Santiago Lima attended the University of Georgia as an undergrad, where he was also a Division I Swimmer, and where he obtained a doctoral degree in Biochemistry and Molecular Biology in 2008. His PhD focused on macromolecular X-ray crystallography and enzymology under the direction of Robbie Phillips. He continued his training as a post-doctoral fellow in Bob Sauer’s lab at MIT, where he discovered that lipopolysaccharides are a co-activator of the bacterial envelope stress response (published in Science, 2013). He then expanded his training by joining the research group of Sarah Spiegel at VCU, who is a world-renown lipid biologist. In her lab, Santiago developed a passion for the roles that cellular glycosphingolipids play in Cancer.
Lung cancer is the leading cause of cancer deaths in the US and worldwide, and in the US surpasses the second, third, and fourth most common cancer deaths combined. Around 80% of all lung cancers are non-small cell lung cancer (NSCLC). Unfortunately, five-year survival rates for NSCLC are very low, a rate second only to pancreatic cancer, and the prognosis following metastatic NSCLC diagnosis can be less than one year. In the US alone, over 221,000 new cases of lung cancer were estimated for 2015. Current treatment options are mostly palliative with goals to reduce symptoms and extend life. Although lung cancers are already the leading cause of cancer deaths in the US, their incidence is 18% higher amongst non-Hispanic men of color, who are also 1.2-times more likely to die from lung cancer than White men. 5-year lung cancer survival rates are 5% lower for African American men. Although lung cancer health disparities have reduced in the last 30 years, contributing factors are complex, and include biological factors, as well as access to health care and socioeconomic variables. However, addressing socioeconomic risk factors in and of by itself has not been sufficient to fully explain disparities, as correcting for socioeconomic factors and access to care, African Americans still show worse cancer outcomes and increased mortality. Some of my research is focused on understanding the sphingolipid alterations that occur in cancer, particularly in NSCLC, and how these contribute to the onset of disease, how aggressive it is, and the role that sphingolipids play in acquired and intrinsic drug resistance. Ultimately, these processes are important to all patients with cancer, but as Hispanic-American myself, I believe that taking a closer look at potential molecular origins of health disparities amongst racial minorities in the US population is of critical importance. I use mass spectrometry to analyze the lipid profiles of NSCLC tumors to evaluate if there are any biologically relevant variables that might contribute to the health disparities observed in NSCLC between Black men of color and other races.
Chemotherapeutic agents such as cisplatin enter cells at least in part through endocytic pathways, which are altered in many cancers, and autophagy is recognized as a major mechanism used by cancer cells to evade therapeutic cytotoxicity. Ultimately, we wish to understand how genetic and non-genetic changes in sphingolipid metabolism and the composition of cellular membranes lead to alterations of these two critical pathways, and how these contribute to decreased delivery, levels, and efficacy of chemotherapeutics. There is extensive evidence demonstrating the critical role of sphingolipids in cellular trafficking processes like endocytosis. In addition, because many important lipids are transported by ATP binding cassette (ABC) transporters, and many of these are implicated with drug resistance in cancer, we seek to characterize any correlations between ABC transporters, sphingolipids, and chemoresistance. Some of the important questions my lab seeks to answer are; Whether reduced endocytic traffic leads to lower levels of internalization of chemotherapeutic agents? Or do alterations in lipid metabolism lead do increased ABC transporter levels and thus higher efflux of drugs? Do changes in membrane sphingolipid composition affect the trafficking and activity of strong oncogenic growth factor receptors such as EGFR that play such important roles in cancers such as NSCLC?
In my lab, we use various molecular approaches and techniques to study these questions including confocal and phase contrast microscopy, CRISPR-CAS9, protein biochemistry, mass spectrometry, cell culture, and cancer animal models.
Lima S, Takabe K, Newton J, Saurabh K, Young MM, et al. TP53 is required for BECN1- and ATG5-dependent cell death induced by sphingosine kinase 1 inhibition. Autophagy. 2018 Jan 25;:1-50. PubMed PMID: 29368980.
Vettorazzi M, Angelina E, Lima S, Gonec T, Otevrel J, et al. An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors. Eur J Med Chem. 2017 Oct 20;139:461-481. PubMed PMID: 28822281.
Lima S, Milstien S, Spiegel S. Sphingosine and Sphingosine Kinase 1 Involvement in Endocytic Membrane Trafficking. J Biol Chem. 2017 Feb 24;292(8):3074-3088. PubMed PMID: 28049734; PubMed Central PMCID: PMC5336145.
Newton J, Lima S, Maceyka M, Spiegel S. Revisiting the sphingolipid rheostat: Evolving concepts in cancer therapy. Exp Cell Res. 2015 May 1;333(2):195-200. PubMed PMID: 25770011; NIHMSID: NIHMS671493; PubMed Central PMCID: PMC4415605.
Kim EY, Sturgill JL, Hait NC, Avni D, Valencia EC, et al. Role of sphingosine kinase 1 and sphingosine-1- phosphate in CD40 signaling and IgE class switching. FASEB J. 2014 Oct;28(10):4347-58. PubMed PMID: 25002116; PubMed Central PMCID: PMC4202100.
Lima S, Milstien S, Spiegel S. A real-time high-throughput fluorescence assay for sphingosine kinases. J Lipid Res. 2014 Jul;55(7):1525-30. PubMed PMID: 24792926; PubMed Central PMCID: PMC4076073.
Lima S, Guo MS, Chaba R, Gross CA, Sauer RT. Dual molecular signals mediate the bacterial response to outer-membrane stress. Science. 2013 May 17;340(6134):837-41. PubMed PMID: 23687042; NIHMSID: NIHMS553004; PubMed Central PMCID: PMC3928677.
Lima S, Spiegel S. Sphingosine kinase: a closer look at last. Structure. 2013 May 7;21(5):690-2. PubMed PMID: 23664359; NIHMSID: NIHMS477294; PubMed Central PMCID: PMC3711075.
Parrill AL, Lima S, Spiegel S. Structure of the first sphingosine 1-phosphate receptor. Sci Signal. 2012 May 22;5(225):pe23. PubMed PMID: 22623751; NIHMSID: NIHMS451629; PubMed Central PMCID: PMC3632326.
Phillips RS, Ghaffari R, Dinh P, Lima S, Bartlett D. Properties of tryptophan indole-lyase from a piezophilic bacterium, Photobacterium profundum SS9. Arch Biochem Biophys. 2011 Feb 1;506(1):35-41. PubMed PMID: 21081107.
Phillips RS, Lima S, Khristoforov R, Sudararaju B. Insights into the mechanism of Pseudomonas dacunhae aspartate beta-decarboxylase from rapid-scanning stopped-flow kinetics. Biochemistry. 2010 Jun 22;49(24):5066-73. PubMed PMID: 20469880.
Lima S, Sundararaju B, Huang C, Khristoforov R, Momany C, et al. The crystal structure of the Pseudomonas dacunhae aspartate-beta- decarboxylase dodecamer reveals an unknown oligomeric assembly for a pyridoxal- 5'-phosphate- dependent enzyme. J Mol Biol. 2009 Apr 24;388(1):98-108. PubMed PMID: 19265705.
Lima S, Kumar S, Gawandi V, Momany C, Phillips RS. Crystal structure of the Homo sapiens kynureninase-3- hydroxyhippuric acid inhibitor complex: insights into the molecular basis of kynureninase substrate specificity. J Med Chem. 2009 Jan 22;52(2):389-96. PubMed PMID: 19143568.
Lima S, Khristoforov R, Momany C, Phillips RS. Crystal structure of Homo sapiens kynureninase. Biochemistry. 2007 Mar 13;46(10):2735-44. PubMed PMID: 17300176; NIHMSID: NIHMS61910; PubMed Central PMCID: PMC2531291.
Lima A, Lima S, Wong JH, Phillips RS, Buchanan BB, et al. A redox-active FKBP-type immunophilin functions in accumulation of the photosystem II supercomplex in Arabidopsis thaliana. Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12631-6. PubMed PMID: 16894144; PubMed Central PMCID: PMC1567930.
Phillips RS, Chen HY, Shim D, Lima S, Tavakoli K, et al. Role of lysine-256 in Citrobacter freundii tyrosine phenol-lyase in monovalent cation activation. Biochemistry. 2004 Nov 16;43(45):14412-9. PubMed PMID: 15533046.
Gawandi VB, Liskey D, Lima S, Phillips RS. Reaction of Pseudomonas fluorescens kynureninase with beta- benzoyl-L- alanine: detection of a new reaction intermediate and a change in rate-determining step. Biochemistry. 2004 Mar 23;43(11):3230-7. PubMed PMID: 15023073.
Momany C, Levdikov V, Blagova L, Lima S, Phillips RS. Three-dimensional structure of kynureninase from Pseudomonas fluorescens. Biochemistry. 2004 Feb 10;43(5):1193-203. PubMed PMID: 14756555.