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Molecular Medicine for Care Program (MMC)

Mission and Vision

There is an impelling need to speed up the transfer of scientific results from the laboratory to the clinic: clinicians require it, society demands it, and scientists must respond. Each interest group depends on the other two to achieve this aim. This is why we established the Molecular Medicine for Care (MMC) program at IEO. Through the mutual collaboration of scientists, clinicians and patients, we are driving discoveries from the basic research programs conducted in the laboratory of Pier Paolo Di Fiore [1-11] into the clinical domain, through four scientific programs that focus on breast, lung and ovarian cancers. While these are being carried forward, we have brewing in the pipeline a number of other new discovery projects that will ultimately translate into the improved clinical management of breast, lung, ovarian and prostate cancer.
Our current scientific programs aim to:
1) Identify stem cell markers for the diagnosis, prognosis and therapeutic stratification of breast, lung and ovarian cancers.
2) Develop a blood test for the early diagnosis of lung cancer.
3) Understand breast and ovarian cancer for early diagnosis.
4) Make new discoveries to increase our molecular understanding of cancer and feed new translational research projects.

  • Research activities

    MMC Scientific Programs

    Stem cell markers for the diagnosis, prognosis and therapeutic stratification of breast, lung and ovarian cancer
    Lead scientific contacts
    Breast cancer: Salvatore Pece, Fabrizio Bianchi, Stefano Confalonieri, Manuela Vecchi
    Lung cancer: Elena Belloni

    Ovarian Cancer: Ugo Cavallaro

    Stem cells are a rare population of cells necessary for tissue integrity and regeneration in case of injury. Their numbers within any normal tissue are very tightly controlled, but it is now widely accepted that these restraints can malfunction in cancer, leading to an inappropriate expansion of stem cell populations. We discovered that genes expressed in breast stem cells can be used as biomarkers to improve the stratification of breast tumors according to their pathological, molecular and clinical characteristics [3]. However, the original stem cell signature we identified contained too many genes to be of clinical use. Therefore, we are now developing a smaller stem cell profile that still retains the predictive features of the stem cell profile, but that can be analyzed more easily in a clinical setting using immunohistochemistry or quantitative PCR analysis. We are assessing the ability of these biomarkers to classify breast tumors according to aggressiveness, associated metastatic risk and therapeutic response to hormonal and/or chemo-/radio-therapy. Ultimately, we aim to develop a clinical test that will fine-tune the current diagnostic/prognostic ability of clinicians and to improve the clinical management of breast cancer.

    Using a similar approach to that pursued for breast [3], we are now trying to identify and isolate cells with stem properties in non-small cell lung cancer (NSCLC) and in ovarian cancer, for which stem cell identity remains poorly defined. The identification and characterization of the cells that initiate, sustain, and disseminate lung tumors should create new opportunities for the early detection and/or improved treatment for these diseases.

    Development of a blood test for the early diagnosis of lung cancer
    Lead scientific contacts
    Fabrizio Bianchi

    The absence of national screening programs for lung cancer, and the lack of symptoms in early stage disease means that the detection of early lung cancer is difficult. The development of clinical tools for the early diagnosis of lung cancer is, therefore, a pressing clinical necessity, particularly for at-risk subjects (smokers or ex-smokers, aged 50 years or more). We have previously identified and validated in independent patient cohorts a circulating miRNA signature (based on 34 miRNA species) that can be used in a blood test to detect early stage lung cancer in asymptomatic patients [1]. In collaboration with theDivision of Thoracic Surgery and the Division of Radiology, we are currently assessing the clinical applicability of this test through its large-scale validation in a prospective multicenter trial launched by the Lung Cancer Early Detection Unit in September 2012 (COSMOS II). The trial has already recruited close to 6,000 of the planned 10,000 patients. If effective, this blood test will be significantly cheaper and easier to apply in national lung cancer screening programs than the only currently available clinical test, which is based on low-dose computer assisted tomography screening.

    Understanding breast and ovarian cancer for early diagnosis
    Lead scientific contacts
    Breast cancer: Fabrizio Bianchi
    Ovarian Cancer: Ugo Cavallaro, Fabrizio Bianchi

    This scientific program is designed to investigate whether prognostic/diagnostic miRNA profiles exist for breast and ovarian cancers. Based on our experience in developing a blood test to detect early stage lung cancer, we are now collaborating with the Molecular Senology Unit of the Division of Senology, and the Gynaecologic Oncology Unit in serum screening projects, involving breast and ovarian cancer patients, to identify a diagnostic cancer-specific miRNA profile. If we are successful, a small blood sample is all that will be necessary to determine if these miRNAs are present, and this could be sufficient to diagnose breast or ovarian cancers. Our work will lead to the development of a comparatively inexpensive first level diagnostic test for breast and ovarian cancers that can easily be implemented within national screening programs. We have previously shown that more aggressive breast cancers tend to have a larger number of stem cells than less aggressive tumors [3]. Within the context of this program, we are also analyzing the miRNA profile of breast stem cells. If these stem cell-specific miRNAs are also present within the sera of breast cancer patients, they might reflect the proportion of stem cells within a tumor. Though we are still a long way from our endpoint, we hope that testing for the presence of circulating stem-cell miRNAs in blood could form the basis for a prognostic test for breast cancer, which will complement the clinico-pathological parameters that are currently used to assess the aggressiveness of the disease.

    New discoveries to feed cancer research
    Lead scientific contacts
    Breast cancer: Salvatore Pece, Ivan Colaluca, Daniela Tosoni
    Lung cancer: Elena Belloni, Fabrizio Bianchi
    Ovarian Cancer: Ugo Cavallaro

    Our translational medicine program would be short-lived if it were not continually fed by new discoveries in basic research that are improving our understanding of the molecular mechanisms that lie at the root of normal and cancer cell behavior. A number of these projects were born in the laboratory of Pier Paolo Di Fiore, while others are fostered directly within the MMC scientific programs. Amongst these, we are studying the molecular mechanisms that regulate normal stem cell division and we are defining how these are subverted in breast cancer. We are also characterizing critical signaling/endocytic pathways involving Numb/Notch/p53 [12, 13] and factors that cause loss of Numb in cancer, with a view to developing targeted drugs for lung and breast cancer. Several members of the group are involved in high-resolution studies on individual markers that were identified in past genome-wide screening projects, and that potentially have significant clinical relevance as prognostic or therapeutic targets. Our ovarian cancer group is generating molecular tools for the identification and characterization of ovarian cancer stem cells, whose precise identity still remains uncertain today. As well as these classical approaches to research, our group is using cutting edge next-generation sequencing technology to define the genetic determinants of lung cancer in smokers and in non-smokers, and to analyze the clonal origin of breast and lung cancers and their metastases.

    MMC Support Infrastructures
    Tissue Bank
    Lead scientist: Giuseppina Bonizzi
    Technicians (Tissue Bank): Marialucia Longo, Giulio Taliento, Andrea Uggetti
    Technician (Lab Support): Alessandro Di Nasta
    Research Nurse: Anna Carmagnola
    Data entry/Data manager: Maria Capra, Fulvia Fusar

    The Tissue Bank (IEO Biobank and Biomolecular Resource Infrastructure - IBBRI) collects, catalogues and stores biological samples (surgically excised tissue samples non-essential for diagnosis, plasma/serum, total blood, DNA and RNA) from patients who have provided informed consent for the use of their tissues for research purposes. We have established a direct pipeline with the operating theatres for the collection of tissue samples and these are stored according to specific protocols and standard operating procedures. We also store any primary cell cultures, stem cell preparations, and xenotransplanted tumors derived from collected samples. All biobanked samples are managed and tracked through a software package that is fully integrated with the hospital medical records database, pathology database and central registry of patient demographic information. This ensures that each sample is linked to a full complement of anonymous or anonymized (according to patient choice) patient information (accessible solely by authorized Biobank personnel). The high quality biospecimens we collect are used for biomarker and drug discovery experiments, both for basic research and for MMC translational research projects.

    Molecular Pathology Laboratory
    Lead scientist: Stefano Confalonieri
    Pathologist: Giovanni Bertalot
    Postdoctoral Fellow: Elena Miranda
    Technician: Giovanna Jodice, Chiara Luise, Valentina Mattei

    The IEO Molecular Pathology Laboratory works to identify novel putative cancer targets for drug discovery, diagnostic and/or prognostic applications through high-throughput Tissue Microarrays (TMAs) and in situ detection methods (in situ hybridization and immunohistochemistry). TMA technology allows gene expression analysis on thousands of patient tissues simultaneously, and is a powerful tool for determining the relevance of basic research findings to cancer.

    We collaborate closely with the Pathology Department at IEO, who maintain tissue archives dating back to 1994, when IEO was established. These are an invaluable source of material for the construction and continuous replenishment of our TMAs. Thanks to data stored by the IEO Tumor Registry, all arrayed tissues are linked to complete clinico-pathological and follow-up information. The Molecular Pathology Laboratory can therefore link the expression patterns of genes of interest to clinical evaluation and outcome, a necessary step for the validation of new diagnostic and prognostic markers.

    Primary Epithelial and Stem Cell Culture /Xenotransplant Laboratory
    Lead scientist: Tamara Tanos
    Staff scientist (xenotransplants): Daniela Tosoni
    Technicians (cell culture): Rossana Bettolini, Ivan Cuccovillo, Donatella Genovese
    Technicians (xenotransplants): Barbara Giulini , Stefania Amodio

    The Primary Epithelial and Stem Cell Culture Laboratory derives bulk primary epithelial cells and stem cells from human biopsy specimens. Primary-derived cells are used for the establishment of either in vitro or in vivo (xenotransplant) model-systems that retain many features of their parental tissues. These are a valuable tool for studying the molecular features of naturally occurring human cancers. We have developed efficient protocols for the processing of tissue biopsy specimens, and for the preparation of bulk primary epithelial cell and stem cell cultures from breast [14], lung, ovary and prostate tissues, and for their xenotransplantation in immunocompromised murine hosts. Samples arrive to our laboratory via a continuous pipeline from the operating theatres, coordinated by the Tissue Bank.

    Clinical Biomarkers Laboratory
    Lead scientist: Manuela Vecchi
    Scientist: Flavia Troglio
    Technicians: Francesca de Santis, Luca Napolitano, Stefania Pirroni

    The Clinical Biomarkers Laboratory performs screening, pre-clinical validation, and optimization of biomarker candidates, as well as the design, execution and technological development of cancer diagnostic assays to aid the translation of candidates markers into the clinical setting. In this role, we also support collaborative study programs between biotech companies, researchers and clinicians for the co-development of biomarkers and novel therapies. This facility is also responsible for the optimization of protocols for the extraction of nucleic acids (including total RNA, DNA and miRNAs) from human tissues, such as blood, plasma, fresh tissue biopsies, paraffin-embedded tissue specimens. We also set up and implement novel technological platforms for the group. Finally, we select the appropriate patient cohorts and tissue samples for prospective and retrospective studies in collaboration with the Genomics and Bioinformatics Laboratory.

    Genomics and Bioinformatics Laboratory
    Lead scientist: Fabrizio Bianchi
    Postdoc: Francesca Montani
    PhD students: Eleonora Lusito, Valentina Melocchi, Simona Monterisi
    Fellows: Elisa Dama (co-supervised by Eng. Patrick Maisonneuve, Epidemiology and Biostatiscs Division, IEO), Fabio Dezi
    Technicians: Rosemary Carletti

    The Genomics and Bioinformatics Laboratory draws together the fields of genomics, biostatistics and applied bioinformatics. We apply ‘omics strategies’ to identify novel cancer biomarkers and potential therapeutic targets and use computational biology and biostatistical approaches to prioritize cancer biomarkers. We are primarily involved in the screening for circulating miRNA biomarkers for the early diagnosis of lung, breast and ovarian cancer patients, and in the transcriptome analysis of primary tumors and cancer stem cells.

    One of our key roles is to provide support to other MMC units. We are responsible for: i) coordinating, centralizing and managing clinical information associated with biological samples collected by the Tissue Bank; ii) designing and analyzing studies involving the screening, pre-clinical validation, and optimization of biomarker candidates, identified by the Clinical Biomarkers Laboratory.

  • Publications

    • Bianchi, F., F. Nicassio, M. Marzi, E. Belloni, V. Dall'olio, L. Bernard, G. Pelosi, P. Maisonneuve, G. Veronesi, and P.P. Di Fiore, A serum circulating miRNA diagnostic test to identify asymptomatic high-risk individuals with early stage lung cancer. EMBO molecular medicine, 2011. 3(8): p. 495-503.
    • Luise, C., M. Capra, M. Donzelli, G. Mazzarol, M.G. Jodice, P. Nuciforo, G. Viale, P.P. Di Fiore, and S. Confalonieri, An atlas of altered expression of deubiquitinating enzymes in human cancer. PloS one, 2011. 6(1): p. e15891.
    • Pece, S., D. Tosoni, S. Confalonieri, G. Mazzarol, M. Vecchi, S. Ronzoni, L. Bernard, G. Viale, P.G. Pelicci, and P.P. Di Fiore, Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content. Cell, 2010. 140(1): p. 62-73.
    • Confalonieri, S., M. Quarto, G. Goisis, P. Nuciforo, M. Donzelli, G. Jodice, G. Pelosi, G. Viale, S. Pece, and P.P. Di Fiore, Alterations of ubiquitin ligases in human cancer and their association with the natural history of the tumor. Oncogene, 2009. 28(33): p. 2959-68.
    • Bianchi, F., F. Nicassio, and P.P. Di Fiore, Unbiased vs. biased approaches to the identification of cancer signatures: the case of lung cancer. Cell cycle, 2008. 7(6): p. 729-34.
    • Vecchi, M., S. Confalonieri, P. Nuciforo, M.A. Vigano, M. Capra, M. Bianchi, D. Nicosia, F. Bianchi, V. Galimberti, G. Viale, G. Palermo, A. Riccardi, R. Campanini, M.G. Daidone, M.A. Pierotti, S. Pece, and P.P. Di Fiore, Breast cancer metastases are molecularly distinct from their primary tumors. Oncogene, 2008. 27(15): p. 2148-58.
    • Bianchi, F., P. Nuciforo, M. Vecchi, L. Bernard, L. Tizzoni, A. Marchetti, F. Buttitta, L. Felicioni, F. Nicassio, and P.P. Di Fiore, Survival prediction of stage I lung adenocarcinomas by expression of 10 genes. The Journal of clinical investigation, 2007. 117(11): p. 3436-44.
    • Vecchi, M., P. Nuciforo, S. Romagnoli, S. Confalonieri, C. Pellegrini, G. Serio, M. Quarto, M. Capra, G.C. Roviaro, E. Contessini Avesani, C. Corsi, G. Coggi, P.P. Di Fiore, and S. Bosari, Gene expression analysis of early and advanced gastric cancers. Oncogene, 2007. 26(29): p. 4284-94.
    • Capra, M., P.G. Nuciforo, S. Confalonieri, M. Quarto, M. Bianchi, M. Nebuloni, R. Boldorini, F. Pallotti, G. Viale, M.L. Gishizky, G.F. Draetta, and P.P. Di Fiore, Frequent alterations in the expression of serine/threonine kinases in human cancers. Cancer research, 2006. 66(16): p. 8147-54.
    • Nicassio, F., F. Bianchi, M. Capra, M. Vecchi, S. Confalonieri, M. Bianchi, D. Pajalunga, M. Crescenzi, I.M. Bonapace, and P.P. Di Fiore, A cancer-specific transcriptional signature in human neoplasia. The Journal of clinical investigation, 2005. 115(11): p. 3015-25.
    • Bianchi, F., J. Hu, G. Pelosi, R. Cirincione, M. Ferguson, C. Ratcliffe, P.P. Di Fiore, K. Gatter, F. Pezzella, and U. Pastorino, Lung cancers detected by screening with spiral computed tomography have a malignant phenotype when analyzed by cDNA microarray. Clinical cancer research : an official journal of the American Association for Cancer Research, 2004. 10(18 Pt 1): p. 6023-8.
    • Colaluca, I.N., D. Tosoni, P. Nuciforo, F. Senic-Matuglia, V. Galimberti, G. Viale, S. Pece, and P.P. Di Fiore, NUMB controls p53 tumour suppressor activity. Nature, 2008. 451(7174): p. 76-80.
    • Westhoff, B., I.N. Colaluca, G. D'Ario, M. Donzelli, D. Tosoni, S. Volorio, G. Pelosi, L. Spaggiari, G. Mazzarol, G. Viale, S. Pece, and P.P. Di Fiore, Alterations of the Notch pathway in lung cancer. Proceedings of the National Academy of Sciences of the United States of America, 2009. 106(52): p. 22293-8.
    • Tosoni, D., P.P. Di Fiore, and S. Pece, Functional purification of human and mouse mammary stem cells. Methods in molecular biology, 2012. 916: p. 59-79.
    • Bianchi, F., F. Nicassio, G. Veronesi, and P.P. di Fiore, Circulating microRNAs: next-generation biomarkers for early lung cancer detection. Ecancermedicalscience, 2012. 6: p. 246.
    • Boniolo, G. and P.P. Di Fiore, Deliberative ethics in a biomedical institution: an example of integration between science and ethics. Journal of medical ethics, 2010. 36(7): p. 409-14.
    • Boniolo, G., P.P. Di Fiore, and S. Pece, Trusted consent and research biobanks: towards a 'new alliance' between researchers and donors. Bioethics, 2012. 26(2): p. 93-100.

A SMALL GESTURE IS A GREAT HELP FOR US

PARTNERSHIP

Università degli Studi di Milano Ecancer Medical Science IFOM-IEO Campus

CREDITS

Ministero della Salute Joint Commission International Breastcertification bollinirosa

© 2013 Istituto Europeo di Oncologia - via Ripamonti 435 Milano - P.I. 08691440153

IRCCS - ISTITUTO DI RICOVERO E CURA A CARATTERE SCIENTIFICO

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