Specializing In:Breast cancer Neuroblastoma GTP metabolism Cancer metabolism
Research Interests:Breast cancer Metabolism Metastasis Tumor-microenvironment interactions
About Anna Bianchi-Smiraglia
I joined the faculty of the Cell Stress Biology Department at Roswell Park Comprehensive Cancer Center in October 2018 as an Assistant Member and Assistant Professor of Oncology. I earned my MS in Industrial Biotechnology from the University of Milan, Italy and my PhD in Cellular and Molecular Biology from The State University of New York at Buffalo, within the Roswell Park division.
I performed my post-doctoral training in the laboratory of Dr. Mikhail Nikiforov and was awarded an NIH F32 Fellowship to study the role of GTP metabolism in melanoma invasion and progression. Our work contributed to seminal papers in the field of GTP and invasion as well as resulted in the generation and characterization of the first genetically engineered fluorescent GTP reporters for detection of intracellular GTP levels in live cells (Cell Reports, 2013; Cell Death and Differentiation, 2015; Oncogene, 2017; Nature Methods, 2017). Additionally, we identified a novel transcriptional regulator of polyamine metabolism and a drug to suppress this pathway in multiple myeloma (Journal of Clinical Investigation, 2018).
My laboratory is currently NCI-funded by an R37 and is interested in understanding the metabolic pathways and signaling events that contribute to breast cancer and neuroblastoma progression, as well as identifying novel therapeutic options for these cancers. In particular, we are focusing on canonical and non-canonical roles of GTP metabolic enzymes in TNBC progression, and novel pro-tumorigenic roles of transcription factor AhR in neuroblastoma.
- Assistant Professor of Oncology
- Cell Stress Biology
Education and Training:
- 2007-2012 - PhD - State University of New York at Buffalo, Roswell Park Division, Buffalo, NY
- 1997-2002 - MS - Industrial Biotechnologies, University of Milan, Milan, Italy
- 2015-2018 - Ruth L. Kirschstein National Research Service Award (NIH-F32), GTP metabolism, Roswell Park Comprehensive Cancer Center
- American Association of Cancer Research (AACR)
- 2012-2018 - Post-Doctoral Fellow - Roswell Park Cancer Institute, Department of Cell Stress Biology, Buffalo, NY
- 2007-2012 - Graduate Student - Roswell Park Cancer Institute, Department of Cancer Genetics, Buffalo, NY
- 2006-2007 - Research Affiliate - Roswell Park Cancer Institute, Department of Immunology, Buffalo, NY
- 2002-2006 - Research Affiliate - University of Milan, Department of Medical Chemistry, Biochemistry and Biotechnology
Honors & Awards:
- 2020 - R37
- 2015 - Ruth L. Kirschstein National Research Service Award (NIH-F32)
- 2011 - Susan G. Komen for the Cure, Scholar-in-Training Award
Breast cancer is the leading cancer for incidence and second for mortality, in women in the United States. Metastasis is the primary cause of breast cancer associated mortality and once tumors are able to disseminate a patient’s survival chances decrease precipitously. Recently, our group has unveiled a fundamental connection between GTP metabolism and tumor invasion. GTP biosynthesis at its final steps requires the activity of two key enzymes (IMPDH1/2 and GMPS) to convert the purine precursor IMP into GMP. A functional antagonist (GMPR) converts GMP back into IMP. High levels of IMPDH2/GMPS and low levels of GMPR are associated with poor survival in breast cancer patients, especially those with triple negative breast cancer (TNBC, the deadliest subtype, which has higher rates of recurrence and metastasis). Currently, we are investigating the molecular interactions and signaling cascades connecting GTP production to invasion capability in TNBC.
Polyamines are small polycationic molecules that have been implicated in virtually every aspect of eukaryotic cells, including DNA replication, transcription, translation, and proliferation. Polyamine levels are increased in malignancies, where they contribute to disease progression and metastasis. We recently reported the discovery of the aryl hydrocarbon receptor (AHR) as a major transcriptional regulator of polyamine biosynthesis in both normal and transformed cells and provided evidence suggesting that inhibition of AHR by the FDA-approved drug clofazimine is clinically-relevant as an anti-multiple myeloma strategy. We are currently investigating polyamines metabolism and its inhibition in neuroblastoma, one of the most common extra-cranial solid tumors in children. Neuroblastoma is often characterized by MYCN amplification, and the MYC family was the first transcriptional regulator identified for one of the rate-limiting enzymes for polyamine production, ODC. We are currently investigating the role of AHR and its suppression in respect to neuroblastoma progression as well as to the inter-relationship between AHR and MYCN in the control of polyamine biosynthesis.
1. Bianchi-Smiraglia A*, Wolff DW, Marston DJ, Deng Z, Han Z, Moparthy S, Wombacher RM, Mussell AL, Shen S, Chen J, Yun DH, O’Brien Cox A, Furdue C, Hurley E, Feltri ML, Qu J, Hollis T, Nde Kengne JB, Fongang, B Sousa RJ, Kandel ME, Kandel ES, Hahn KM, and Nikiforov MA (2021). Localized GTP availability is an essential step in regulation of RAC1 activity and cell invasion.
Nature Communications Oct 19;12(1):6091. doi: 10.1038/s41467-021-26324-6.
* Co-corresponding author
2. Bianchi-Smiraglia A, Bagati A, Fink EE, Affronti HC, Lipchick BC, Mopharty S, Long MD, Rosario SR, Lightman SM, Moparthy K, Wolff DW, Yun DH, Han Z, Polechetti AJ, Roll MV, Gitlin II, Leonova KI, Rowsam AM, Kandel ES, Gudkov AV, Bergsagel PL, Lee KP, Smiraglia DJ, and Nikiforov MA (2018). Inhibition of the aryl hydrocarbon receptor / polyamine biosynthesis axis suppresses multiple myeloma.
Journal of Clinical Investigation Oct 1;128(10):4682-4696. doi: 10.1172/JCI70712.
Commentary by Dr. Casero RA; J Clin Invest, Oct 1; 128 (10), 4254-4256. doi: 10.1172/JCI123266.
3. Bianchi-Smiraglia A, Rana MS, Foley CE, Paul LM, Lipchick BC, Moparthy S., Moparthy K, Fink EE, Bagati A, Hurley E, Affronti HC, Bakin AV, Kandel ES, Smiraglia DJ, Feltri ML, Sousa R, and Nikiforov MA (2017). Internally ratiometric fluorescent sensors for evaluation of intracellualr GTP levels and distribution.
Nature Methods Oct;14(10):1003-1009. doi: 10.1038/nmeth.4404. Epub 2017 Sep 4.
4. Bianchi-Smiraglia A, Bagati A, Fink EE, Moparthy S, Wawrzyniak JA, Marvin EK, Battaglia S, Jowdy P, Kolesnikova M, Foley CE, Berman AE, Kozlova NI, Lipchick BC, Paul-Rosner LM, Bshara W, Ackroyd JJ, Shewach DS, Nikiforov MA. Microphthalmia-associated transcription factor suppresses invasion by reducing intracellular GTP pools. Oncogene. 2017 Jan 5;36(1):84-96. doi: 10.1038/onc.2016.178. Epub 2016 May 16. PMID: 27181209; PMCID: PMC5112150.
5. Bianchi-Smiraglia A, Wawrzyniak JA, Bagati A, Marvin EK, Ackroyd J, Moparthy S, Bshara W, Fink EE, Foley CE, Morozevich GE, Berman AE, Shewach DS, Nikiforov MA. Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity. Cell Death Differ. 2015 Nov;22(11):1858-64. doi: 10.1038/cdd.2015.47. Epub 2015 Apr 24. PMID: 25909885; PMCID: PMC4648332.