73 results found
Ferrari N, Ranftl R, Chicherova I, et al., 2019, Dickkopf-3 links HSF1 and YAP/TAZ signalling to control aggressive behaviours in cancer-associated fibroblasts., Nat Commun, Vol: 10
Aggressive behaviours of solid tumours are highly influenced by the tumour microenvironment. Multiple signalling pathways can affect the normal function of stromal fibroblasts in tumours, but how these events are coordinated to generate tumour-promoting cancer-associated fibroblasts (CAFs) is not well understood. Here we show that stromal expression of Dickkopf-3 (DKK3) is associated with aggressive breast, colorectal and ovarian cancers. We demonstrate that DKK3 is a HSF1 effector that modulates the pro-tumorigenic behaviour of CAFs in vitro and in vivo. DKK3 orchestrates a concomitant activation of β-catenin and YAP/TAZ. Whereas β-catenin is dispensable for CAF-mediated ECM remodelling, cancer cell growth and invasion, DKK3-driven YAP/TAZ activation is required to induce tumour-promoting phenotypes. Mechanistically, DKK3 in CAFs acts via canonical Wnt signalling by interfering with the negative regulator Kremen and increasing cell-surface levels of LRP6. This work reveals an unpredicted link between HSF1, Wnt signalling and YAP/TAZ relevant for the generation of tumour-promoting CAFs.
Patten DK, Corleone G, Gyorffy B, et al., 2018, Enhancer mapping uncovers phenotypic heterogeneity and evolution in patients with luminal breast cancer, NATURE MEDICINE, Vol: 24, Pages: 1469-+, ISSN: 1078-8956
Ottaviani S, Stebbing J, Frampton AE, et al., 2018, TGF-beta induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progression, NATURE COMMUNICATIONS, Vol: 9, ISSN: 2041-1723
Ottaviani S, Stebbing J, Frampton A, et al., 2018, TGF-ß induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progression, Nature Communications, Vol: 9, ISSN: 2041-1723
TGF-ß/Activin induces epithelial-to-mesenchymal transition (EMT) and stemness in pancreatic ductal adenocarcinoma (PDAC). However, the microRNAs (miRNAs) regulated during this response have remained yet undetermined. Here, we show that TGF-ß transcriptionally induces MIR100HG lncRNA, containing miR-100, miR-125b and let-7a in its intron, via SMAD2/3. Interestingly, we find that although the pro-tumourigenic miR-100 and miR-125b accordingly increase, the amount of anti-tumourigenic let-7a is unchanged, as TGF-ß also induces LIN28B inhibiting its maturation. Notably, we demonstrate that inactivation of miR-125b or miR-100 affects the TGF-ß-mediated response indicating that these miRNAs are important TGF-ß effectors. We integrate AGO2-RIP-seq with RNA-seq to identify the global regulation exerted by these miRNAs in PDAC cells. Transcripts targeted by miR-125b and miR-100 significantly overlap and mainly inhibit p53 and cell-cell junctions’ pathways. Together, we uncover that TGF-ß induces an lncRNA, whose encoded miRNAs, miR-100, let-7a and miR-125b, play opposing roles in controlling PDAC tumourigenesis.
Noberini R, Osti D, Miccolo C, et al., 2018, Extensive and systematic rewiring of histone post-translational modifications in cancer model systems, NUCLEIC ACIDS RESEARCH, Vol: 46, Pages: 3817-3832, ISSN: 0305-1048
Patten DK, Corleone G, Magnani L, 2018, Chromatin Immunoprecipitation and High-Throughput Sequencing (ChIP-Seq): Tips and Tricks Regarding the Laboratory Protocol and Initial Downstream Data Analysis., Methods Mol Biol, Vol: 1767, Pages: 271-288
Chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) has become an essential tool for epigenetic scientists. ChIP-seq is used to map protein-DNA interactions and epigenetic marks such as histone modifications at the genome-wide level. Here we describe a complete ChIP-seq laboratory protocol (tailored toward processing tissue samples as well as cell lines) and the bioinformatic pipelines utilized for handling raw sequencing files through to peak calling.
Magnani L, Frigè G, Gadaleta RM, et al., 2017, Corrigendum: Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ERα metastatic breast cancer., Nat Genet, Vol: 49
Harrod A, Fulton J, Nguyen VTM, et al., 2017, Genomic modelling of the ESR1 Y537S mutation for evaluating function and new therapeutic approaches for metastatic breast cancer, ONCOGENE, Vol: 36, Pages: 2286-2296, ISSN: 0950-9232
Magnani L, Frige G, Gadaleta RM, et al., 2017, Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ER alpha metastatic breast cancer, NATURE GENETICS, Vol: 49, Pages: 444-450, ISSN: 1061-4036
, 2017, Fundamental pathways in breast cancer 3: Estrogen biology, Breast Cancer: Innovations in Research and Management, Pages: 19-26, ISBN: 9783319488486
© Springer International Publishing AG 2017. Over the last two decades, it has become evident that breast cancer should be considered as a family of diseases rather than as a unique malignancy. Pathological, molecular, and genetic analysis have revealed the existence of five to ten main subgroups [1-3]. Over 70% of all patients are generally classified by the tumor dependencies on estrogenic compounds . These dependencies are principally mediated by the nuclear receptor estrogen receptor a (ERa) [5, 6]. For all these reasons, ERa remains the key driver in the majority of breast cancers and is commonly used as a molecular biomarker for stratification while serving as the main target for systemic adjuvant chemotherapy. In this chapter I will discuss the molecular mechanisms of ERa activation focusing on integrative analysis that have recently exposed the intimate link between ERa and chromatin structure.
Patel H, Abduljabbar R, Lai C-F, et al., 2016, Expression of CDK7, Cyclin H, and MAT1 Is Elevated in Breast Cancer and Is Prognostic in Estrogen Receptor-Positive Breast Cancer, CLINICAL CANCER RESEARCH, Vol: 22, Pages: 5929-5938, ISSN: 1078-0432
Menyhart O, Harami-Papp H, Sukumar S, et al., 2016, Guidelines for the selection of functional assays to evaluate the hallmarks of cancer, BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER, Vol: 1866, Pages: 300-319, ISSN: 0304-419X
Hong SP, Lombardo Y, Corleone G, et al., 2016, Epigenetic plasticity identifies seed breast cancer cells driving drug resistance and metastatic progression, UK Breast Cancer Research Symposium, Publisher: SPRINGER, Pages: 191-191, ISSN: 0167-6806
Bhat-Nakshatri P, Goswami CP, Badve S, et al., 2016, Molecular Insights of Pathways Resulting from Two Common PIK3CA Mutations in Breast Cancer, CANCER RESEARCH, Vol: 76, Pages: 3989-4001, ISSN: 0008-5472
Perone Y, Magnani L, 2016, Going off the grid: ER alpha breast cancer beyond estradiol, JOURNAL OF MOLECULAR ENDOCRINOLOGY, Vol: 57, Pages: F1-F5, ISSN: 0952-5041
Chen X, Jung J-G, Shajahan-Haq AN, et al., 2016, ChIP-BIT: Bayesian inference of target genes using a novel joint probabilistic model of ChIP-seq profiles, NUCLEIC ACIDS RESEARCH, Vol: 44, ISSN: 0305-1048
Zhang Y, Clausmeyer J, Babakinejad B, et al., 2016, Spearhead Nanometric Field-Effect Transistor Sensors for Single-Cell Analysis, ACS NANO, Vol: 10, Pages: 3214-3221, ISSN: 1936-0851
Nguyen VTM, Barozzi I, Faronato M, et al., 2015, Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion, NATURE COMMUNICATIONS, Vol: 6, ISSN: 2041-1723
Periyasamy M, Patel H, Lai C-F, et al., 2015, APOBEC3B-Mediated Cytidine Deamination Is Required for Estrogen Receptor Action in Breast Cancer, CELL REPORTS, Vol: 13, Pages: 108-121, ISSN: 2211-1247
Faronato M, Nguyen VTM, Patten DK, et al., 2015, DMXL2 drives epithelial to mesenchymal transition in hormonal therapy resistant breast cancer through notch hyper-activation, ONCOTARGET, Vol: 6, Pages: 22467-22479, ISSN: 1949-2553
Magnani L, Patten DK, Nguyen VTM, et al., 2015, The pioneer factor PBX1 is a novel driver of metastatic progression in ER'-positive breast cancer, ONCOTARGET, Vol: 6, Pages: 21878-21891, ISSN: 1949-2553
Xu Y, Zhang H, Van TMN, et al., 2015, LMTK3 represses tumor suppressor-like genes through chromatin remodeling in breast cancer, Cell Reports, Vol: 12, Pages: 837-849, ISSN: 2211-1247
LMTK3 is an oncogenic receptor tyrosine kinase (RTK) implicated in various types of cancer, including breast, lung, gastric, and colorectal cancer. It is localized in different cellular compartments, but its nuclear function has not been investigated so far. We mapped LMTK3 binding across the genome using ChIP-seq and found that LMTK3 binding events are correlated with repressive chromatin markers. We further identified KRAB-associated protein 1 (KAP1) as a binding partner of LMTK3. The LMTK3/KAP1 interaction is stabilized by PP1α, which suppresses KAP1 phosphorylation specifically at LMTK3-associated chromatin regions, inducing chromatin condensation and resulting in transcriptional repression of LMTK3-bound tumor suppressor-like genes. Furthermore, LMTK3 functions at distal regions in tethering the chromatin to the nuclear periphery, resulting in H3K9me3 modification and gene silencing. In summary, we propose a model where a scaffolding function of nuclear LMTK3 promotes cancer progression through chromatin remodeling.
Nakshatri H, Goswami C, Badve S, et al., 2015, Divergent activation of AKT1 and AKT2 isoforms downstream of PI3K mutation impacts response of breast cancer cells to estradiol and PI3K inhibitors, 37th Annual CTRC-AACR San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Varghese V, Magnani L, Harada N, et al., 2015, Inhibition of FOXM1 by thiostrepton increases sensitivity to 5-fluorouracil (5-FU) by downregulating thymidylate synthase (TS) in colorectal cancer, AACR Precision Medicine Conference on Drug Sensitivity and Resistance - Improving Cancer Therapy, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 1078-0432
Okamoto OK, Matheu A, Magnani L, 2015, Stem Cells in Translational Cancer Research, STEM CELLS INTERNATIONAL, ISSN: 1687-966X
, 2015, Histone Posttranslational Modifications in Breast Cancer and Their Use in Clinical Diagnosis and Prognosis, Epigenetic Biomarkers and Diagnostics, Pages: 467-477, ISBN: 9780128019214
© 2016 Elsevier Inc. All rights reserved. Epigenetic regulation plays a key role in normal physiology and disease. In breast cancer, multiple epigenetic regulators have been found to be causally involved in tumorigenesis and treatment resistance. Since treatment resistance in breast cancer is commonly observed, epigenetic modifiers may represent promising targets for pharmaceutical intervention. Multiple epigenetic modifiers are currently being targeted in clinical trials with varying success rates. Yet, biological roles of epigenetic modifiers are complex and lack tissue specificity, which may diminish any therapeutic window. Is epigenetic profiling the "new black" of biomarker discovery in breast cancer? and would epigenetic drugs yield the new "silver bullet" in breast cancer treatment, or are we dealing with a "red herring"?
Brown R, Curry E, Magnani L, et al., 2014, Poised epigenetic states and acquired drug resistance in cancer, NATURE REVIEWS CANCER, Vol: 14, Pages: 747-753, ISSN: 1474-175X
Jangal M, Couture J-P, Bianco S, et al., 2014, The transcriptional co-repressor TLE3 suppresses basal signaling on a subset of estrogen receptor alpha target genes, NUCLEIC ACIDS RESEARCH, Vol: 42, Pages: 11339-11348, ISSN: 0305-1048
Varghese V, Magnani L, Harada N, et al., 2014, Forkhead box transciption factor M1 (FOXM1) plays a critical role in colorectal cancer resistance by regulating thymidylate synthase (TS), 105th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Gadaleta RM, Magnani L, 2014, Nuclear receptors and chromatin: an inducible couple, JOURNAL OF MOLECULAR ENDOCRINOLOGY, Vol: 52, Pages: R137-R149, ISSN: 0952-5041
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