Sergio Gradilone - The Hormel Institute

Sergio Gradilone, Ph.D. 
Associate Professor
sgradilone@hi.umn.edu

Cancer Cell Biology & Translational Research

Biography

Dr. Gradilone initiated his basic research interests back in his home country, Argentina, where he first obtained a B.S. degree in Chemistry, then a M.S. in Biotechnology and finally the Ph.D. in Biological Sciences degree at the National University of Rosario. He moved to the U.S. in 2006 to continue his research training in the biomedical field at the prestigious Mayo Clinic in Rochester, MN, where he was a postdoctoral research fellow until 2010 when he obtained his first faculty position there and focused his research in the biology and pathobiology of a peculiar cellular organelle, the primary cilium.

Dr. Gradilone has been honored with several awards including:  the “New Named Investigator Award” from the Mayo Clinic Center for Cell Signaling in Gastroenterology; the Wendy Will Case Cancer Fund Award and a Fraternal Order of Eagles Fellowship, awards that initiated Dr. Gradilone cancer research focus; the “Outstanding Research Fellow” award from the department of medicine at Mayo Clinic Rochester, as well as the American Liver Foundation and PKD Foundation research fellowships.

Gradilone’ s laboratory focuses on understanding the basic biological processes involved with a normal cell transforming into a cancerous one. In particular, Gradilone is investigating the role of the primary cilium in tumor biology. Primary cilia are multisensory organelles – similar to a cell antenna – that sense and receive signals from the environment surrounding the cells. Gradilone has found that these antennae are lost in tumor cells, and is trying to understand the mechanisms of ciliary loss and determine the consequences of such a loss. The lab primary cilia research is focused now on an aggressive, lethal form of liver cancer known as “cholangiocarcinoma” that derives from epithelial cells of the bile ducts. Its incidence has been increasing worldwide in recent decades and there is no effective treatment for it. Loss of primary cilia also has been described in other solid tumors, including pancreatic, prostate, breast and kidney cancers, broadening the spectrum of potential applications of this research.

Education

Postdoctoral training

Mayo Clinic, Rochester, MN 2006-2010

Degrees

Ph.D., 2005, School of Biochemical and Pharmaceutical Sciences. National University of Rosario. Argentina.

M.S., 1999, Biotechnology. School of Biochemical and Pharmaceutical Sciences. National University of Rosario. Argentina.

B.S., 1992, Chemistry. Superior Polytechnic Institute. National University of Rosario. Argentina.

Professional memberships

 2007 – Member, American Society for Cell Biology (ASCB). 

2008 – Member, American Gastroenterological Association (AGA). 

2010 – Member, American Association for the Study of Liver Diseases (AASLD). 

2010 – Member, Argentine Society of Physiology (SAFIS). 

2014 – External Advisory Board. Argentine Society of Physiology (SAFIS). 

2015- Member, Masonic Cancer Center, University of Minnesota. 

2015 – Member, American Association for Cancer Research (AACR). 

2015- International Advisor – European Network for the Study of Cholangiocarcinoma (ENS-CCA) 

Publications

1. Mansini AP, Lorenzo Pisarello MJ, Thelen KM, Cruz-Reyes M, Peixoto E, Jin S, Howard BN, Trussoni CE, Gajdos GB, LaRusso NF, Perugorria MJ, Banales JM, Gradilone SA. “MiR-433 and miR-22 dysregulations induce HDAC6 overexpression and ciliary loss in cholangiocarcinoma”. Hepatology. 2018 Feb 6. doi: 10.1002/hep.29832. [Epub ahead of print]
https://doi.org/10.1002/hep.29832

2. Mansini AP, Peixoto E, Thelen KM, Gaspari CI, Jin S, Gradilone SA. “The Cholangiocyte Primary Cilium in Health and Disease” Biochim Biophys Acta, in press, 2017.
https://doi.org/10.1016/j.bbadis.2017.06.006

3. Peixoto E, Mansini AP, Thelen KM, Gaspari CI, Jin S, Gradilone SA. “The Role of Primary Cilia in Cancer” Physiological Mini Reviews, 10(1), 2017.
https://pmr.safisiol.org.ar/archive/vol/10

4. Gradilone SA. “Extracellular vesicles as therapeutic carriers of microRNAs for cholangiocarcinoma”. Hepatology, 65(2):404-406, 2017.
https://doi.org/10.1002/hep.28925

5. Ji B, Harris BR, Liu Y, Deng Y, Gradilone SA, Cleary MP, Liu J, Yang DQ. “Targeting IRES-Mediated p53 Synthesis for Cancer Diagnosis and Therapeutics”. Int J Mol Sci, 18(1), 2017.
https://doi.org/10.3390/ijms18010093

6. Merino-Azpitarte M, Lozano E, Perugorria MJ, Esparza-Baquer A, Erice O, Santos-Laso Á, O’Rourke CJ, Andersen JB, Jiménez-Agüero R, Lacasta A, D’Amato M, Briz Ó, Jalan-Sakrikar N, Huebert RC, Thelen KM, Gradilone SA, Aransay AM, Lavín JL, Fernández-Barrena MG, Matheu A, Marzioni M, Gores GJ, Bujanda L, Marin JJ, Banales JM. “SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma”. J Hepatol, 67(1):72-83, 2017.

https://doi.org/10.1016/j.jhep.2017.02.017

7. Gradilone SA*, Lorenzo Pisarello MJ, LaRusso NF. “Primary Cilia in Tumor Biology: The Primary Cilium as a Therapeutic Target in Cholangiocarcinoma”. Current Drug Targets, 18:958-963, 2017. *Corresponding author.
https://doi.org/10.2174/1389450116666150223162737

8. Gradilone SA*, O’Hara SP, Masyuk TV, Lorenzo Pisarello MJ, LaRusso NF. “miRNAs and Benign Biliary Tract Diseases”. Semin Liver Dis, 35(1):26-35, 2015. *Corresponding author.

9. O’Hara SP, Gradilone SA, Masyuk TV, Tabibian JH, LaRusso NF. “MicroRNAs in Cholangiopathies.” Curr Pathobiol Rep, 2(3):133-142, 2014.

10. Masyuk AI, Gradilone SA, LaRusso NF. “Calcium signaling in cilia and ciliary-mediated intracellular calcium signaling: Are they independent or coordinated molecular events?” Hepatology, 60(5):1783-5, 2014.

11. Gradilone SA*, Habringer S, Masyuk TV, Radtke BN, LaRusso NF. “HDAC6 is overexpressed in cystic cholangiocytes and its inhibition reduces cystogenesis” Am J Pathol, 184(3):600-8, 2014. *Co-corresponding author.

12. Razumilava M, Gradilone SA, Smoot RL, Mertens JC, Bronk SF, Sirica AE, Gores GJ. “Noncanonical Hedgehog Signaling Contributes to Chemotaxis in Cholangiocarcinoma” J Hepatol, 60(3):599-605, 2014.

13. Masyuk TV, Lee SO, Radtke BN, Stroope AJ, Huang BQ, Banales JM, Masyuk AI, Splinter PL, Gradilone SA, Gajdos GB, LaRusso NF. “Centrosomal abnormalities characterize human and rodent cystic cholangiocytes and are associated with Cdc25A over-expression“. Am J Pathol, 184:110-21, 2014.

14. Gradilone SA,* Radtke BN, Bogert PS, Huang BQ, Gajdos GB, LaRusso NF. “Inhibition of HDAC6 restores ciliary expression and decreases cholangiocarcinoma growth in vitro and in vivo.” Cancer Research, 73(7):2259-70, 2013. *Corresponding author.

15. Masyuk AI, Huang BQ, Radtke BN, Gajdos GB, Splinter PL, Masyuk TV, Gradilone SA, Larusso NF. “Ciliary subcellular localization of TGR5 determines the cholangiocyte functional response to bile acid signaling.” Am J Physiol Gastrointest Liver Physiol, 304(11):G1013-24, 2013.

16. Tietz Bogert PS, Huang BQ, Gradilone SA, Masyuk TV, Moulder GL, Ekker SC, Larusso NF. “The Zebrafish as a Model to Study Polycystic Liver Disease.” Zebrafish, 10(2):211-7, 2013.

17. Masyuk TV, Radtke BN, Stroope AJ, Banales JM, Gradilone SA, Huang B, Masyuk AI, Hogan MC, Torres VE, Larusso NF. “Pasireotide is more effective than Octreotide in reducing hepato-renal cystogenesis in rodents with polycystic kidney and liver diseases.” Hepatology, 58(1):409-21, 2013.

18. Masyuk TV, Radtke BN, Stroope AJ, Banales JM, Masyuk AI, Gradilone SA, Gajdos GB, Chandok N, Bakeberg JL, Ward CJ, Ritman EL, Kiyokawa H, Larusso NF. “Inhibition of Cdc25A Suppresses Hepato-renal Cystogenesis in Rodent Models of Polycystic Kidney and Liver Disease” Gastroenterology, 142(3):622-633.e4, 2012.

19. Masyuk AI, Huang BQ, Ward CJ, Gradilone SA, Banales JM, Masyuk TV, Radtke B, Splinter PL, Larusso NF*. “Biliary exosomes influence cholangiocyte regulatory mechanisms and proliferation through interaction with primary cilia” Am J Physiol Gastrointest Liver Physiol, 299(4):G990-9, 2010.

20. Gradilone SA, Masyuk TV, Banales JM, Radtke BN, Huang BQ, Masyuk AI, LaRusso NF*. “Trpv4 is a Potential Target to Reduce the Hyperproliferative Phenotype of Cholangiocytes in Polycystic Liver Disease” Gastroenterology, 139(1):304-14, 2010.

21. Soria LR, Gradilone SA, Larocca MC, Marinelli RA*. “Glucagon induces the gene expression of aquaporin-8 but not that of aquaporin-9 water channels in the rat hepatocytes” Am J Physiol, 296(4):R1274-81, 2009.

22. Banales JM, Gradilone SA.* “Primers on Molecular Pathways – Ion Channels: Key Regulators of Pancreatic Physiology” Pancreatology, 9(5):556-559, 2009.

23. Banales JM, Masyuk TV, Gradilone SA, Masyuk AI, Medina JF, LaRusso NF*. “The cAMP Effectors Epac and PKA are Involved in the Hepatic Cystogenesis of an Animal Model of ARPKD” Hepatology, 49(1):160-74, 2008.

24. Banales JM, Masyuk TV, Bogert PS, Huang BQ, Gradilone SA, Lee SO, Stroope AJ, Masyuk AI, Medina JF, LaRusso NF*. “Hepatic Cystogenesis is Associated with Abnormal Expression and Location of Ion Transporters and Water Channels in an Animal Model of ARPKD” Am J Pathol, 173(6):1637-46, 2008.

25. Masyuk AI, Gradilone SA, Banales JM, Masyuk TV, LaRusso NF*. “Cholangiocyte primary cilia are chemosensory organelles that detect biliary nucleotides via P2Y12 purinergic receptors” Am J Physiol, 295(4):G725-34, 2008.

26. Lehmann GL, Carreras FI, Soria LR, Gradilone SA, Marinelli RA*. “LPS induces the TNF-mediated down-regulation of rat liver aquaporin-8: role in sepsis-associated cholestasis.” Am J Physiol, 294(2):G567-75, 2008.

27. Gradilone SA, Masyuk AI, Splinter PL, Banales JM, Huang BQ, Tietz PS, Masyuk TV, Larusso NF*. “Cholangiocyte cilia express TRPV4 and detect changes in luminal tonicity inducing bicarbonate secretion.” Proc Natl Acad Sci U S A 104(48):19138-43, 2007.

28. Mottino AD, Carreras FI, Gradilone SA, Marinelli RA, Vore M*. “Canalicular membrane localization of hepatocyte aquaporin-8 is preserved in estradiol-17beta-d-glucuronide-induced cholestasis.” J Hepatol 44(1):232-3, 2006.

29. Gradilone SA, Tietz PS, Splinter PL, Marinelli RA, Larusso NF*. “Expression and subcellular localization of aquaporin water channels in the polarized hepatocyte cell line, WIF-B.” BMC Physiol. 5(1):13, 2005.

30. Gradilone SA, Carreras FI, Lehmann GL, Marinelli RA*. “Phosphatidylinositol-3-Kinase is involved in the Glucagon-Induced Translocation of Aquaporin-8 to Hepatocyte Plasma Membrane”. Biol. Cell, 97(11):831-6, 2005.

31. Gradilone SA, Carreras FI, Lehmann GL, Marinelli RA*. “Rol de las Aquaporinas en la Secreción Biliar”. Sociedad Iberoamericana de Información Científica (SIIC). Sección Expertos Invitados. http://www.siicsalud.com/dato/dat041/05207007.htm , 2005.

32. Marinelli RA*, Gradilone SA, Carreras FI, Calamita G, Lehmann GL. “Liver Aquaporins: Significance in Canalicular and Ductal Bile Formation”. Annals of Hepatology 3:130-136, 2004.

33. Lehmann GL, Gradilone SA, Marinelli RA*. “Aquaporin Water Channels in Central Nervous System”. Current Neurovascular Research 1: 269-281, 2004.

34. Gradilone SA, García F, Huebert RC, Tietz PS, Larocca MC, Kierbel A, Carreras FI, LaRusso NF, Marinelli RA*. “Glucagon Induces the Plasma Membrane Insertion of Functional Aquaporin-8 Water Channels in Isolated Rat Hepatocytes” Hepatology 37:1435-1441, 2003.

35. Carreras FI, Gradilone SA, Mazzone A, García F, Huang BQ, Ochoa JE, Tietz PS, LaRusso NF, Calamita G, Marinelli RA*. “Rat hepatocyte aquaporin-8 water channels are down-regulated in extrahepatic cholestasis” Hepatology 37:1026-1033, 2002.

36. Gradilone SA, Ochoa JE, García F, Larocca MC, Pellegrino JM, Marinelli RA* “Water Permeability Measured by Silicone Layer Filtering Centrifugation.” Anal. Biochem. 302:104-107, 2002.

37. García F, Kierbel A, Larocca MC, Gradilone SA, Splinter P, LaRusso NF, Marinelli RA*. “The water channel aquaporin-8 is mainly intracellular in rat hepatocytes and its plasma membrane insertion is stimulated by cyclic AMP”. J. Biol. Chem. 276:12147-12152, 2001.

38. Gradilone SA, Arranz SE, Cabada MO*. “Detection of Highly Glycosylated Proteins in Polyacrylamide Gels” Anal. Biochem. 261:224-227, 1998.

 

Contact Information

Primary Research Areas

Tumor cell biology and translational research
Primary cilia in tumor biology

Our section started in November 2014 and we equipped the new laboratory, putting together a small team to start moving our research forward. The “Cancer Cell Biology and Translational Research” section focuses on understanding the basic biological processes involved with a normal cell transforming into a cancerous one. By understanding these mechanisms, potential therapeutic interventions might be envisioned. We currently are investigating the role of the primary cilium in tumor biology. Primary cilia are multisensory organelles, similar to a cell antenna, that sense and receive signals from the environment surrounding the cells. We.ve found that these antennae are lost in tumor cells; therefore, we are trying to understand the mechanisms of ciliary loss and what are the consequences of such a loss. Furthermore, as we gain knowledge on these mechanisms, we now are able to induce the restoration of primary cilia or emulate their functions in tumor cells and bring back the malignant cells to a more normal phenotype, which might contribute to the development of new therapeutic strategies based on the rescue of primary cilia integrity. The lab primary cilia research is focused now on an aggressive, lethal form of liver cancer known as cholangiocarcinoma, that derives from epithelial cells of the bile ducts. Its incidence has been increasing worldwide in recent decades and there is no effective treatment for it. Loss of primary cilia also has been described in other solid tumors, including pancreatic, prostate, breast and kidney cancers . broadening the spectrum of potential applications of this research. Our work is funded by the National Cancer Institute, part of the National Institutes of Health. The results of our research are uncovering novel and generalizable information on fundamental, ciliary-dependent mechanisms controlling the proliferation of malignant cells and provide the foundation for plausible, novel anti-cancer therapies based on the restoration of primary cilia architecture and function. By partnering with collaborators directly engaged in the treatment of patients and with pharmaceutical industries, our ultimate goal is to translate our basic research to the bedside by developing new clinical trials for these diseases.

Research Specialties

Liver Cancer
Bile duct cancer, Cholangiocarcinoma

Awards

2012                 New Named Investigator Award. Mayo Clinic Center for Cell Signaling in Gastroenterology

2011                 Wendy Will Case Cancer Fund Award

2009                 Outstanding Research Fellow. DOM Education and Research Awards.

2009                 Mayo Clinic Cancer Center. The Fraternal Order of Eagles Fellowship.

2009                 Mayo Clinic Nominee for the Pew Scholarship in the Biomedical Sciences.

2008                 AASLD Single Topic Conference Travel Award.

2008                 FASEB Summer Conference Poster Award.

2008-2009         American Liver Foundation. Irwin M. Arias, MD Postdoctoral Research Fellowship.

2006-2007        PKD Foundation Research Fellowship, USA.

2004-2006         Research Fellowship from the Argentinean National Council of Research (CONICET).

2003-2004        Research Fellowship from ANTORCHAS Foundation.

1999-2002         Research Fellowship from Argentinean National Agency for the Promotion of Science and Technology.