss-of-function somatic mutations in NOTCH1 arising in solid tumors imply a tumor suppressor function, which highlights the need to understand Notch signaling more completely. Here, we describe the small GTPase RhoE/Rnd3 as a downstream mediator of Notch signaling in squamous cell carcinomas (SCC) that arise in skin epithelia. RhoE is a transcriptional target of activated Notch1, which is attenuated broadly in SCC cells. RhoE depletion suppresses Notch1-mediated signaling in vitro, rendering primary keratinocytes resistant to Notch1-mediated differentiation and thereby favoring a proliferative cell fate. Mechanistic investigations indicated that RhoE controls a key step in Notch1 signaling by mediating nuclear translocation of the activated portion of Notch1 (N1IC) through interaction with importins. Our results define RhoE as a Notch1 target that is essential for recruitment of N1IC to the promoters of Notch1 target genes, establishing a regulatory feedback loop in Notch1 signaling. This molecular circuitry may inform distinct cell fate decisions to Notch1 in epithelial tissues, where carcinomas such as SCC arise., (©2014 AACR)
- Published
- 2014
- Full Text
- View/download PDF
45. Multifocal epithelial tumors and field cancerization: stroma as a primary determinant.
- Author
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Dotto GP
- Subjects
- Disease Progression, Epigenesis, Genetic, Epithelium pathology, Female, Fibroblasts pathology, Humans, Inflammation complications, Male, Mesenchymal Stem Cells pathology, Models, Biological, Neoplasm Recurrence, Local etiology, Neoplasms, Glandular and Epithelial physiopathology, Signal Transduction, Stromal Cells pathology, Neoplasms, Glandular and Epithelial etiology, Neoplasms, Glandular and Epithelial pathology
- Abstract
It is increasingly evident that cancer results from altered organ homeostasis rather than from deregulated control of single cells or groups of cells. This applies especially to epithelial cancer, the most common form of human solid tumors and a major cause of cancer lethality. In the vast majority of cases, in situ epithelial cancer lesions do not progress into malignancy, even if they harbor many of the genetic changes found in invasive and metastatic tumors. While changes in tumor stroma are frequently viewed as secondary to changes in the epithelium, recent evidence indicates that they can play a primary role in both cancer progression and initiation. These processes may explain the phenomenon of field cancerization, i.e., the occurrence of multifocal and recurrent epithelial tumors that are preceded by and associated with widespread changes of surrounding tissue or organ "fields."
- Published
- 2014
- Full Text
- View/download PDF
46. miR-34a/SIRT6 in squamous differentiation and cancer.
- Author
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Dotto GP and Karine L
- Subjects
- Humans, Carcinoma, Squamous Cell metabolism, Cell Differentiation physiology, Gene Expression Regulation, Neoplastic physiology, Keratinocytes physiology, MicroRNAs metabolism, Sirtuins metabolism
- Published
- 2014
- Full Text
- View/download PDF
47. Mesenchymal stroma: primary determinant and therapeutic target for epithelial cancer.
- Author
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Goruppi S and Dotto GP
- Subjects
- Animals, Autophagy, Cellular Senescence, Humans, Stromal Cells pathology, Mesoderm pathology, Molecular Targeted Therapy, Neoplasms, Glandular and Epithelial pathology, Neoplasms, Glandular and Epithelial therapy
- Abstract
Multifocal and recurrent epithelial tumors, originating from either dormant or de novo cancer cells, are major causes of morbidity and mortality. The age-dependent increase of cancer incidence has long been assumed to result from the sequential accumulation of cancer-driving or -facilitating mutations with induction of cellular senescence as a protective mechanism. However, recent evidence suggests that the initiation and development of epithelial cancer results from a close interplay with its altered tissue microenvironment, with chronic inflammation, stromal senescence, autophagy, and the activation of cancer-associated fibroblasts (CAFs) playing possible primary roles. We will discuss recent progress in these areas, and highlight how this understanding may be used for devising novel preventive and therapeutic approaches to the epithelial cancer problem., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
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- 2013
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48. A miR-34a-SIRT6 axis in the squamous cell differentiation network.
- Author
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Lefort K, Brooks Y, Ostano P, Cario-André M, Calpini V, Guinea-Viniegra J, Albinger-Hegyi A, Hoetzenecker W, Kolfschoten I, Wagner EF, Werner S, and Dotto GP
- Subjects
- Cell Differentiation radiation effects, DNA Primers genetics, Humans, Keratinocytes metabolism, Microarray Analysis, Real-Time Polymerase Chain Reaction, Receptor, Notch1 metabolism, Tumor Suppressor Protein p53 metabolism, Ultraviolet Rays, Carcinoma, Squamous Cell metabolism, Cell Differentiation physiology, Gene Expression Regulation, Neoplastic physiology, Keratinocytes physiology, MicroRNAs metabolism, Sirtuins metabolism
- Abstract
Squamous cell carcinomas (SCCs) are highly heterogeneous tumours, resulting from deranged expression of genes involved in squamous cell differentiation. Here we report that microRNA-34a (miR-34a) functions as a novel node in the squamous cell differentiation network, with SIRT6 as a critical target. miR-34a expression increases with keratinocyte differentiation, while it is suppressed in skin and oral SCCs, SCC cell lines, and aberrantly differentiating primary human keratinocytes (HKCs). Expression of this miRNA is restored in SCC cells, in parallel with differentiation, by reversion of genomic DNA methylation or wild-type p53 expression. In normal HKCs, the pro-differentiation effects of increased p53 activity or UVB exposure are miR-34a-dependent, and increased miR-34a levels are sufficient to induce differentiation of these cells both in vitro and in vivo. SIRT6, a sirtuin family member not previously connected with miR-34a function, is a direct target of this miRNA in HKCs, and SIRT6 down-modulation is sufficient to reproduce the miR-34a pro-differentiation effects. The findings are of likely biological significance, as SIRT6 is oppositely expressed to miR-34a in normal keratinocytes and keratinocyte-derived tumours.
- Published
- 2013
- Full Text
- View/download PDF
49. The retinoid-related orphan receptor RORα promotes keratinocyte differentiation via FOXN1.
- Author
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Dai J, Brooks Y, Lefort K, Getsios S, and Dotto GP
- Subjects
- Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell metabolism, Forkhead Transcription Factors metabolism, Gene Expression Regulation, Gene Expression Regulation, Neoplastic, Humans, Keratinocytes pathology, Protein Isoforms, Skin Neoplasms genetics, Skin Neoplasms metabolism, Cell Differentiation genetics, Forkhead Transcription Factors genetics, Keratinocytes cytology, Keratinocytes metabolism, Nuclear Receptor Subfamily 1, Group F, Member 1 genetics
- Abstract
RORα is a retinoid-related orphan nuclear receptor that regulates inflammation, lipid metabolism, and cellular differentiation of several non-epithelial tissues. In spite of its high expression in skin epithelium, its functions in this tissue remain unclear. Using gain- and loss-of-function approaches to alter RORα gene expression in human keratinocytes (HKCs), we have found that this transcription factor functions as a regulator of epidermal differentiation. Among the 4 RORα isoforms, RORα4 is prominently expressed by keratinocytes in a manner that increases with differentiation. In contrast, RORα levels are significantly lower in skin squamous cell carcinoma tumors (SCCs) and cell lines. Increasing the levels of RORα4 in HKCs enhanced the expression of structural proteins associated with early and late differentiation, as well as genes involved in lipid barrier formation. Gene silencing of RORα impaired the ability of keratinocytes to differentiate in an in vivo epidermal cyst model. The pro-differentiation function of RORα is mediated at least in part by FOXN1, a well-known pro-differentiation transcription factor that we establish as a novel direct target of RORα in keratinocytes. Our results point to RORα as a novel node in the keratinocyte differentiation network and further suggest that the identification of RORα ligands may prove useful for treating skin disorders that are associated with abnormal keratinocyte differentiation, including cancer.
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- 2013
- Full Text
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50. Gene profiling analysis of the early effects of ablative fractional carbon dioxide laser treatment on human skin.
- Author
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Kim JE, Won CH, Bak H, Kositratna G, Manstein D, Dotto GP, and Chang SE
- Subjects
- Carbon Dioxide, Collagen metabolism, Cysteine-Rich Protein 61 metabolism, Dermabrasion, HSP90 Heat-Shock Proteins metabolism, Humans, Matrix Metalloproteinases metabolism, Microscopy, Confocal, Proto-Oncogene Proteins metabolism, Tissue Array Analysis, Up-Regulation physiology, Wnt Proteins metabolism, Wnt-5a Protein, Laser Therapy methods, Skin radiation effects, Wound Healing physiology
- Abstract
Background: The use of carbon dioxide (CO2) laser-mediated ablative fractional resurfacing (AFR) is currently under extensive clinical investigation, but the molecular mechanisms underlying this process are unclear., Objectives: To determine the early expressed genes that are upregulated in human skin after treatment using a CO2 fractional laser., Methods: Whole human skin was irradiated using an AFR CO2 laser, and changes in gene expression after 2 and 24 hours were analyzed using microarray analysis. The results were validated using reverse transcriptase polymerase chain reaction (RT-PCR). Laser scanning confocal microscopy (LSCM) was used to investigate the expression of the validated proteins after AFR CO2 laser treatment of skin that had been biopsied from seven Korean patients., Results: Gene expression profiling showed that the most significantly upregulated genes in these skin samples were those encoding Wnt5a, cysteine-rich angiogenic inducer 61 (CYR61), and heat shock protein (HSP) 90. These results were confirmed using real-time RT-PCR and LSCM., Conclusions: Irradiation using an AFR laser may induce the expression of Wnt5a, CYR61, and HSP90 in human skin during the early remodeling phases, suggesting that the induction of proteins may be the preceding event that is associated with the clinical effects of laser treatment., (© 2013 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc.)
- Published
- 2013
- Full Text
- View/download PDF
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