FIRC Institute of Molecular Oncology IFOM

Milano, Italy

FIRC Institute of Molecular Oncology IFOM

Milano, Italy

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Esposito A.,Instituto Europeo Of Oncologia | Bardelli A.,University of Turin | Bardelli A.,IRCC Institute for Cancer Research and Treatment | Bardelli A.,FIRC Institute of Molecular Oncology IFOM | And 8 more authors.
Cancer Treatment Reviews | Year: 2014

Circulating cell-free DNA represents a non-invasive biomarker, as it can be isolated from human plasma, serum and other body fluids. Circulating tumor DNA shed from primary and metastatic cancers may allow the non-invasive analysis of the evolution of tumor genomes during treatment and disease progression through 'liquid biopsies'. The serial monitoring of tumor genotypes, which are instable and prone to changes under selection pressure, is becoming increasingly possible. The "liquid biopsy" provide novel biological insights into the process of metastasis and may elucidate signaling pathways involved in cell invasiveness and metastatic competence.This review will focus on the clinical utility of circulating cell free DNA in main solid tumors, including genetic and epigenetic alterations that can be detected. © 2013 Elsevier Ltd.

Ferrai C.,San Raffaele Scientific Institute | Ferrai C.,Imperial College London | Xie S.Q.,Imperial College London | Luraghi P.,San Raffaele Scientific Institute | And 8 more authors.
PLoS Biology | Year: 2010

The position of genes in the interphase nucleus and their association with functional landmarks correlate with active and/or silent states of expression. Gene activation can induce chromatin looping from chromosome territories (CTs) and is thought to require de novo association with transcription factories. We identify two types of factory: "poised transcription factories," containing RNA polymerase II phosphorylated on Ser5, but not Ser2, residues, which differ from "active factories" associated with phosphorylation on both residues. Using the urokinase-type plasminogen activator (uPA) gene as a model system, we find that this inducible gene is predominantly associated with poised (S5p+S2p-) factories prior to activation and localized at the CT interior. Shortly after induction, the uPA locus is found associated with active (S5p+S2p+) factories and loops out from its CT. However, the levels of gene association with poised or active transcription factories, before and after activation, are independent of locus positioning relative to its CT. RNA-FISH analyses show that, after activation, the uPA gene is transcribed with the same frequency at each CT position. Unexpectedly, prior to activation, the uPA loci internal to the CT are seldom transcriptionally active, while the smaller number of uPA loci found outside their CT are transcribed as frequently as after induction. The association of inducible genes with poised transcription factories prior to activation is likely to contribute to the rapid and robust induction of gene expression in response to external stimuli, whereas gene positioning at the CT interior may be important to reinforce silencing mechanisms prior to induction. © 2009 Ferrai et al.

Di Nicolantonio F.,University of Turin | Di Nicolantonio F.,IRCC Institute for Cancer Research and Treatment at Candiolo | Bardelli A.,University of Turin | Bardelli A.,IRCC Institute for Cancer Research and Treatment at Candiolo | Bardelli A.,FIRC Institute of Molecular Oncology IFOM
Clinical Cancer Research | Year: 2013

The development of effective therapies for colorectal cancer depends on the ability of preclinical models to faithfully recapitulate the molecular and biologic behavior of human tumors. This study reports on the characterization of colorectal genetically engineered mouse models and their derivative cell lines carrying wild-type or oncogenic Kras with concomitant Apc and p53 loss. ©2013 AACR.

Russo M.,University of Turin | Russo M.,Institute for Cancer Research and Treatment at Candiolo | Di Nicolantonio F.,University of Turin | Di Nicolantonio F.,Institute for Cancer Research and Treatment at Candiolo | And 3 more authors.
Cancer Discovery | Year: 2014

Mutations that activate the small GTP-binding protein KRAS are the most common oncogenic event in human tumors. Thirty years after its discovery, mutant KRAS has yet to be therapeutically conquered. © 2014 AACR.

Corada M.,FIRC Institute of Molecular Oncology IFOM | Orsenigo F.,FIRC Institute of Molecular Oncology IFOM | Morini M.F.,FIRC Institute of Molecular Oncology IFOM | Pitulescu M.E.,Max Planck Institute for Molecular Biomedicine | And 9 more authors.
Nature Communications | Year: 2013

The functional diversity of the arterial and venous endothelia is regulated through a complex system of signalling pathways and downstream transcription factors. Here we report that the transcription factor Sox17, which is known as a regulator of endoderm and hemopoietic differentiation, is selectively expressed in arteries, and not in veins, in the mouse embryo and in mouse postnatal retina and adult. Endothelial cell-specific inactivation of Sox17 in the mouse embryo is accompanied by a lack of arterial differentiation and vascular remodelling that results in embryo death in utero. In mouse postnatal retina, abrogation of Sox17 expression in endothelial cells leads to strong vascular hypersprouting, loss of arterial identity and large arteriovenous malformations. Mechanistically, Sox17 acts upstream of the Notch system and downstream of the canonical Wnt system. These data introduce Sox17 as a component of the complex signalling network that orchestrates arterial/venous specification. © 2013 Macmillan Publishers Limited. All rights reserved.

Van Emburgh B.O.,Candiolo Cancer Institute FPO | Van Emburgh B.O.,FIRC Institute of Molecular Oncology IFOM | Sartore-Bianchi A.,Niguarda Cancer Center | Di Nicolantonio F.,Candiolo Cancer Institute FPO | And 4 more authors.
Molecular Oncology | Year: 2014

Cetuximab and panitumumab are anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies used as therapies for metastatic colorectal cancer patients. Intrinsic mechanisms of resistance, such as RAS mutations, can prevent patients from having a response with clinical benefit. The clinical efficacy of EGFR targeted antibodies is limited by the development of acquired (secondary) resistance, which typically occurs within 3-12 months from the start of therapy. Preclinical models and analyses of clinical samples have uncovered some of the alterations that confer a selective advantage to tumor cells when under the pressure of anti-EGFR therapy. Molecular profiling of clinical specimens confirmed that genetic alterations of genes in the EGFR-RAS-RAF-MEK signaling pathway and of receptor tyrosine kinases are mechanisms of acquired resistance to anti-EGFR antibodies. The escape from anti-EGFR blockade appears to converge on the (re)activation of MEK-ERK or AKT as revealed in preclinical studies. Circulating tumor DNA and patient derived xenografts have proven useful tools to monitor patients for resistance to anti-EGFR therapy and test combination therapies to overcome or reverse resistance. © 2014 Published by Elsevier B.V.

Misale S.,University of Turin | Misale S.,Candiolo Cancer Institute FPO | Di Nicolantonio F.,University of Turin | Di Nicolantonio F.,Candiolo Cancer Institute FPO | And 5 more authors.
Cancer Discovery | Year: 2014

The EGFR-targeted antibodies cetuximab and panitumumab are used to treat metastatic colorectal cancers. Mutations in K RAS, N RAS, and B RAF and amplifi-cation of ERBB2 and MET drive primary (de novo) resistance to anti-EGFR treatment. Recently, the emergence of alterations in the same genes was detected in patients who responded to EGFR blockade and then relapsed. These results illuminate a striking overlap between genes that, when mutated, drive primary and secondary resistance to anti-EGFR antibodies. Remarkably, although the mechanisms of resistance are genetically heterogeneous, they biochemically converge on key signaling pathways. This knowledge is being translated in the rational design of additional lines of therapy.Significance: Anti-EGFR-targeted therapies are used for the treatment of metastatic colorectal cancer. Molecular heterogeneity impairs their efficacy by fuelling de novo and acquired resistance. In this review, we highlight how genetically distinct resistance mechanisms biochemically converge on a limited number of signaling pathways that can be therapeutically intercepted. © 2014 American Association for Cancer Research.

Siravegna G.,University of Turin | Siravegna G.,Candiolo Cancer Institute FPO | Bardelli A.,University of Turin | Bardelli A.,Candiolo Cancer Institute FPO | Bardelli A.,FIRC Institute of Molecular Oncology IFOM
Clinical Cancer Research | Year: 2014

A blood-based molecular test might direct recommendations for systemic therapies in patients with earlystage breast cancer undergoing surgery with curative intent. A new study suggests that droplet digital PCR (ddPCR) can be used to detect cancer-specific DNA alterations in plasma with sensitivity suitable for monitoring minimal residual disease. © 2014 American Association for Cancer Research.

Lamba S.,University of Turin | Lamba S.,Candiolo Cancer Institute FPO | Russo M.,University of Turin | Russo M.,Candiolo Cancer Institute FPO | And 12 more authors.
Cell Reports | Year: 2014

KRAS is the most frequently mutated oncogene in human cancer, yet no therapies are available to treat KRAS mutant cancers. We used two independent reverse genetic approaches to identify components of the RAS-signaling pathways required for growth of KRAS mutant tumors. Small interfering RNA (siRNA) screening of 37 KRAS mutant colorectal cancer cell lines showed that RAF1 suppression was synthetic lethal with MEK inhibition. An unbiased kinome short hairpin RNA (shRNA)-based screen confirmed this synthetic lethal interaction in colorectal as well as in lung cancer cells bearing KRAS mutations. Compounds targeting RAF kinases can reverse resistance to the MEK inhibitor selumetinib. MEK inhibition induces RAS activation and BRAF-RAF1 dimerization and sustains MEK-ERK signaling, which is responsible for intrinsic resistance to selumetinib. Prolonged dual blockade of RAF and MEK leads to persistent ERK suppression and efficiently induces apoptosis. Our data underlie the relevance of developing combinatorial regimens of drugs targeting the RAF-MEK pathway in KRAS mutant tumors. © 2014 The Authors.

Hobor S.,University of Turin | Van Emburgh B.O.,University of Turin | Crowley E.,University of Turin | Crowley E.,FIRC Institute of Molecular Oncology IFOM | And 3 more authors.
Clinical Cancer Research | Year: 2014

Purpose: Targeted inhibition of EGFR with the mAbs cetuximab or panitumumab is a valuable treatment for RAS wild-type colorectal cancers. The efficacy of EGFR blockade is limited by the emergence of acquired resistance often attributed to secondary KRAS mutations. Remarkably, tumor biopsies from resistant patients show that only a fraction of the resilient cells carry KRAS mutations. We hypothesized that a paracrine cross-talk driven by the resistant subpopulation may provide in trans protection of surrounding sensitive cells. Experimental design: Conditioned medium assays and three-dimensional cocultures were used to assess paracrine networks between cetuximab-sensitive and -resistant cells. Production of EGFR ligands by cells sensitive to cetuximab and panitumumab was measured. The ability of recombinant EGFR ligands to protect sensitive cells from cetuximab was assessed. Biochemical activation of the EGFR signaling pathway was measured by Western blotting.Results: Colorectal cancer cells sensitive to EGFR blockade can successfully grow despite cetuximab treatment when in the company of their resistant derivatives. Media conditioned by resistant cells protect sensitive parental cells from cetuximab. EGFR blockade triggers increased secretion of TGFa and amphiregulin. Increased secretion of ligands by resistant cells can sustain EGFR/ERK signaling in sensitive cells.Conclusions: Colorectal cancer cells that develop resistance to cetuximab and panitumumab secrete TGFa and amphiregulin, which protect the surrounding cells from EGFRblockade. This paracrine protective mechanism might be therapeutically exploitable. © 2014 AACR.

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