FIRC Institute of Molecular Oncology IFOM

Milano, Italy

FIRC Institute of Molecular Oncology IFOM

Milano, Italy
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Uhler C.,Massachusetts Institute of Technology | Shivashankar G.V.,National University of Singapore | Shivashankar G.V.,FIRC Institute of Molecular Oncology IFOM
Trends in Cell Biology | Year: 2017

Cells sense physical and chemical signals from their local microenvironment and transduce them to the nucleus to regulate genomic programs. In this review, we first discuss different modes of mechanotransduction to the nucleus. We then highlight the role of the spatial organization of chromosomes for integrating these signals. In particular, we emphasize the importance of chromosome intermingling for gene regulation. We also discuss various geometric models and recent advances in microscopy and genomics that have allowed access to these nanoscale chromosome intermingling regions. Taken together, the recent work summarized in this review culminates in the hypothesis that chromosome intermingling regions are mechanical hotspots for genome regulation. Maintenance of such mechanical hotspots is crucial for cellular homeostasis, and alterations in them could be precursors for various cellular reprogramming events, including diseases. Microenvironment signals are transmitted to the cell nucleus via both physical and biochemical intermediates.The spatial organization of chromosomes is critical to regulating microenvironmental control of gene expression.Intermingling regions between chromosomes are enriched with transcription factors and RNA Pol II.The functional clustering of genes is modulated by microenvironmental signals to exhibit differential gene expression programs. © 2017 Elsevier Ltd.

Pierotti M.A.,FIRC Institute of Molecular Oncology IFOM | Pierotti M.A.,Foundation IRP Citta della Speranza
ecancermedicalscience | Year: 2017

The beginning of our understanding of the molecular basis of cancer and the discovery in the 1980s of cancer associated genes, oncogenes, and tumour suppressor genes has led to cancer becoming a treatable condition rather than an unspeakable disease. In 1971, the then USA President, Richard Nixon, declared 'war against cancer' with a far too optimistic perspective of winning in just a few years. This tactic failed because our knowledge of the disease was still very limited and even its origin-viral or due to exposure to external agents-was still highly debated. A better understanding of the cause(s) of the origin of cancer led to its definition as a genetic disease at the somatic level and heralded a new era for molecular diagnosis and the development of more mechanistic evidence-based, targeted cancer therapies. However, the initial positive results were soon overshadowed by a major limitation of targeted agents, namely resistance mechanisms, which still represent an obstacle for the full eradication of the disease. More recently, effective therapeutic approaches have been developed in the field of 'immunotherapy'. The combination of novel therapies will hopefully result in effective cancer growth control and make the disease 'chronic'. The launch of the 'Moonshot Cancer Program' by President Barack Obama aims to significantly reduce cancer deaths in the next decade-let us see. © the authors.

De Lazzari E.,CNRS Laboratory of Computational and Quantitative Biology | Grilli J.,University of Chicago | Maslov S.,University of Illinois at Urbana - Champaign | Lagomarsino M.C.,CNRS Laboratory of Computational and Quantitative Biology | Lagomarsino M.C.,FIRC Institute of Molecular Oncology IFOM
Nucleic Acids Research | Year: 2017

Among several quantitative invariants found in evolutionary genomics, one of the most striking is the scaling of the overall abundance of proteins, or protein domains, sharing a specific functional annotation across genomes of given size. The size of these functional categories change, on average, as power-laws in the total number of protein-coding genes. Here, we show that such regularities are not restricted to the overall behavior of high-level functional categories, but also exist systematically at the level of single evolutionary families of protein domains. Specifically, the number of proteins within each family follows family-specific scaling laws with genome size. Functionally similar sets of families tend to follow similar scaling laws, but this is not always the case. To understand this systematically, we provide a comprehensive classification of families based on their scaling properties. Additionally, we develop a quantitative score for the heterogeneity of the scaling of families belonging to a given category or predefined group. Under the common reasonable assumption that selection is driven solely or mainly by biological function, these findings point to fine-tuned and interdependent functional roles of specific protein domains, beyond our current functional annotations. This analysis provides a deeper view on the links between evolutionary expansion of protein families and the functional constraints shaping the gene repertoire of bacterial genomes. © 2017 The Author(s).

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.

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.

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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