Institute of Oncology Research

Bellinzona, Switzerland

Institute of Oncology Research

Bellinzona, Switzerland
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Bujisic B.,University of Lausanne | De Gassart A.,University of Lausanne | Tallant R.,University of Lausanne | Demaria O.,University of Lausanne | And 6 more authors.
Blood | Year: 2017

The endoplasmic reticulum kinase inositol-requiring enzyme 1 (IRE1) and its downstream target X-box-binding protein 1 (XBP1) drive B-cell differentiation toward plasma cells and have been showntocontribute tomultiplemyeloma development; yet, little isknownofthe role of this pathway in diffuse large B-cell lymphoma (DLBCL). Here, we show that in the germinal center B-cell-like(GCB)DLBCL sub type, IRE1 expression is reduced to a level that prevents XBP1 activation. Gene expression profiles indicated that, in GCB DLBCL cancer samples, expression of IRE1 messenger RNA was inversely correlated with the levels and activity of the epigenetic repressor, histone methyltransferase enhancer of zestehomolog 2 (EZH2). Correspondingly, in GCB-derived cell lines, the IRE1 promoter carried increased levelsof the repressive epigenetic mark histone 3 lysine27 trimethylation. Pharmacological inhibition of EZH2 erased those marks and restored IRE1 expression and functioninvitro andinvivo. Moreover, reconstitutionofthe IRE1-signaling pathway,by expressionofthe XBP1-active form, compromised GCB DLBCL tumor growthinamouse xenograft cancer model. These findings indicatethat IRE1-XBP1 downregulation distinguishes GCB DLBCL from other DLBCL subtypes and contributes to tumor growth. © 2017 by The American Society of Hematology.

Valeri N.,University of Glasgow | Valeri N.,The Institute of Cancer Research | Braconi C.,University of Glasgow | Braconi C.,The Institute of Cancer Research | And 33 more authors.
Cancer Cell | Year: 2014

MicroRNA deregulation is frequent in human colorectal cancers (CRCs), but little is known as to whether itrepresents a bystander event or actually drives tumor progression invivo. We show that miR-135b overexpression is triggered in mice and humans by APC loss, PTEN/PI3K pathway deregulation, and SRC overexpression and promotes tumor transformation and progression. We show that miR-135b upregulation is common in sporadic and inflammatory bowel disease-associated human CRCs and correlates with tumor stage and poor clinical outcome. Inhibition of miR-135b in CRC mouse models reduces tumor growth by controlling genes involved in proliferation, invasion, and apoptosis. We identify miR-135b as a key downsteam effector of oncogenic pathways and a potential target for CRC treatment. © 2014 Elsevier Inc.

Agnelli L.,University of Milan | Mereu E.,University of Turin | Pellegrino E.,University of Turin | Limongi T.,University of Turin | And 17 more authors.
Blood | Year: 2012

Anaplastic large-cell lymphomas (ALCLs) are a group of clinically and biologically heterogeneous diseases including the ALK+ and ALK+ systemic forms. Whereas ALK+ ALCLs are molecularly characterized and can be readily diagnosed, specific immunophenotypic or genetic features to define ALK- ALCL are missing, and their distinction from other T-cell non-Hodgkin lymphomas (T-NHLs) remains controversial. In the present study, we undertook a transcriptional profiling meta-analysis of 309 cases, including ALCL and other primary T-NHL samples. Pathway discovery and prediction analyses defined a minimum set of genes capable of recognizing ALK- ALCL. Application of quantitative RT-PCR in independent datasets from cryopreserved and formalin-fixed paraffin-embedded samples validated a 3-gene model (TNFRSF8, BATF3, and TMOD1) able to successfully separate ALK- ALCL from peripheral T-cell lymphoma not otherwise specified, with overall accuracy near 97%. In conclusion, our data justify the possibility of translating quantitative RT-PCR protocols to routine clinical settings as a new approach to objectively dissect T-NHL and to select more appropriate therapeutic protocols. © 2012 by The American Society of Hematology.

Logarinho E.,University of Porto | Maffini S.,University of Porto | Maffini S.,Max Planck Institute of Molecular Physiology | Barisic M.,University of Porto | And 8 more authors.
Nature Cell Biology | Year: 2012

Loss of spindle-pole integrity during mitosis leads to multipolarity independent of centrosome amplification. Multipolar-spindle conformation favours incorrect kinetochore-microtubule attachments, compromising faithful chromosome segregation and daughter-cell viability. Spindle-pole organization influences and is influenced by kinetochore activity, but the molecular nature behind this critical force balance is unknown. CLASPs are microtubule-, kinetochore-and centrosome-associated proteins whose functional perturbation leads to three main spindle abnormalities: monopolarity, short spindles and multipolarity. The first two reflect a role at the kinetochore-microtubule interface through interaction with specific kinetochore partners, but how CLASPs prevent spindle multipolarity remains unclear. Here we found that human CLASPs ensure spindle-pole integrity after bipolarization in response to CENP-E-and Kid-mediated forces from misaligned chromosomes. This function is independent of end-on kinetochore-microtubule attachments and involves the recruitment of ninein to residual pericentriolar satellites. Distinctively, multipolarity arising through this mechanism often persists through anaphase. We propose that CLASPs and ninein confer spindle-pole resistance to traction forces exerted during chromosome congression, thereby preventing irreversible spindle multipolarity and aneuploidy. © 2012 Macmillan Publishers Limited. All rights reserved.

Boi M.,Institute of Oncology Research | Stathis A.,Oncology Institute of Southern Switzerland | Zucca E.,Oncology Institute of Southern Switzerland | Inghirami G.,University of Turin | And 3 more authors.
Cancer Science | Year: 2012

Mature (peripheral) T-cell and natural killer (NK)-cell lymphomas comprise a series of rather different neoplasms. Based on morphologic, immunophenotypic, genetic, and clinical data, the World Health Organization classification recognizes more than 20 entities or provisional entities. The variable clinical presentations, the objective recognition and pathological stratification, the difficulties regarding treatment, and the hardly predictable response to therapy indicate that the management of these entities requires novel tools. In contrast to B-cell lymphomas or precursor T-cell neoplasms, few recurrent translocations have been identified so far in T-cell non-Hodgkin's and NK-cell lymphomas. Additionally, some of the entities recognized by the World Health Organization classification are very rare and very scarce molecular data are available for T-cell lymphomas. Here, we have reviewed published reports focusing on the genetic lesions and gene expression profiling underlying systemic nodal and extranodal non-cutaneous mature T-cell and NK-cell lymphomas. We also provide a summary of new agents in clinical development and outline some future directions. © 2012 Japanese Cancer Association.

Rossi D.,University of Piemonte Orientale | Fangazio M.,University of Piemonte Orientale | Rasi S.,University of Piemonte Orientale | Vaisitti T.,University of Turin | And 24 more authors.
Blood | Year: 2012

The genetic lesions identified to date do not fully recapitulate the molecular pathogenesis of chronic lymphocytic leukemia (CLL) and do not entirely explain the development of severe complications such as chemorefractoriness. In the present study, BIRC3, a negative regulator of noncanonical NF-κB signaling, was investigated in different CLL clinical phases. BIRC3 lesions were absent in monoclonal B-cell lymphocytosis (0 of 63) and were rare in CLL at diagnosis (13 of 306, 4%). Conversely, BIRC3 disruption selectively affected 12 of 49 (24%) fludarabine-refractory CLL cases by inactivating mutations and/or gene deletions that distributed in a mutually exclusive fashion with TP53 abnormalities. In contrast to fludarabinerefractory CLL, progressive but fludarabine-sensitive patients were consistently devoid of BIRC3 abnormalities, suggesting that BIRC3 genetic lesions associate specifically with a chemorefractory phenotype. By actuarial analysis in newly diagnosed CLL (n ∇ 306), BIRC3 disruption identified patients with a poor outcome similar to that associated with TP53 abnormalities and exerted a prognostic role that was independent of widely accepted clinical and genetic risk factors. Consistent with the role of BIRC3 as a negative regulator of NF-κB, biochemical studies revealed the presence of constitutive noncanonical NF-κB activation in fludarabinerefractory CLL patients harboring molecular lesions of BIRC3. These data identify BIRC3 disruption as a recurrent genetic lesion of high-riskCLL devoid of TP53 abnormalities. © 2012 by The American Society of Hematology.

Roos M.,ETH Zurich | Rebhan M.A.E.,ETH Zurich | Lucic M.,ETH Zurich | Pavlicek D.,ETH Zurich | And 5 more authors.
Nucleic Acids Research | Year: 2015

MicroRNAs (miRNAs) originate from stem-loop-containing precursors (pre-miRNAs, pri-miRNAs) and mature by means of the Drosha and Dicer endonucleases and their associated factors. The let-7 miRNAs have prominent roles in developmental differentiation and in regulating cell proliferation. In cancer, the tumor suppressor function of let-7 is abrogated by overexpression of Lin28, one of several RNA-binding proteins that regulate let-7 biogenesis by interacting with conserved motifs in let-7 precursors close to the Dicer cleavage site. Using in vitro assays, we have identified a binding site for short modified oligoribonucleotides ('looptomirs') overlapping that of Lin28 in pre-let-7a-2. These looptomirs selectively antagonize the docking of Lin28, but still permit processing of pre-let-7a-2 by Dicer. Looptomirs restored synthesis of mature let-7 and inhibited growth and clonogenic potential in Lin28 overexpressing hepatocarcinoma cells, thereby demonstrating a promising new means to rescue defective miRNA biogenesis in Lin28-dependent cancers. © 2015 The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Civenni G.,Institute of Oncology Research | Civenni G.,Oncology Institute of Southern Switzerland | Malek A.,Institute of Oncology Research | Malek A.,Oncology Institute of Southern Switzerland | And 17 more authors.
Cancer Research | Year: 2013

Several studies link disease progression, recurrence, and treatment failures to the cancer stem-like cell (CSC) subpopulation within the heterogeneous tumor cell population. Myc is a transcription factor having a central function in stem cell biology and in human cancers. Hence, Myc represents an attractive target to develop CSC-specific therapies. Recent findings suggest that Myc transcription can be silenced using an RNA interference (RNAi)-based strategy that targets noncoding promoter-associated RNA (paRNA) overlapping the transcription start site. In this study, we investigated the effects of silencing Myc transcription on prostate CSC in cell culture and xenograft models of human prostate cancer. Treatment with an effective promotertargeting siRNA reduced the fraction of CSCs, leading to reduced self-renewal, tumor-initiating, and metastatic capability. Combined analysis of stem-like cells and senescence markers indicated that Myc silencing triggered a phenotypic shift and senescence in the CSC subpopulation. Notably, systemic delivery of the promoter-targeting siRNA in the xenograft model produced a striking suppression in the development of prostate tumors. Our results support a pivotal role for Myc in CSC maintenance and show that Myc targeting via RNAi-based transcriptional silencing can trigger CSC senescence and loss of their tumor-initiating capability. More generally, our findings demonstrate the efficacy of RNAi-based transcriptional strategies and the potential to target regulatory noncoding paRNAs for therapeutic applications. ©2013 AACR.

Napoli S.,Institute of Oncology Research
Methods in Molecular Biology | Year: 2013

The detailed analysis of noncoding RNA is an upcoming necessity due to a plethora of recently identified components of this class of molecules. The investigation of their structure, directionality, intracellular localization, interaction with other cellular elements is useful to understand the role they play in transcriptional regulation. In this chapter, we describe some techniques, meant to determine very important features of promoter-associated RNAs, in order to clarify their functionality. © Springer Science+Business Media, New York 2013.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of human lymphoma. DLBCL is a heterogeneous disease characterized by different genetic lesions. We herein report the functional characterization of a recurrent gain mapping on chromosome 11q24.3, found in 23% of 166 DLBCL cases analyzed. The transcription factors ETS1 and FLI1, located within the 11q24.3 region, had significantly higher expression in clinical samples carrying the gain. Functional studies on cell lines showed that ETS1 and FLI1 cooperate in sustaining DLBCL proliferation and viability and regulate genes involved in germinal center differentiation. Taken together, these data identify the 11q24.3 gain as a recurrent lesion in DLBCL leading to ETS1 and FLI1 deregulated expression, which can contribute to the pathogenesis of this disease.

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