Molecular mechanisms of cancer and aging


Awarded a European Research Council (ERC) Advanced Grant, within the 2013 “Ideas” program, for the research project InMec (Inside mechanisms sustaining cancer stem cells).
The €2.5M project will run for 5 years and aims to elucidate the molecular mechanisms at the basis of the altered self-renewal properties of cancer stem cells, determining how these cells contribute to the sustainability of tumor growth and generation of tumor heterogeneity. The identification of cancer stem cell-specific phenotypes and the deconvolution of the underlying genetic mechanisms and networks might provide cancer stem cell-specific markers or targets that could be used to definitively prove the cancer stem cell hypothesis and create the grounds for pharmacological interventions.


One of the challenges for the next decade is to understand how distinct, simple molecular functions may be part of complex pathways and systems, how multiple systems may come together to control complicated cellular behaviours and how alteration of this composite molecular machinery may ultimately lead to cancer. The Pelicci laboratory is investigating these molecular mechanisms/interactions with research that extends from regulation of cell division and proliferation to control of DNA transcription and replication, to the role of tumour-associated oncogenes and suppressors in tumour development and progression, and to the links between cancer and metabolism and cancer and aging.

Accumulating evidence suggests that only rare cancer cells endowed with self-renewal properties, the cancer stem cells, have the capacity to maintain tumour growth, so a considerable part of the group’s research efforts is specifically devoted to the characterization of normal and cancer stem cells, and to study whether common mechanisms are controlling the growth and maintenance of both these types of cells across different normal and cancer tissues. To this end, the laboratory has generated accurate models of carcinogenesis in mammals, creating, in these model systems, mutations that mimic those that occur spontaneously in human cancers (especially leukaemia and breast). These model systems are used in combination with primary patient derived samples to identify biological markers of disease and to develop innovative strategies to target cancer stem cells in a clinical setting.

Studies in the Pelicci laboratory are supported by state of the art technologies and an experienced bio-computational team.

  • Research projects

    Specific lines of research:

    1. Biological and molecular mechanisms underlying the behaviour of normal and cancer stem cells. Currently, little is known about the biological and molecular mechanisms that govern the initiation, progression and maintenance of cancer stem cells. The lab’s experimental approach is based on the purification of normal and cancer stem cells from the same tissues and on the biological and molecular analysis of self-renewal mitotic divisions.
    2. Role of quiescence, DNA damage repair, and reprogramming in tumour progression and relapse. The tumour suppressor p53, the cell cycle inhibitor p21 and the oncogene Myc have been demonstrated by the group to have a key and specific role in these events, in both breast and haematopoietic stem cells; the Pelicci lab is now investigating these molecules and their interdependence in cancer stem cells, as well as ways to target them for therapy.
    3. Study of the molecular basis of chemoresistance in acute myeloid leukaemia (AML) through next generation sequencing. The lab is testing the hypothesis that relapse acquired chemoresistance is due to the selection of rare tumour cell populations harbouring specific genetic and/or epigenetic mutations. Functional comparison between primary and recurrent tumours may allow the identification of markers predictive of therapy response.
    4. Role of oncogenes (i.e. PML-RAR, AML1-ETO, NPMmut, Myc) and cooperative events that lead to the development of cancer. Often, oncogene expression per se cannot initiate or sustain cancer developmentand progression; it may require the accumulation, inside a cell, of other genetic and epigenetic changes, each conferring a selective advantage to the cell at a specific stage of tumorigenesis.
    5. Replication origins and replication stress in cancer. A correct execution of the DNA replication program is crucial for cell division and for limiting cancer risk by preserving genome integrity. Human DNA replication depends on the activation of thousands of origins; recent evidence suggests that their distribution/timing varies between specific cell types or cell states, and that oncogenes induce alterations of the replication program, triggering replicative stress and DNA damage.
    6. Longevity and cancer. Aging is associated with a number of events at the molecular, cellular and physiological levels that might influence carcinogenesis, thus understanding these events can help cancer prediction and treatment.
    7. Metabolism and cancer. Closely connected also with the aging process as there is growing awareness that diet and environmental factors have a profound effect in the initiation, promotion, and progression of cancer; these factors are being investigated in animal models and human samples.
  • Publications

    • Insinga A, Cicalese A, Faretta M, Gallo B, Albano L, Ronzoni S, Furia L, Viale A, Pelicci PG. DNA damage in stem cells activates p21, inhibits p53, and induces symmetric self-renewing divisions. Proc Natl Acad Sci U S A 110(10):3931-6, 2013.
    • Dellino GI, Cittaro D, Piccioni R, Luzi L, Banfi S, Segalla S, Cesaroni M, Mendoza-Maldonado R, Giacca M, Pelicci PG. Genome-wide mapping of human DNA-replication origins: Levels of transcription at ORC1 sites regulate origin selection and replication timing. Genome Res 23(1):1-11, 2013.
    • Gambino V, De Michele G, Venezia O, Migliaccio P, Dall'olio V, Bernard L, Minardi SP, Fazia MA, Bartoli D, Servillo G, Alcalay M, Luzi L, Giorgio M, Scrable H, Pelicci PG, Migliaccio E. Oxidative stress activates a specific p53 transcriptional-response that regulates cellular senescence and aging. Aging Cell 12(3):435-45, 2013.
    • Viale A, De Franco F, Orleth A, Cambiaghi V, Giuliani V, Bossi D, Ronchini C, Ronzoni S, Muradore I, Monestiroli S, Gobbi A, Alcalay M, Minucci S, Pelicci PG. Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells. Nature 457(7225):51-6, 2009.
    • Cicalese A, Bonizzi G, Pasi CE, Faretta M, Ronzoni S, Giulini B, Brisken C, Minucci S, Di Fiore PP, Pelicci PG. The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell 138:1083-95, 2009.


  • Funding


    • EC-FP7-ERC-Adv Grant, InMec
    • EC-FP7, ATHENA
    • Italian Association for Research on Cancer (AIRC)
    • MIUR Italian Ministry for University and Research (FIRB project)
    • Italian Health Ministry (Ricerca Finalizzata)
    • Cariplo Foundation
    • National Institute on Aging (NIA-USA)
    • Fondazione Umberto Veronesi (FUV)




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


Ministero della Salute Joint Commission International Breastcertification bollinirosa

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