A joint study between the groups of Valeria Poli and Enzo Calautti demonstrates that a moderate but sustained increase of STAT3 activity enhances epidermal stem cell properties, delays differentiation and favors spontaneous immortalization of keratinocytes.
Skin tumorigenesis is enhanced by overexpression in keratinocytes of the constitutively active STAT3C mutant, which also induces robust, psoriasis-like epidermal hyperplasia. In this paper published in Experimental Dermatology http://www.ncbi.nlm.nih.gov/pubmed/25382846, Valeria Orecchia, Gabriella Regis and colleagues demonstrated that STAT3C expression at physiological levels in knock-in mice leads to mild epidermal hyperplasia and attenuated expression of terminal differentiation markers. This correlates with enhanced proliferative and clonogenic potential, attenuated senescence and, strikingly, high frequency spontaneous immortalization. These results suggest that moderate levels of continuous STAT3 activation, which mimic chronic inflammatory conditions, may establish a pre-neoplastic state in part by promoting the escape of epidermal progenitor cells from differentiation and senescence checkpoints.
The Bioinformatics & Genomics group together with the System Biology Group, at the Computer Science Dept. www.unito.it/di/, have recently published on Bioinformatics chimera, a tool for secondary analysis of fusion events.
Chimera is a Bioconductor package that organizes, annotates, analyses and validates fusions reported by different fusion detection tools; current implementation can deal with output from bellerophontes, chimeraScan, deFuse, fusionCatcher, FusionFinder, FusionHunter, FusionMap, mapSplice, Rsubread, tophat-fusion and STAR. The core of Chimera is a fusion data structure that can store fusion events detected with any of the aforementioned tools. Fusions are then easily manipulated with standard R functions or through the set of functionalities specifically developed in Chimera with the aim of supporting the user in managing fusions and discriminating false-positive results. Pubmed id: http://www.ncbi.nlm.nih.gov/pubmed/25286921
A paper from the Immunogenetics group demonstrates that the extracellular form of the NAD biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT) is a critical element in the induction of an immunosuppressive and tumor-promoting microenvironment in chronic lymphocytic leukemia (CLL).
NAMPT is the rate-limiting enzyme in NAD biosynthesis. In the extracellular compartment it exhibits cytokine/adipokine-like properties. Extracellular NAMPT (eNAMPT) levels are increased in various metabolic and inflammatory diseases as well as in tumors, rendering this pleiotropic molecule a novel player in tumor/host cross-talk. In this paper published in Blood http://www.ncbi.nlm.nih.gov /pubmed/25368373, Valentina Audrito and colleagues from the Immunogenetics Unit show that NAMPT levels are increased in CLL lymphocytes and that eNAMPT production is induced upon activation of the leukemic cells. In the CLL microenvironment, eNAMPT is an important element in inducing monocyte polarization to M2 macrophages secreting immunosuppressive and tumor promoting cytokines and reducing T cell responses. These effects are independent of the enzymatic activity of NAMPT, as inferred from the use of an enzymatically inactive mutant. Overall, these results reveal that eNAMPT is a critical element in the induction of an immunosuppressive and tumor-promoting microenvironment of CLL.
A collaboration between the University of Novara (Davide Rossi and Gianluca Gaidano) and University of Torino (Roberto Piva’s and Silvia Deaglio’s groups) identified the transcription factor KLF2 as frequently mutated in splenic marginal zone lymphoma (SMZL) and other mature B-cell tumors.
To identify novel genetic lesions recurrently associated with B-cell lymphoma, the authors screened a set of genes involved in post-germinal center B cell differentiation. The paper published in Leukemia http://www-ncbi-nlm-nih- gov.offcampus.dam.unito.it/pubmed/25283840, disclosed recurrent structural alterations of the Krüppel-like factor 2 (KLF2) zinc finger gene, a transcription factor important for the homeostasis and differentiation of peripheral B-cell subsets. The authors show that alterations of KLF2 represent one of the most frequent genomic abnormalities of SMZL and demonstrate that KLF2 mutations cause functional defects by inducing the cytoplasmic delocalization of the KLF2 protein and the impairment of its transcriptional function. The study provides the first evidence of the molecular deregulation of KLF family genes in hematologic malignancies. The distribution of KLF2 molecular lesions in SMZL and in other mature B-cell tumors strongly suggests that selection of these mutations plays a role in transformation common to several lymphoma subtypes.
A paper from the Computational Biology Unit describes a new method for drug repositioning.
Rare genetic diseases represent an extremely important medical and social challenge, because the ~ 6000 known disorders affect about 10% of the population in developed countries and because only in less than 5% of cases a treatment is available. Drug repositioning, i.e. finding new indications for approved drugs, represents to date one of the most cost- and time-effective strategies to identify a therapy for at least a subset of rare diseases. In recent years, the availability of huge information on the genetic basis of human disorders, on gene regulation, on protein structure and on drug-target interactions has generated unprecedented opportunities to pursue drug repositioning on a more rational ground. In this manuscript, Molineris et al. have developed a new computational strategy based on the search for conserved anti-correlation between known drug targets and human disease genes, performed on public microarray databases. On this basis, they propose new potential candidate drug targets and drugs for many rare human disorders for which no specific gene expression data are available. The experimental validation of these predictions could lead in the future to the development of new therapeutic strategies for at least some of these diseases.
A paper from the group of Valeria Poli demonstrates that STAT3β controls inflammatory responses and early tumor onset in skin and colon experimental cancer models.
In this paper published in American Journal of Cancer Research Marino Francesca, Orecchia Valeria, Regis Gabriella and colleagues demonstrate the contribution of the shorter isoform of the transcriptional factor STAT3, STAT3β, to inflammation-driven tumorigenesis in the colon or in the skin, induced by AOM/DSS or DMBA/TPA treatments, respectively. The lack of STAT3β leads to exacerbated acute inflammatory responses to both colon and skin irritants used, correlating with earlier tumor onset in both compartments but unaffected overall tumor development and progression. Thus STAT3β, by limiting inflammation during the initial phases of tumorigenesis, contributes to tissue homeostasis and counteracts malignant transformation and initial tumor growth. Thus the balance between the two STAT3 isoforms, determined by the complex signaling networks shaping the tumor microenvironment, is crucial in determining initial tumor transformation rates in inflammation-associated cancers.
A publication from a joint research between the Molecular Imaging team (corresponding author Enzo Terreno) and Porto Conte Ricerche (Alghero) boosts the potential of liposomes loaded with paramagnetic complexes as MRI contrast agents.
In the paper published on Magnetic Resonance in Medicine (doi: 10.1002/mrm.25412), Gilberto Mulas and co-workers demonstrate that Curie spin relaxation is the predominant relaxation mechanism accounting for the MRI T2-contrast generated by liposomes loaded with lanthanide complexes. This mechanism can be usefully exploited to switch from the often undesirable negative contrast (i.e. appearance of dark spots in the image) of T2-agents to a positive (bright spots) response using specific MRI pulse sequences that magnify the Curie spin mechanism. Access to this contrast mode extends the potential of paramagnetic liposomes as MRI contrast agents.
A paper from the group of Silvia Deaglio demonstrates that the enzymatic activities of the surface molecule CD38 regulate growth and trafficking of chronic lymphocytic leukemia B cells (CLL) paving the way for its therapeutic targeting in hematological malignancies.
CD38 is a cell surface molecule endowed with enzymatic and receptor functions. Its expression on chronic lymphocytic leukemia (CLL) cells correlates with a poor clinical outcome. Besides being a negative prognosticator, CD38 plays a critical role in the pathogenetic network underlying the disease, mediating proliferative and migratory signals. However, the molecular mechanisms at the basis of CD38 behavior in the leukemic context remain undetermined. In this paper published in Leukemia http://www.ncbi.nlm.nih.gov/pubmed/24990614, Tiziana Vaisitti and collegues demonstrate that the molecule in enzymatically active in primary CLL cells and that these functions are critical in the control of proliferation and migration, both in vitro and in vivo. Inhibition of the enzymatic activities of CD38 using kuromanin, a molecule belonging to the flavonoid family, reduces CLL chemotaxis and homing. Indeed, in short term xenograft experiments using primary leukemic cells, flavonoid treatment results in the trapping of CLL cells in the blood, thereby increasing responses to chemotherapy. These results suggest that the use of selective reagents able to interfere with CD38 enzymatic activities may represent a novel therapeutic approach for selected hematological malignancies.
A paper from the group of Silvia Deaglio demonstrates that the surface molecule PD-L1 plays a critical role in suppressing immune responses in metastatic melanoma patients. PD-L1 expression in melanoma identifies a biologically more aggressive form of the disease, carrying prognostic relevance.
In this paper published in Annals of Oncology http://www.ncbi.nlm.nih.gov/pubmed/25223485, Davide Brusa and collegues demonstrate that PD-L1 expression defines a subset of the BRAF-mutated A375 cell line characterized by a highly invasive phenotype and by enhanced ability to grow in vitro and in xenograft models. These results point to PD-L1 as a negative prognostic factor in melanoma patients. Future studies will tell whether PD-L1 may be successfully exploited alone or in combination as a target for specific subsets of melanoma patients.
A paper from the group of Federica Cavallo shows that adjuvant immunization with a xenogeneic DNA vaccine is effective for the treatment of surgically controlled staged II-III oral canine malignant melanoma, laying the foundation for its translation to a human clinical setting.
Due to the many similarities with its human counterpart, canine malignant melanoma (CMM) represents a valuable model to assess the efficacy of novel therapeutic strategies. In this study Federica Riccardo and coworkers (http://clincancerres.aacrjournals.org/cgi/content/abstract/1078-0432.CCR-13-3042) took advantage of this model to evaluate immunogenicity, safety and therapeutic efficacy of a human (h) chondroitin sulfate proteoglycan-4 (CSPG4) DNA-based vaccine. CSPG4 represents an attractive target for immunotherapy because of its high expression in a high percentage of human melanoma and CMM tumors and its restricted distribution in normal tissues. The high homology between human and canine CSPG4 has provided the rationale for testing the potential of a hCSPG4 DNA vaccine in dogs with stage II-III surgically resected CSPG4-positive oral CMM. Intramuscular plasmid administration followed by electroporation resulted in significantly longer overall and disease-free survival times in 14 vaccinated dogs as compared to 13 non-vaccinated controls. All vaccinated dogs developed antibodies against both human and canine CSPG4. The induction of CSPG4-specific antibodies is likely to inhibit CSPG4 oncogenic role in the biology of melanoma cells, interfering with the progression of the disease by inhibiting the proliferation of CSPG4-positive residual melanoma cells in canine patients. Thanks to the high translational value of CMM model, hopefully these finding will help improving treatment of human melanoma patients. Also in the fight against cancer, dogs may give a helping paw to humans.
A paper from the group of Ferdinando Di Cunto uncovers the mechanisms by which the Down syndrome critical region gene TTC3 affects neuronal differentiation and neuronal Golgi architecture.
A crucial topic in Down Syndrome (DS) research is to establish how much dosage imbalance of single Chromosome 21 genes mapped to the Down Critical Region (DCR) are responsible for the intellectual disability (ID) which characterizes this disorder. Indeed, elucidating the molecular mechanisms that determine abnormal brain function in DS patients is fundamental to develop rational pharmacological strategies. TTC3 is one of the genes, located in the DCR, whose increased expression levels are suspected to play a significant role in determining ID. In this work Gaia Berto and colleagues have found that the dosage of the TTC3 gene is critically important for neurons, since a decrease or an increase of its levels can strongly affect the extension of neuronal processes and the structure of the neuronal Golgi apparatus, through modulation of the actin cytoskeleton. Moreover, they have characterized the complex molecular machinery linking TTC3 to actin rearrangements, which comprises drugable targets such as the protein kinase ROCK.
A paper from the group of Emanuela Tolosano described a key role for the heme exporter FLVCR1a in hepatic heme metabolism and cytochrome P450 function.
The liver has one of the highest rate of synthesis of heme, 50% of of which is used to support the synthesis of cytochromes P450. These enzymes metabolize exogenous and endogenous compounds, including natural products, hormones, drugs, and carcinogens. FLVCR1a is a ubiquitously expressed plasma membrane heme exporter that has been shown to control intracellular heme content in hematopoietic lineages. In a recent paper published on Gastroenterology, Vinchi et al. addressed FLVCR1a function in the liver, by generating mice with conditional disruption of Flvcr1a in hepatocytes. With aging, these mice accumulated heme and iron in liver. As a mechanism to compensate for the lack of heme export, heme catabolism (HO-1) and iron storage (Ferritin) are increased. These findings highlight a crucial role for FLVCR1a in the maintenance of hepatic heme homeostasis. Flvcr1a export function was found closely associated with heme biosynthesis, required to sustain cytochrome induction. Hepatic heme accumulation in these mice causes the early inhibition of heme synthesis and increased degradation of heme, which finally reduced the expression and activity of cytochromes P450. As a consequence, these mice show a reduced ability to upregulate cytochrome P450 in response to drugs and xenobiotics. These observations suggest a direct implication of heme export in cytochromes P450 function and drug metabolism.
A paper from the group of Federica Cavallo discloses new roles of perforin in tumor immune surveillance and male mammary gland reabsorption during embryogenesis
Observational studies linked to clinical outcome analysis in cancer patients that have been carried out in recent years have displayed the prognostic and predictive value of the tumor microenvironment inflammatory state. This has generated a new wave of interest in the immunosurveillance phenomenon. Natural immune surveillance against the onset of cancer is one of the most important tenets in experimental tumor immunology. Perforin-mediated cytotoxicity is one of the principal immunosurveillance mechanisms involved in the fight against cancer. However, its importance in spontaneous epithelial cancer is still poorly defined. In a recent paper published on Journal of Immunology, Marco Macagno and colleagues provide further proof of the complex role that the immune system plays in the body and gives new insight into the pathogenesis ofepithelial tumors, demonstrating that the penetrance and malignancy of a tumor may be dramatically affected by pfp-dependent mechanisms. In addition, their findings unveiled the previously unsuspected involvement of pfp in male mammary gland reabsorption during embryogenesis.
Convenzione per l'attivazione di una Cell Factory presso l'Università di Torino (Torino, 28 novembre 2013).
Oggi nel Salone del Rettorato, il Rettore dell'Università degli Studi di Torino, Prof. Gianmaria Ajani, e il Responsabile Emea LA di Fresenius Medical Care, Prof. Emanuele Gatti, hanno firmato la Convenzione per l'attivazione di una Cell Factory presso l'Università di Torino per la produzione di cellule staminali finalizzate alla terapia dell'insufficienza renale ed epatica.