The FIRC Institute for Molecular Oncology Foundation

Milano, Italy

The FIRC Institute for Molecular Oncology Foundation

Milano, Italy
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Segrey C.V.,Italian National Cancer Institute | Senesey S.,Italian National Cancer Institute | Senesey S.,University of California at Los Angeles | Lopontey S.,Italian National Cancer Institute | And 10 more authors.
mAbs | Year: 2016

Histone deacetylases (HDACs) are modification enzymes that regulate a plethora of biological processes. HDAC1, a crucial epigenetic modifier, is deregulated in cancer and subjected to a variety of post-translational modifications. Here, we describe the generation of a new monoclonal antibody that specifically recognizes a novel highly dynamic prophase phosphorylation of serine 406-HDAC1, providing a powerful tool for detecting early mitotic cells. © 2016 Taylor and Francis Group, LLC.


Bianchi F.,The FIRC Institute for Molecular Oncology Foundation | Bianchi F.,University of Milan | Nicassio F.,The FIRC Institute for Molecular Oncology Foundation | Marzi M.,The FIRC Institute for Molecular Oncology Foundation | And 9 more authors.
EMBO Molecular Medicine | Year: 2011

Lung cancer is the first cause of cancer mortality worldwide, and its early detection is currently the main available strategy to improve disease prognosis. While early diagnosis can be successfully achieved through tomography-based population screenings in high-risk individuals, simple methodologies are needed for effective cancer prevention programs. We developed a test, based on the detection of 34 microRNAs (miRNAs) from serum, that could identify patients with early stage non-small cell lung carcinomas (NSCLCs) in a population of asymptomatic high-risk individuals with 80% accuracy. The signature could assign disease probability accurately either in asymptomatic or symptomatic patients, is able to distinguish between benign and malignant lesions, and to capture the onset of the malignant disease in individual patients over time. Thus, our test displays a number of features of clinical relevance that project its utility in programs for the early detection of NSCLC. © 2011 EMBO Molecular Medicine.


Hosono Y.,Tohoku University | Abe T.,The FIRC Institute for Molecular Oncology Foundation | Ishiai M.,Kyoto University | Takata M.,Kyoto University | And 2 more authors.
Biochemical and Biophysical Research Communications | Year: 2011

DNA double strand breaks (DSBs) induced by etoposide, an inhibitor of DNA topoisomerase II, are repaired mainly by non-homologous end joining (NHEJ). Unexpectedly, it was found that at high doses of etoposide, proteins involved in NHEJ, such as KU70/80, DNA-PKcs and ARTEMIS/SNM1C, trigger apoptosis rather than repair of DSBs. Because ARTEMIS is a member of the SNM1 protein family that includes SNM1A and APOLLO/SNM1B, this study examined whether SNM1A and/or APOLLO are also involved in etoposide-induced apoptosis. Using SNM1A-/- and APOLLO-/- cells, it was found that both SNM1A and APOLLO participate in etoposide-induced apoptosis. Although cell viability monitored by MTT assay did not differ between SNM1A-/-/. APOLLO-/-/. ARTEMIS-/-, SNM1A-/-/. APOLLO-/-, and single gene knockout cells, DNA fragmentation monitored by TUNEL assay differed between these cells, suggesting that the three SNM1 family nucleases function independently, at least during the induction of apoptotic DNA fragmentation. © 2011 Elsevier Inc.


PubMed | University of Turin, the FIRC Institute for Molecular Oncology Foundation and University of Milan Bicocca
Type: Journal Article | Journal: Journal of pharmaceutical sciences | Year: 2016

Surface functionalization with antitransferrin receptor (TfR) mAbs has been suggested as the strategy to enhance the transfer of nanoparticles (NPs) across the blood-brain barrier (BBB) and to carry nonpermeant drugs from the blood into the brain. However, the efficiency of BBB crossing is currently too poor to be used in vivo. In the present investigation, we compared 6 different murine mAbs specific for different epitopes of the human TfR to identify the best performing one for the functionalization of NPs. For this purpose, we compared the ability of mAbs to cross an in vitro BBB model made of human brain capillary endothelial cells (hCMEC/D3). Liposomes functionalized with the best performing mAb (MYBE/4C1) were uptaken, crossed the BBB in vitro, and facilitated the BBB in vitro passage of doxorubicin, an anticancer drug, 3.9 folds more than liposomes functionalized with a nonspecific IgG, as assessed by confocal microscopy, radiochemical techniques, and fluorescence, and did not modify the cell monolayer structural or functional properties. These results show that MYBE/4C1 antihuman TfR mAb is a powerful resource for the enhancement of BBB crossing of NPs and is therefore potentially useful in the treatment of neurologic diseases and disorders including brain carcinomas.


Peleg B.,Weizmann Institute of Science | Disanza A.,The FIRC Institute for Molecular Oncology Foundation | Scita G.,The FIRC Institute for Molecular Oncology Foundation | Scita G.,University of Milan | Gov N.,Weizmann Institute of Science
PLoS ONE | Year: 2011

Cells exhibit propagating membrane waves which involve the actin cytoskeleton. One type of such membranal waves are Circular Dorsal Ruffles (CDR) which are related to endocytosis and receptor internalization. Experimentally, CDRs have been associated with membrane bound activators of actin polymerization of concave shape. We present experimental evidence for the localization of convex membrane proteins in these structures, and their insensitivity to inhibition of myosin II contractility in immortalized mouse embryo fibroblasts cell cultures. These observations lead us to propose a theoretical model which explains the formation of these waves due to the interplay between complexes that contain activators of actin polymerization and membrane-bound curved proteins of both types of curvature (concave and convex). Our model predicts that the activity of both types of curved proteins is essential for sustaining propagating waves, which are abolished when one type of curved activator is removed. Within this model waves are initiated when the level of actin polymerization induced by the curved activators is higher than some threshold value, which allows the cell to control CDR formation. We demonstrate that the model can explain many features of CDRs, and give several testable predictions. This work demonstrates the importance of curved membrane proteins in organizing the actin cytoskeleton and cell shape. © 2011 Peleg et al.


PubMed | Fondazione IRCCS Institute of Neurology Carlo Besta, The FIRC Institute for Molecular Oncology Foundation and Ecole Polytechnique Federale de Lausanne
Type: Journal Article | Journal: Nanomedicine (London, England) | Year: 2015

The use of nanotechnology for drug delivery in cancer therapy has raised high expectations. Additionally, the use of nanomaterials in sensors to extract and detect tumor specific biomarkers, circulating tumor cells, or extracellular vesicles shed by the tumor holds the promise to detect cancer much earlier and hence improve long-term survival of the patients. Moreover, the monitoring of the anticancer drug concentration, which has a narrow therapeutic window, will allow for a personalized dosing of the drug and will lead to improved therapeutic outcome and life quality of the patient. This review will provide an overview on the use of nanosensors for the early diagnosis of cancer and for the therapeutic drug monitoring, giving some examples. We envision nanosensors to make significant improvements in the cancer management as easy-to-use point-of-care devices for a broad population of users.


PubMed | Osaka University, the FIRC Institute for Molecular Oncology Foundation, Chromosome Dynamics Group and University of Tokyo
Type: Journal Article | Journal: Oncotarget | Year: 2016

Replication fork-associated factors promote genome integrity and protect against cancer. Mutations in the DDX11 helicase and the ESCO2 acetyltransferase also cause related developmental disorders classified as cohesinopathies. Here we generated vertebrate model cell lines of these disorders and cohesinopathies-related genes. We found that vertebrate DDX11 and Tim-Tipin are individually needed to compensate for ESCO2 loss in chromosome segregation, with DDX11 also playing complementary roles with ESCO2 in centromeric cohesion. Our study reveals that overt centromeric cohesion loss does not necessarily precede chromosome missegregation, while both these problems correlate with, and possibly originate from, inner-centromere defects involving reduced phosphorylation of histone H3T3 (pH3T3) in the region. Interestingly, the mitotic pH3T3 mark was defective in all analyzed replication-related mutants with functions in cohesion. The results pinpoint mitotic pH3T3 as a postreplicative chromatin mark that is sensitive to replication stress and conducts with different kinetics to robust centromeric cohesion and correct chromosome segregation.


Conte A.,The FIRC Institute for Molecular Oncology Foundation | Sigismund S.,The FIRC Institute for Molecular Oncology Foundation
Progress in Molecular Biology and Translational Science | Year: 2016

Epidermal growth factor receptor (EGFR)-dependent signaling is involved in many physiological processes, and its deregulation leads to cellular dysfunctions and pathologies, of which cancer tops the list.Ubiquitin is the major determinant of EGFR fate all along the endocytic pathway, directly controlling EGFR signaling output. Indeed, the EGFR-ubiquitin network is often hijacked by cancer cells in order to have a proliferative advantage.In this chapter, we will review the different steps of EGFR activation and signal propagation, starting from the plasma membrane all the way down to the endosomal station, with a particular focus on the role of the ubiquitin system in controlling the balance between signal sustaining and downmodulation. © 2016.


Abe T.,The FIRC Institute for Molecular Oncology Foundation | Branzei D.,The FIRC Institute for Molecular Oncology Foundation
DNA Repair | Year: 2014

Transient induction or suppression of target genes is useful to study the function of toxic or essential genes in cells. Here we apply a Tet-On 3G system to DT40 lymphoma B cell lines, validating it for three different genes. Using this tool, we then show that overexpression of the chicken BRC4 repeat of the tumor suppressor BRCA2 impairs cell proliferation and induces chromosomal breaks. Mechanistically, high levels of BRC4 suppress double strand break-induced homologous recombination, inhibit the formation of RAD51 recombination repair foci, reduce cellular resistance to DNA damaging agents and induce a G2 damage checkpoint-mediated cell-cycle arrest. The above phenotypes are mediated by BRC4 capability to bind and inhibit RAD51. The toxicity associated with BRC4 overexpression is exacerbated by chemotherapeutic agents and reversed by RAD51 overexpression, but it is neither aggravated nor suppressed by a deficit in the non-homologous end-joining pathway of double strand break repair. We further find that the endogenous BRCA2 mediates the cytotoxicity associated with BRC4 induction, thus underscoring the possibility that BRC4 or other domains of BRCA2 cooperate with ectopic BRC4 in regulating repair activities or mitotic cell division. In all, the results demonstrate the utility of the Tet-On 3G system in DT40 research and underpin a model in which BRC4 role on cell proliferation and chromosome repair arises primarily from its suppressive role on RAD51 functions. © 2014 The Authors.


PubMed | The FIRC Institute for Molecular Oncology Foundation
Type: Evaluation Studies | Journal: EMBO molecular medicine | Year: 2011

Lung cancer is the first cause of cancer mortality worldwide, and its early detection is currently the main available strategy to improve disease prognosis. While early diagnosis can be successfully achieved through tomography-based population screenings in high-risk individuals, simple methodologies are needed for effective cancer prevention programs. We developed a test, based on the detection of 34 microRNAs (miRNAs) from serum, that could identify patients with early stage non-small cell lung carcinomas (NSCLCs) in a population of asymptomatic high-risk individuals with 80% accuracy. The signature could assign disease probability accurately either in asymptomatic or symptomatic patients, is able to distinguish between benign and malignant lesions, and to capture the onset of the malignant disease in individual patients over time. Thus, our test displays a number of features of clinical relevance that project its utility in programs for the early detection of NSCLC.

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