Andrew N. Lane, PhD

Connect

859-218-2868
andrew.lane@uky.edu
525 Lee T. Todd Jr. Building

Positions

  • Professor

College Unit(s)

Other Affiliation(s)
  • Markey Cancer Center

Biography and Education

Education

B.Sc., University College London, England Ph.D., University College London, England Post Doctoral: Biozentrum Basel, Switzerland EMBO Fellow at Stanford Magnetic Resonance Laboratory, California Scientist, National Institute for Medical Research, London, England Program Leader, Structural Biology, JG Brown Cancer Center, Louisville KY Professor, Dept. Toxicology and Cancer Biology, University of Kentucky

Research

My research is primarily in the area of cancer metabolism and biophysics, and I am co-director of the Center for Environmental and Systems Biochemistry (CESB), with primary responsibility for NMR.  The Center maintains high-end analytical instrumentation, especially mass spectrometry and NMR, for metabolism and structural biology [http://bioinformatics.cesb.uky.edu/RCSIRM/WebHome].

The group specializes in user stable isotope tracer methods to follow the fate of individual atoms from source molecules through metabolic transformations in human subjects and in a variety of model systems that have been developed in the laboratory, including freshly resected human tissue, mouse models (PDX and transgenic) and 2 and 3 D cell cultures.

Table 1

 

Lane AN, Higashi RM, Fan TW-M: Preclinical models for interrogating drug action in human cancers using Stable Isotope Resolved Metabolomics (SIRM) Metabolomics 2016, 12:1-15

1. Lung Cancer

Our primary interest is in lung cancer where we use the various models to dissect the complexity and heterogeneity of tumors (Table 1), using patient derived tissues.  We are particularly interested in the tumor microenvironment, how the tumor architecture changes as the cancer progresses, and the interactions between cancer cells and stromal cells and the immune system.  We combine the Stable Isotope Resolved Metabolomics (SIRM) approach with genomics, targeted proteomics and modeling to produce a Systems level view of cancer development.  As such this research requires extensive collaborations physicians and surgeons, pathologists, cell biologists and informaticians.

  1. 1.            Cellular Systems Biochemistry: Microenvironmental nutrient availability and immunomodulation in patient derived cancer and immune cells  
  2. 2.            Complex Systems Biochemistry: Determining tumor metabolism and biochemical mechanism  of immune modulation in vivo and in human lung tissue slices
  3. 3.            Integrative Systems Biochemistry: Determining molecular mechanisms of NSCLC and immune responses by genetic and computational approaches. 

Using these approaches, we have identified pyruvate carboxylase as an important enzyme in NSCLC (Sellers K, et al. (2015) Pyruvate carboxylase is critical for non–small-cell lung cancer proliferation. J Clin Invest 125:687-698). (Figure 1)

 

We have also developed improved means of introducing tracers into mice for longer labelling periods without stressing the animals (Sun et al. 2017 Nature Commun. 8, 1646). This enables a more detailed metabolic analysis of the tumor in the in vivo context. We now have the capability of in situ NMR imaging of tumors, as well as metabolic analyses, prior to extraction of tissues (Figure 2).

 

2. Immune Metabolism

There is considerable interest in how the immune system acts in tumors and the influence of the microenvironment on macrophages and T-cells, as well as for the potential for therapeutic modulation of immune cell activity.  We have been using SIRM to analyse immune metabolism in mouse cells and NSCLC tissue slices, and activation of macrophages by beta glucan (Figure 3).

Liu M, Luo F, Ding C, Albeituni S, Hu X, Ma Y, Cai Y, McNally L, Sanders MA, Jain D, Kloecker G, Bousamra M 2nd, Zhang HG, Higashi RM, Lane AN, Fan TW, Yan J. (2015) Particulate β-Glucan Converts Immunosuppressive Macrophages into M1 Phenotype Through Dectin-1-induced Syk-Card9-Erk Pathway and Raf-1-c-Maf Pathway. J. Immunol. 195, 5055-5065

Fan, T. W-M.,  Warmoes, M.O., Sun, Q., Song, H., Turchan-Cholewo, J., Martin, J.T.,  Mahan, A.L., Higashi, R.M., Lane, A.N. (2016) Distinctly perturbed metabolic networks underlie differential tumor tissue damages induced by immune modulator -glucan in a two-case ex vivo non-small cell lung cancer study. CSH Molec. Case Studies J. 2, a000893

 

 We are also collaborating with Dr. Ruoning Wang at Nationwide Childrens Hospital, Columbus OH on the metabolism of CAR-T cells in vitro, and most recently with Dr. Elizabeth Repasky at Roswell Park Cancer Institute, Buffalo, on understanding how adrenergic signaling influences immune contexture of tumors and the efficacy of checkpoint inhibitors.

3. Other cancers

We also collaborate with a group at NCI on rare familial kidney cancers that have lesions in fumarate hydratase or succinate dehydrogenase, that lead to interesting metabolic reprogramming  (Yang et al. (2013) PlosOne 8, e27179; Saxena et al. (2015) JNCI 108, djv287

4. Metabolism, epigenetics and biophysics

 The control of DNA methylation in CpG steps has numerous important biological consequences. Both methylation via DNA methyl transferases utilizing SAM as the methyl donor, and demethylation by successive oxidations by TET are intimately associated with cell metabolism (Figure 4), which can be dissected by SIRM techniques. 

 

The biophysical influence of the 5-methyl group on C, and its various oxidation products (5-hydroxymethyl, 5-formyl and 5-carboxy) are less clear, and the mechanisms by which enzymes recognize the modified cytosine are unclear.  In collaboration with Prof. Tom Brown at the University of Oxford, we have been applying X-ray crystallography, NMR and other biophysical approaches to address the structural properties of these modifications.  NMR showed that the 5-formyl group has only local effects on DNA structure, which in solution is in the B-form (Figure 5), compared with crystallographic analyses that show the DNA in the A-form.

 

Hardwick, J.S., Ptchelkine , D., El Sagheer, A.H., Tear, I., Singleton, D., Phillips, S.E.V.,  J.,

Lane, A.N., Brown, T. (2017) X-ray crystallography and NMR show that 5-formylcytosine does not change the global structure of DNA. Nat. Struct. Biol. 24,

544–552; Hardwick, J., Lane, A.N., Brown, T. (2018) Epigenetic modifications of cytosine: biophysical properties, regulation and function in mammalian DNA. BioEssays 40, 1700199

Selected Publications

1. Fan, T.W-M., Higashi, R.M., Lane, A.N. & Jardetzky, O. (1986) Combined Use of 1H NMR and GC-MS for Monitoring Metabolites and in vivo  1H NMR. Biochim. Biophys. Acta882: 154-167

2. Nair,M., McIntosh, P.B.,Frenkiel, T.A., Kelly, G., Taylor,I.A., Smerdon, S.J., & LaneA.N. (2003) NMR Structure of the DNA-binding Domain of the Cell Cycle protein, Mbp1 from Saccharomyces cerevisiae.  Biochemistry, 42 1266 –1273  

3. Fan, T. W-M., Bandura, L.L., Lane, A.N. & Higashi, R.M. (2005) Metabolomics-Edited Transcriptomics Analysis of Se Anticancer Action in human lung cancer cells. Metabolomics  1, 325-339

4. Thornburg, J.M., Nelson, K.K., Lane, A.N., Arumugam, S., Simmons, A. Eaton, J.W., Telang, S., & Chesney, J. (2008) Targeting Aspartate Aminotransferase in Breast Cancer Breast Cancer Res. 10:R84 PMCID:PMC2614520

5. Lane, A.N., Chaires, J.B., Gray, R.D. & Trent, J.O. (2008)  “Stability and kinetics of G-quartet structures” Nucl. Acids Res. 36, 5482-5515. PMCID: PMC2553573

6. Lane AN, Fan TW-M, Xie X, Moseley HN, Higashi RM.  (2009) Stable isotope analysis of lipid biosynthesis by high resolution mass spectrometry and NMR.  Anal Chim Acta651:201-8; PMC2757635.

7. Yalcin A, Clem BF, Simmons S, Lane AN, Nelson KK, Clem AL, Brock E, Siow D, Wattenberg B, Telang S, Chesney J.  (2009) Nuclear targeting of 6-phosphofructo-2-kinase(PFKFB3) increases proliferation via cyclin-dependent kinases.  J. Biol. Chem. 284:24223-32; PMCID: PMC2782016.

8. Fan, T.WM., Lane, A.N., Higashi, R.M., Farag, M.A., Gao, H., Bousamra, M.  & Miller, D.M. (2009)

9. Miller, M.C., Buscaglia, R., Chaires, J.B., Lane, A.N., Trent, J.O. (2010) Hydration determines the G-quadruplex stability and conformation of the human telomere 3’ sequence d(A(GGGTTA)3GGG)). JACS. 132, 17105-17107.

10. Fan, T. W-M., Lane, A.N., Higashi, R.M., Yan, J. (2011) Stable Isotope Resolved Metabolomics of Lung Cancer in a SCID Mouse Model. Metabolomics 7, 257-269 PMCID: PMC3109995

11. Moseley, H.N.B., Lane, A.N.,Belshoff, A.C, Higashi, R.M. Fan, W. W-M. (2011) Non-Steady State Modeling of UDP-GlcNAc Biosynthesis Enabled by Stable Isotope Resolved Metabolomics. BMC Biology. 9:37. PMCID: PMC3126751

12. Fan, T.W-M. & Lane, A.N. (2011)NMR-based  Stable Isotope Resolved Metabolomics  in Systems Biochemistry. J. Biomolec. NMR Sp. Edn. 49:267–280 PMCID: PMC3125551

13. Le, A., Lane, A.N., Hamaker, M., Bose, S., Gouw, A., Barbi, J., Tsukamoto, T., Rojas, C.J., Slusher, B.S., Zhang, H., Zimmerman, L.J., Liebler, D.C., Slebos, R.J.C., Lorkiewicz, P.K., Higashi, R.M., Fan, T.W-M., Dang, C.V. (2012) MYC induction of hypoxic glutamine metabolism and a glucose-independent TCA cycle in human B lymphocytes. Cell Metabolism. 15, 110-121. PMCID: PMC3345194

14. Fan, T.W-M., Lorkiewicz, P.,  Sellers, K., Moseley, H.N.B.,  Higashi, R.M., Lane, A.N. (2012). Stable Isotope-resolved metabolomics: past, present, and future. Pharmacology & Therapeutics.  133:366-391 PMCID: PMC3471671

15. Liu, W., Le, A., Fan, T. W-M., Lane, A.N.,  Dang, C.V., Phang, J.M.(2012) The reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses to c-MYC.  PNAS 109:8983-8988. PMCID: PMC3384197

16. Yang, Y., Lane, A.N., Ricketts, C.R., Wei, M-H., Wu, M., Rouault, T.A., Boros, L.G., Fan, T.W-M., Linehan, W.M. (2013)Metabolic Reprogramming for Producing Energy and Reducing Power in Fumarate Hydratase Null Cells from Hereditary Leiomyomatosis Renal Cell Carcinoma.   PlosOne 8:e72179 PMCID:PMC3744468

17. Lane A.N. (2013) Bacterial repression: The Lac and Trp Systems. Online Encyclopedia of Biophysics, Edited by G.C.K. Roberts. Springer Verlag. DOI 10.1007/978-3-642-16712-6 Pp 168-172. 

18. Reynolds,M.R., Lane, A.N., Kemp, S., Liu, Y., Hill, B., Dean, D.C., Clem, B.F. (2014)Control of Glutamine Metabolism By the Tumor Suppressor Rb. Oncogene 33(5):556-66. PMCID: PMC3918885

19. Xie, H., Hanai, J-i., Ren, J-G., Kats, L., Burgess, K., Bhargava, P., Signoretti, S., Billiard, J., Duffy, K.J., Grant, A., Wang, X., Lorkiewicz, P.K., Schatzman, S., Bousamra, M. II, Lane, A.N., Higashi, R.M., Fan, T. W-M., Pandolfi, P.P.,  Sukhatme, V.P., and Seth, P. (2014) Targeting lactate dehydrogenase-A (LDH-A) inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor initiating cells. Cell Metabolism 19, 795–809. PMCID:PMC4096909

20. D.B. Wilburn, K.E. Bowen, K.A. Doty, S. Arumugam,  A.N. Lane, P.W. Feldhoff, and R.C. Feldhoff (2014). Sexual selection drives a novel disulfide bond pattern in a three-finger protein pheromone. PLosOne. 9(5):e96975 PMC4029566

21. Buscaglia, R., Miller, M.C., Gray, R.D., Lane, A.N., Trent, J.O., Chaires, J.B. (2013) Contributions of hydration, molecular crowding, and differential binding to the cosolvents driven conversion of the human telomeric G-quadruplex. Nucl. Acids. Res.41:7934-46. doi: 10.1093/nar/gkt440:

22. Yang, Y., Lane, A.N.#, Ricketts, C.R., Wei, M-H., Wu, M., Roualt, T.A., Boros, L.G., Fan, T.W-M., Linehan, W.M. (2013) Metabolic Reprogramming for Producing Energy and Reducing Power in Fumarate Hydratase Null Cells from Hereditary Leiomyomatosis Renal Cell Carcinoma.   PlosOne 8, e72179

23. Reynolds, M.R., Lane, A.N., Kemp, S., Liu, Y., Hill, B., Dean, D.C., Clem, B.F. (2014) Control of Glutamine Metabolism By the Tumor Suppressor Rb. Oncogene 33(5):556-66. doi: 10.1038/onc.2012.635

24. Guin, S., Pollard, C., Owens, C., Ru, Y., Lew, C.R., Dancik, G., Spencer, A., Knight, S., HoGupta, S., Hansel, D., Hellerstein, M., Lorkiewicz, P.K., Lane, A.N., Fan, T. W-M.,& Theodorescu, D. (2014) . AGL, a glycogen debranching enzyme lost in humanglycogen storage disease, suppresses tumor growth. JNCI  106 dju062 doi:10.1093/jnci/dju062

25. Xie, H., Hanai, J-i., Ren, J-G., Kats, L., Burgess, K., Bhargava, P., Signoretti, S., Billiard, J., Duffy, K.J., Grant, A., Wang, X., Lorkiewicz, P.K., Schatzman, S., Bousamra, M. II, Lane, A.N., Higashi, R.M., Fan, T. W-M., Pandolfi, P.P.,  Sukhatme, V.P., and Seth, P. (2014) Targeting lactate dehydrogenase-A (LDH-A) inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor initiating cells. Cell Metabolism, 19, 795–809

26. D.B. Wilburn, K.E. Bowen, K.A. Doty, S. Arumugam,  A.N. Lane, P.W. Feldhoff, and R.C. Feldhoff. (2014) Sexual selection drives a novel disulfide bond pattern in a three-finger protein pheromone. PLosOne. 9(5):e96975

27. Ren, J-G., Seth, P.,  Clish, C.B., Lorkiewicz, P.K., Higashi, R.M., Lane, A.N., Fan, T. W-M., Sukhatme, V.P. (2014) Knockdown of Malic Enzyme 2 Suppresses Lung Tumor Growth. Knockdown of Malic Enzyme 2 Suppresses Lung Tumor Growth, Induces Differentiation and Impacts PI3K/AKT Signaling. Scient. Rep. 4, 5414

28. Chesney, J., Clark, J., Klarer, A.C., Imbert-Fernandez, Y., Lane, A.N. and Telang, S. (2014) Fructose-2,6-Bisphosphate Synthesis by PFKFB4 is Required for the Glycolytic Response to Hypoxia and Tumor Growth. Oncotarget 5, 6670-6686

29. Sellers, K., Fox, M.P., Bousamra, M., Slone, S., Higashi, R.M.,Miller, D.M., Wang, Y.,Yan, J., Yuneva, M., Deshpande, R., Lane, A.N.,* Fan, T. W-M.* (2015) Pyruvate carboxylase is upregulated in NSCLC. J. Clin Invest.  125(2): 687-698

30. Lane, A.N.*, Arumugam, S., Lorkiewicz P.K., Higashi, R.M., Laulhe, S., Nantz, M.H.,Moseley, H.N.B., Fan, T. W-M. (2015) Chemoselective detection of carbonyl compounds in metabolite mixtures by NMR. Mag Res Chem. 53, 337-343 DOI 10.1002/mrc.4199

31. Lane, A.N.* & Fan,T-WM.  (2015) Regulation of nucleic acid metabolism in mammalian cells. Nucl.Acids Res. 43, 2466-85

32. Saxena, N., Maio, N.,  Crooks, D.R., Ricketts, C.J., Yang, Y.,  Wei, M-H., Fan, T. W-M., Lane, A.N., Sourbier, C.,  Rouault, T.A.,   Linehan, W.M. (2015) SDHB-Deficient Cancers: The Role of Mutations That Impair Iron Sulfur Cluster Delivery. JNCI 108, djv287

33. Liu M, Luo F, Ding C, Albeituni S, Hu X, Ma Y, Cai Y, McNally L, Sanders MA, Jain D,Kloecker G, Bousamra M 2nd, Zhang HG, Higashi RM, Lane AN, Fan TW, Yan J. (2015) Particulate β-Glucan Converts Immunosuppressive Macrophages into M1Phenotype Through Dectin-1-induced Syk-Card9-Erk Pathway and Raf-1-c-Maf Pathway. J. Immunol. 195, 5055-5065

34. Lane, A.N.*, Fan, T. W-M.,  Yan, J. (2015) 13C Tracer studies in mouse tumor xenografts. Bio-protocol 5(22): e1650. http://www.bio-protocol.org/e1650

35. Fan, T. W-M.,  Lane, A.N., Higashi, R.M. (2016) Stable Isotope Resolved Metabolomics studies in ex vivo tissue slices. Bio-protocol 6, e1730  http://www.bio-protocol.org/e1730

36. Fan, T. W-M. & Lane, A.N. (2016) Applications of NMR to Systems Biochemistry Prog. NMR Spectrosc. 92,18-53

37. Fan, T. W-M.,  Warmoes, M.O., Sun, Q., Song, H., Turchan-Cholewo, J., Martin, J.T.,    Mahan, A.L., Higashi, R.M., Lane, A.N. (2016) Distinctly perturbed metabolic networksunderlie differential tumor tissue damages induced by immune modulator b-glucan in a two-case ex vivo non-small cell lung cancer study. CSH Molec. Case Studies J. 2, a000893

38. Lane, A.N.*, Higashi, R.M. & Fan, T. W-M. (2016) Preclinical models for interrogating drugaction in human cancers using Stable Isotope Resolved Metabolomics (SIRM) Metabolomics 12, 118 

39. Beger, R.D., Dunn, W.,  Schmidt, M.A.; Gross S.S., Kirwan, J.A., Cascante, M., Brennan, L.,Wishart, D.S., Oresic, M.,  Hankemeier, T., Broadhurst, D.I., Hankemeier, Lane, A.N.,Suhre, K., Zanetti, K., Kastenmüller, G. & Kaddurah-Daouk, R. “Metabolomics Enables Precision Medicine - A White Paper, Community Perspective” Metabolomics Precision Medicine Sp. Iss. 12, 149-

40. Wang, Q., Zhou,Y., Rychahou, P., Fan, T.W-M., Lane, A.N.,  Weiss, H.L., Evers, B.M.  (2016) Ketogenesis contributes to intestinal cell differentiation. Cell Death and Differentiation, 24, 458-468

41. Lane, A.N.*, Tan, J.,  Wang, Y., Yan, J., Higashi, R.M., Fan, T.W-M. (2017) Probing themetabolic phenotype of breast cancer cells by multiple tracer Stable Isotope ResolvedMetabolomics. Metabolic engineering sp issue 43, 125-136 10.1016/j.ymben.2017.01.010

42. Lane, A.N.* & Fan, T. W-M. (2017) NMR-Based Stable Isotope Resolved Metabolomics inSystems Biochemistry. Arch Biochem. Biophys 628, 123-131 doi.org/10.1016/j.abb.2017.02.009

43. Hardwick, J.S., Ptchelkine , D., El Sagheer, A.H., Tear, I., Singleton, D., Phillips, S.E.V.,  J., Lane, A.N.*, Brown, T.* (2017) X-ray crystallography and NMR show that 5-formylcytosine does not change the global structure of DNA. Nat. Struct. Biol. 24,544–552

44. Yang, Y., Fan, W. W-M., Lane, A.N. & Higashi, R.M. (2017) Chloroformate Derivatization for Tracing the Fate of Amino Acids in Cells by Multiple Stable Isotope Resolved Metabolomics (mSIRM). Anal. Chim. Acta 976, 63-73

45. Bruntz, R., Higashi, R.M., Lane, A.N.*, Fan, T. W-M.*  (2017) Exploring Cancer Metabolism using Stable Isotope Resolved Metabolomics (SIRM). J. Biol. Chem. 292, 11601-11609.  

46. Matrka, M.C., Watanabe, M., Menon, R.M., Lambert, P.F.,  Lane, A.N., Romick-Rosendale, L.E., Wells, S.I. (2017) Overexpression of the human DEK oncogene reprograms cellular metabolism. PLoS One 12: e0177952

47. Sun, R.C.,  Fan, T. W-M.*, Deng, P., Higashi, R.M., Lane, A.N., Scott, T.L., Sun, Q.,Warmoes, M.O., Yang, Y. (2017) Noninvasive liquid diet delivery of stable isotopes into mouse models for deep metabolic network tracing.  Nat. Commun. 8, 1646

 48. Deng, P., Higashi, R.M., Lane, A.N., Bruntz, R.C., Sun, R.C., Raju, R.R., Nantz, M.H., Qi, Z., Fan, T. W-M. (2018) Quantification and Identification of Carbonyls Using Chemoselective Tagging and Nanospray FT-MS. Analyst. 143, 311-322

49. Hardwick, J., Lane, A.N.*, Brown, T.* (2018) Epigenetic modifications of cytosine: biophysical properties, regulation and function in mammalian DNA. BioEssays DOI: 10.1002/bies.201700199

Pubmed Publications