Rosa Bernardi
e-mail: bernardi.rosa AT hsr.it
website: www.sanraffaele.org/65050.html
affiliation: San Raffaele Scientific Institute
research area(s): Cancer Biology, Experimental Medicine
Course:
Cell and Molecular Biology
University/Istitution: Università Vita-Salute San Raffaele
University/Istitution: Università Vita-Salute San Raffaele
EDUCATION AND TRAINING
1989-1993 Bachelor degree in Biological Sciences, University of Pavia, Italy
1994-1997 Ph.D. in Genetics, Institute of Genetics, Biochemistry and Evolution-CNR, Pavia, Italy
1997-2000 Postdoctoral training, Fels Institute for Cancer Research, Temple University, Philadelphia, USA
2001-2006 Postdoctoral training, Memorial Sloan-Kettering Cancer Center, New York, USA
2006-2007 Senior Research Scientist, Memorial Sloan-Kettering Cancer Center, New York, USA
2007-2008 Research Associate, Beth Israel Deaconess Medical Center, Boston, USA
2007-2008 Instructor, Harvard Medical School, Boston, USA
CURRENT POSITION
2008-present Junior Assistant Professor at San Raffaele Institute, Milano, Italy.
1989-1993 Bachelor degree in Biological Sciences, University of Pavia, Italy
1994-1997 Ph.D. in Genetics, Institute of Genetics, Biochemistry and Evolution-CNR, Pavia, Italy
1997-2000 Postdoctoral training, Fels Institute for Cancer Research, Temple University, Philadelphia, USA
2001-2006 Postdoctoral training, Memorial Sloan-Kettering Cancer Center, New York, USA
2006-2007 Senior Research Scientist, Memorial Sloan-Kettering Cancer Center, New York, USA
2007-2008 Research Associate, Beth Israel Deaconess Medical Center, Boston, USA
2007-2008 Instructor, Harvard Medical School, Boston, USA
CURRENT POSITION
2008-present Junior Assistant Professor at San Raffaele Institute, Milano, Italy.
We are interested in modeling human malignancies in the mouse, with a particolar attention to the interaction of cancer cells with the blood vessels in the microenvironment. To better understand the dynamic evolution of tumor formation in vivo, with the final aim of better interfering with tumor development, it is pivotal to elucidate the complex set of interactions that tumor cells establish with the environment that surrounds and nourishes them.
Processes of neo-angiogenesis have long been described as essential steps in the development of malignant growths. Neo-angiogenesis, or angiogenesis, is the process of forming new capillaries from pre-existing blood vessels. In the past few decades, it has been firmly established that angiogenesis plays an important role in the growth, progression and metastatic spread of solid tumors, because tumor blood vessels provide nutrients and oxygen and also an easy access to the circulation.
While it is firmly established that neo-angiogenesis plays an important role in the progression of solid tumors, recently accumulating evidence is suggesting that neo-angiogenesis may also play a role in the pathophysiology of hematological malignancies. This hypothesis rests mainly on clinical studies, which show that leukemia patients express high levels of pro-angiogenic factors and have increased angiogenesis in the bone marrow. However, these findings are mostly correlative: genetic proof that angiogenesis supports leukemogenesis is still lacking and the molecular mechanisms leading to angiogenesis in leukemia have not yet been established.
We are interested in better understanding causes and consequences of the expression of pro-angiogenic factors in leukemia. While performing these studies, we also aim at creating animal models that better mimic human leukemia and that will be utilized in pre-clinical studies to test the efficacy of anti-angiogenesis therapies for treating leukemia.
Processes of neo-angiogenesis have long been described as essential steps in the development of malignant growths. Neo-angiogenesis, or angiogenesis, is the process of forming new capillaries from pre-existing blood vessels. In the past few decades, it has been firmly established that angiogenesis plays an important role in the growth, progression and metastatic spread of solid tumors, because tumor blood vessels provide nutrients and oxygen and also an easy access to the circulation.
While it is firmly established that neo-angiogenesis plays an important role in the progression of solid tumors, recently accumulating evidence is suggesting that neo-angiogenesis may also play a role in the pathophysiology of hematological malignancies. This hypothesis rests mainly on clinical studies, which show that leukemia patients express high levels of pro-angiogenic factors and have increased angiogenesis in the bone marrow. However, these findings are mostly correlative: genetic proof that angiogenesis supports leukemogenesis is still lacking and the molecular mechanisms leading to angiogenesis in leukemia have not yet been established.
We are interested in better understanding causes and consequences of the expression of pro-angiogenic factors in leukemia. While performing these studies, we also aim at creating animal models that better mimic human leukemia and that will be utilized in pre-clinical studies to test the efficacy of anti-angiogenesis therapies for treating leukemia.
Bernardi R., Scaglioni P.P., Bergmann S., Horn H.F., Vousden K.H., Pandolfi P.P. (2004) "PML regulates p53 stability by sequestering Mdm2 to the nucleolus" Nat. Cell Biol. 6, 665-72
Salomoni P., Bernardi R., Bergmann S., Changou A., Tuttle S., Pandolfi P. P. (2004) "The promyelocytic leukemia protein PML regulates c-Jun function in response to DNA damage" Blood 105, 3686-90
Grisendi S., Bernardi R., Rossi M., Cheng K., Khandker L., Manova K., Pandolfi P. P. (2005) "Role of nucleophosmin in embryonic development and tumorigenesis" Nature 437, 147-53
Bernardi R., Guernah I., Jin D., Grisendi S., Alimonti A., Teuya-Feldstein J., Cordon-Cardo C., Simon M. C., Rafii S., Pandolfi P. P. (2006) "PML inhibits Hif-1α translation and neoangiogenesis through repression of mTOR" Nature 442, 779-785.
Choi Y. H., Bernardi R., Pandolfi P. P., Benveniste E. N. (2006) "The promyelocytic leukemia protein functions as a negative regulator of INF-g signaling" Proc Natl Acad Sci U.S.A. 103, 18715-18720.
Ma L., Teruya-Feldstein J., Bonner P., Bernardi R., Franz D. N., Cordon-Cardo C. and Pandolfi P. P. (2007) "Identification of S664 TSC2 phosphorylation as a marker for Erk-mediated mTOR activation in tuberous sclerosis and human cancer" Cancer Res. 67, 7106-7112.
Cheng K., Grisendi S., Clohessy S., Majid S., Bernardi R., Sportoletti P and Pandolfi P. P. (2007) "Cytoplasmic nucleophosmin leukemic mutant (NPMc+) is an oncogene with paradoxical functions: Arf inactivation and induction of cellular senescence" Oncogene 26, 7391-7400.
Bernardi R. and Pandolfi P. P. (2007) "Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies" Nature Reviews Mol. Cell Biol. 8, 1006-1016.
Ito K., Bernardi R., Morotti A., Matsuoka S., Saglio G., Ikeda Y., Rosenblatt J., Avigan D. E., Teruya-Feldstein J. and Pandolfi P. P. (2008) "PML targeting eradicates quiescent leukaemia-initiating cells" Nature 453, 1072-1078.
Fumagalli S., Di Cara A., Neb-Gulati A., Natt F., Schwemberger S., Hall J., Babcock G. F., Bernardi R., Pandolfi P. P. and Thomas G. (2009) "Absence of nucleolar disruption after impairment of 40S ribosome biogenesis reveals an rpL11-translation-dependent mechanism of p53 induction" Nat. Cell Biol. 11, 501-508.
Giorgi C., Ito K., Lin H. K., Wieckowski M. R., Lebiedzinska M., Bononi A., Bonora M., Duszynski J., Bernardi R., Rizzuto R., Tacchetti C., Pinton P and Pandolfi P. P. (2010) "PML regulates apoptosis at endoplasmic reticulum by modulating calcium release" Science 330, 1247-1251.
Bernardi R.*, Papa A., Egia A., Coltella N., Teruya-Feldstein J., Signoretti S. and Pandolfi P. P.* (2011) "Pml represses tumor progression through inhibition of mTOR" EMBO Mol. Med. 3, 249-257. * Bernardi R. and Pandolfi P. P co-corresponding authors.
Salomoni P., Bernardi R., Bergmann S., Changou A., Tuttle S., Pandolfi P. P. (2004) "The promyelocytic leukemia protein PML regulates c-Jun function in response to DNA damage" Blood 105, 3686-90
Grisendi S., Bernardi R., Rossi M., Cheng K., Khandker L., Manova K., Pandolfi P. P. (2005) "Role of nucleophosmin in embryonic development and tumorigenesis" Nature 437, 147-53
Bernardi R., Guernah I., Jin D., Grisendi S., Alimonti A., Teuya-Feldstein J., Cordon-Cardo C., Simon M. C., Rafii S., Pandolfi P. P. (2006) "PML inhibits Hif-1α translation and neoangiogenesis through repression of mTOR" Nature 442, 779-785.
Choi Y. H., Bernardi R., Pandolfi P. P., Benveniste E. N. (2006) "The promyelocytic leukemia protein functions as a negative regulator of INF-g signaling" Proc Natl Acad Sci U.S.A. 103, 18715-18720.
Ma L., Teruya-Feldstein J., Bonner P., Bernardi R., Franz D. N., Cordon-Cardo C. and Pandolfi P. P. (2007) "Identification of S664 TSC2 phosphorylation as a marker for Erk-mediated mTOR activation in tuberous sclerosis and human cancer" Cancer Res. 67, 7106-7112.
Cheng K., Grisendi S., Clohessy S., Majid S., Bernardi R., Sportoletti P and Pandolfi P. P. (2007) "Cytoplasmic nucleophosmin leukemic mutant (NPMc+) is an oncogene with paradoxical functions: Arf inactivation and induction of cellular senescence" Oncogene 26, 7391-7400.
Bernardi R. and Pandolfi P. P. (2007) "Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies" Nature Reviews Mol. Cell Biol. 8, 1006-1016.
Ito K., Bernardi R., Morotti A., Matsuoka S., Saglio G., Ikeda Y., Rosenblatt J., Avigan D. E., Teruya-Feldstein J. and Pandolfi P. P. (2008) "PML targeting eradicates quiescent leukaemia-initiating cells" Nature 453, 1072-1078.
Fumagalli S., Di Cara A., Neb-Gulati A., Natt F., Schwemberger S., Hall J., Babcock G. F., Bernardi R., Pandolfi P. P. and Thomas G. (2009) "Absence of nucleolar disruption after impairment of 40S ribosome biogenesis reveals an rpL11-translation-dependent mechanism of p53 induction" Nat. Cell Biol. 11, 501-508.
Giorgi C., Ito K., Lin H. K., Wieckowski M. R., Lebiedzinska M., Bononi A., Bonora M., Duszynski J., Bernardi R., Rizzuto R., Tacchetti C., Pinton P and Pandolfi P. P. (2010) "PML regulates apoptosis at endoplasmic reticulum by modulating calcium release" Science 330, 1247-1251.
Bernardi R.*, Papa A., Egia A., Coltella N., Teruya-Feldstein J., Signoretti S. and Pandolfi P. P.* (2011) "Pml represses tumor progression through inhibition of mTOR" EMBO Mol. Med. 3, 249-257. * Bernardi R. and Pandolfi P. P co-corresponding authors.
Project Title:
Project Title:
Role of HIF factors in stem cell maintenance
HIF factors are the main regulators of cellular and systemic adaptive responses to hypoxic conditions, and are highly expressed in the hypoxic areas of solid tumors and in ischemic tissues, where they promote VEGF expression and neo-angiogenesis.
In physiological conditions, in tissues such as the brain and the hematopoietic system in the bone marrow, it has been demonstrated that stem cells reside in hypoxic niches that localize either apart from blood vessels or in contact with specialized, fenestrated blood vessels that maintain a hypoxic state (1). In line with this, it is recently becoming apparent that HIF factors are expressed in stem cell niches in many organs, where they regulate stem cells physiology. Interestingly, it has been suggested that HIF factors regulate stem cell maintenance through mechanisms not directly related to increased angiogenesis, but rather cell-autonomously through the induction of various and perhaps tissue-specific stem cell maintenance programs.
We propose to investigate the role of HIF factors in subsets of neural and bone marrow stem cells in vivo, through a conditional approach that leads to the expression of stable forms of HIF factors in specific cell compartments.
Inducible HIF transgenic mice (2) will be crossed with Cre expressing mice to drive the expression of HIF factors in neural stem cells and in bone marrow stem cell populations. Also, crosses with Cre-inducible YFP transgenic mice will allow ex vivo sorting of cell populations expressing Cre recombinase.
To assess the role of HIF factors in mediating stem cell maintenance in different tissues, and to dissect cell autonomous versus non/cell autonomous mechanisms to stem cell maintenance, we will: 1. assess whether stem cell compartments are expanded in vivo and analyze the effect of such expansion on tissue physiology; 2. sort stem cells ex vivo and analyze gene expression programs by high throughput analysis and analysis of known HIF-target genes; 3. serially propagate various stem cell types in vitro, and test their ability to self-renew in a cell autonomous manner.
(1) Ehninger and Trumpp, 2011, JEM 100, 421
(2) Kim WY et al., EMBO J. 25, 4650-4662, 2009
In physiological conditions, in tissues such as the brain and the hematopoietic system in the bone marrow, it has been demonstrated that stem cells reside in hypoxic niches that localize either apart from blood vessels or in contact with specialized, fenestrated blood vessels that maintain a hypoxic state (1). In line with this, it is recently becoming apparent that HIF factors are expressed in stem cell niches in many organs, where they regulate stem cells physiology. Interestingly, it has been suggested that HIF factors regulate stem cell maintenance through mechanisms not directly related to increased angiogenesis, but rather cell-autonomously through the induction of various and perhaps tissue-specific stem cell maintenance programs.
We propose to investigate the role of HIF factors in subsets of neural and bone marrow stem cells in vivo, through a conditional approach that leads to the expression of stable forms of HIF factors in specific cell compartments.
Inducible HIF transgenic mice (2) will be crossed with Cre expressing mice to drive the expression of HIF factors in neural stem cells and in bone marrow stem cell populations. Also, crosses with Cre-inducible YFP transgenic mice will allow ex vivo sorting of cell populations expressing Cre recombinase.
To assess the role of HIF factors in mediating stem cell maintenance in different tissues, and to dissect cell autonomous versus non/cell autonomous mechanisms to stem cell maintenance, we will: 1. assess whether stem cell compartments are expanded in vivo and analyze the effect of such expansion on tissue physiology; 2. sort stem cells ex vivo and analyze gene expression programs by high throughput analysis and analysis of known HIF-target genes; 3. serially propagate various stem cell types in vitro, and test their ability to self-renew in a cell autonomous manner.
(1) Ehninger and Trumpp, 2011, JEM 100, 421
(2) Kim WY et al., EMBO J. 25, 4650-4662, 2009
Project Title:
Role of HIF factors in multiple myeloma
Pro-angiogenic factors such as VEGF are highly expressed in a subset of hematological malignancies, where their expression correlates with increased bone marrow angiogenesis. In multiple myeloma (MM), increased bone marrow angiogenesis has been observed in patients and also in animal models, but only recently the molecular causes are beginning to be investigated.
HIF factors are the main regulators of cellular and systemic adaptive responses to hypoxia, and for this reason are highly expressed in hypoxic areas within solid tumors, where they promote VEGF expression and neo-angiogenesis. Moreover, activation of certain oncogenic pathways (e.g. Myc, Ras and Akt) has been shown to upregulate HIF activity independently of hypoxic conditioning (1).
In MM, along with high VEGF levels and bone marrow angiogenesis, it was recently reported that HIF factors are upregulated in a significant percentage of patients (2), and activation of c-Myc, which occurs in about 30-50% of MM patients, was suggested to cause HIF-1α upregulation (3).
What remains to be established is whether HIF upregulation, an event that reportedly occurs early upon MM development, promotes disease initiation and/or progression through non cell-autonomous mechanisms, i.e. by stimulating angiogenesis, and/or in a cell autonomous manner by promoting myeloma cells survival, homing to specific bone marrow niches and resistance to therapy.
We propose to overexpress or silence HIF-1alpha in human MM cells lines and in primary murine multiple myeloma cells and analyze: gene expression profiles, in vitro cell autonomous properties (proliferation, differentiation, migration and self-renewal) and in vivo disease progression upon bone marrow transplantation into immunocompromized or syngenic mice. The role of known or novel target genes in mediating HIF effects will be then studied in detail through gene silencing approaches.
Finally, mouse models will be employed to assess the feasibility of inhibiting HIF to inhibit myeloma progression.
(1) Martin et al., 2011, Leukemia 100, 3767
(2) Giatromanolaki et al., 2010, Anticancer Res. 30, 2831
(3) Zhang et al., 2009, Cancer Res. 69, 5082
HIF factors are the main regulators of cellular and systemic adaptive responses to hypoxia, and for this reason are highly expressed in hypoxic areas within solid tumors, where they promote VEGF expression and neo-angiogenesis. Moreover, activation of certain oncogenic pathways (e.g. Myc, Ras and Akt) has been shown to upregulate HIF activity independently of hypoxic conditioning (1).
In MM, along with high VEGF levels and bone marrow angiogenesis, it was recently reported that HIF factors are upregulated in a significant percentage of patients (2), and activation of c-Myc, which occurs in about 30-50% of MM patients, was suggested to cause HIF-1α upregulation (3).
What remains to be established is whether HIF upregulation, an event that reportedly occurs early upon MM development, promotes disease initiation and/or progression through non cell-autonomous mechanisms, i.e. by stimulating angiogenesis, and/or in a cell autonomous manner by promoting myeloma cells survival, homing to specific bone marrow niches and resistance to therapy.
We propose to overexpress or silence HIF-1alpha in human MM cells lines and in primary murine multiple myeloma cells and analyze: gene expression profiles, in vitro cell autonomous properties (proliferation, differentiation, migration and self-renewal) and in vivo disease progression upon bone marrow transplantation into immunocompromized or syngenic mice. The role of known or novel target genes in mediating HIF effects will be then studied in detail through gene silencing approaches.
Finally, mouse models will be employed to assess the feasibility of inhibiting HIF to inhibit myeloma progression.
(1) Martin et al., 2011, Leukemia 100, 3767
(2) Giatromanolaki et al., 2010, Anticancer Res. 30, 2831
(3) Zhang et al., 2009, Cancer Res. 69, 5082