Laura Danai
Lecturer
Office
LGRT 922
(413) 545-0277
Focus
Cellular and systemic metabolism, animal physiology
Background and Training
PhD: University of Massachusetts Medical School
Postdoctoral Training: Massachusetts Institute of Technology
 
Research Summary

A hallmark of cancer cells is aberrant cell proliferation. To proliferate, cancer cells must acquire biosynthetic precursors to make macromolecules such as lipids, proteins, and nucleotides. Thus, cancer cells display metabolic adaptations that allow these cells to carry out diverse metabolic reactions that generate the precursors for these macromolecules (DeBerardinis and Chandel 2016; Vander Heiden and DeBerardinis 2017). Understanding these metabolic adaptations is important, as they are tumor cell vulnerabilities that can be therapeutically targeted.

For the past few years, I have been studying pancreatic ductal adenocarcinoma (PDAC) tumors, which are extremely hypoxic and the dense stromal microenvironment (Hingorani 2014; Perera and Bardeesy 2015; Stylianopoulos et al. 2012) limits tumor perfusion and nutrient access. Therefore, PDAC cells must be uniquely adapted to produce biomass precursors and grow in such a nutrient-limited setting. Yet, most studies examining PDAC metabolism have been performed in vitro, either utilizing PDAC-derived cancer cells or using genetic studies of PDAC-derived cells and re-implanting these cells as subcutaneous xenografts (Guillaumond et al. 2013; Son et al. 2013). Studies using these systems largely ignore the unique physiology and microenvironmental conditions in which cancer cells in PDAC tumors normally grow. Indeed, recent studies and my own work have found that the environmental differences between in vivo tumors and tissue culture can lead to dramatic differences in metabolic adaptations (Davidson et al. 2016; Muir 2016). There is an urgent need for understanding PDAC metabolism in vivo as PDAC is one of the most lethal cancers in the United States with increasing incidence rates and abysmal treatment options (Siegel, Naishadham, and Jemal 2013). My research interests include: (a) to identify the specific metabolic programs that PDAC cells utilize in vivo and (b) to systematically examine how these metabolic adaptations contribute to PDAC initiation, growth, and metastasis.

 
 
Publications

Sullivan MR, Danai LV, Lewis CA, Chan SH, Gui DY, Kunchok T, Dennstedt EA, Vander Heiden MG. Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability. Elife 2019, 16, 8.

Hillis AL*, Lau AN, Devoe CX, Dayton TL, Danai LV, Di Vizio D, Vander Heiden MG. PKM2 is not required for pancreatic ductal adenocarcinoma. Cancer Metab 2018, 6: 17. 

Muir A, Danai LV, Vander Heiden MG. Microenvironmental regulation of cancer cell metabolism: implications for experimental design and translational studies. Dis Model Mech 2018, 11(8).

Sullivan, L. B., Luengo, A., Danai, L. V., Bush, L. N.*, Diehl, F. F., Hosios, A. M., Lau, A. N., Elmiligy, S., Malstrom, S., Lewis, C. A., and Vander Heiden, M. G. (2018) Aspartate is an endogenous metabolic limitation for tumour growth, Nat Cell Biol 20, 782-788.

Danai, L. V., Babic, A., Rosenthal, M. H., Dennstedt, E. A., Muir, A., Lien, E. C., Mayers, J. R., Tai, K.*, Lau, A. N., Jones-Sali, P., Prado, C. M., Petersen, G. M., Takahashi, N., Sugimoto, M., Yeh, J. J., Lopez, N., Bardeesy, N., Fernandez-Del Castillo, C., Liss, A. S., Koong, A. C., Bui, J., Yuan, C., Welch, M. W., Brais, L. K., Kulke, M. H., Dennis, C., Clish, C. B., Wolpin, B. M., and Vander Heiden, M. G. (2018) Altered exocrine function can drive adipose wasting in early pancreatic cancer, Nature 558, 600-604.

Wyant, G. A., Abu-Remaileh, M., Wolfson, R. L., Chen, W. W., Freinkman, E., Danai, L. V., Vander Heiden, M. G., and Sabatini, D. M. (2017) mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient, Cell 171, 642-654 e612.

Muir, A., Danai, L. V., Gui, D. Y., Waingarten, C. Y.*, Lewis, C. A., and Vander Heiden, M. G. (2017) Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition, Elife 6.

Guilherme, A., Pedersen, D. J., Henchey, E., Henriques, F. S., Danai, L. V., Shen, Y., Yenilmez, B., Jung, D., Kim, J. K., Lodhi, I. J., Semenkovich, C. F., and Czech, M. P. (2017) Adipocyte lipid synthesis coupled to neuronal control of thermogenic programming, Mol Metab 6, 781-796.

Roth Flach, R. J., DiStefano, M. T., Danai, L. V., Senol-Cosar, O., Yawe, J. C., Kelly, M., Garcia Menendez, L., and Czech, M. P. (2017) Map4k4 impairs energy metabolism in endothelial cells and promotes insulin resistance in obesity, Am J Physiol Endocrinol Metab 313, E303-E313.

DiStefano, M. T., Roth Flach, R. J., Senol-Cosar, O., Danai, L. V., Virbasius, J. V., Nicoloro, S. M., Straubhaar, J., Dagdeviren, S., Wabitsch, M., Gupta, O. T., Kim, J. K., and Czech, M. P. (2016) Adipocyte-specific Hypoxia-inducible gene 2 promotes fat deposition and diet-induced insulin resistance, Mol Metab 5, 1149-1161.

Mayers, J. R., Torrence, M. E.*, Danai, L. V., Papagiannakopoulos, T., Davidson, S. M., Bauer, M. R., Lau, A. N., Ji, B. W., Dixit, P. D., Hosios, A. M., Muir, A., Chin, C. R., Freinkman, E., Jacks, T., Wolpin, B. M., Vitkup, D., and Vander Heiden, M. G. (2016) Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers, Science 353, 1161-1165.

Roth Flach, R. J., Danai, L. V., DiStefano, M. T., Kelly, M., Menendez, L. G., Jurczyk, A., Sharma, R. B., Jung, D. Y., Kim, J. H., Kim, J. K., Bortell, R., Alonso, L. C., and Czech, M. P. (2016) Protein Kinase Mitogen-activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4) Promotes Obesity-induced Hyperinsulinemia, J Biol Chem 291, 16221-16230.

Roth Flach, R. J., Guo, C. A., Danai, L. V., Yawe, J. C., Gujja, S., Edwards, Y. J., and Czech, M. P. (2016) Endothelial Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 Is Critical for Lymphatic Vascular Development and Function, Mol Cell Biol 36, 1740-1749.

Hosios, A. M., Hecht, V. C., Danai, L. V., Johnson, M. O., Rathmell, J. C., Steinhauser, M. L., Manalis, S. R., and Vander Heiden, M. G. (2016) Amino Acids Rather than Glucose Account for the Majority of Cell Mass in Proliferating Mammalian Cells, Dev Cell 36, 540-549.

Roth Flach, R. J., Skoura, A., Matevossian, A., Danai, L. V., Zheng, W., Cortes, C., Bhattacharya, S. K., Aouadi, M., Hagan, N., Yawe, J. C., Vangala, P., Menendez, L. G., Cooper, M. P., Fitzgibbons, T. P., Buckbinder, L., and Czech, M. P. (2015) Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis, Nat Commun 6, 8995.

Pedersen, D. J., Guilherme, A., Danai, L. V., Heyda, L.*, Matevossian, A., Cohen, J., Nicoloro, S. M., Straubhaar, J., Noh, H. L., Jung, D., Kim, J. K., and Czech, M. P. (2015) A major role of insulin in promoting obesity-associated adipose tissue inflammation, Mol Metab 4, 507-518.

DiStefano, M. T., Danai, L. V., Roth Flach, R. J., Chawla, A., Pedersen, D. J., Guilherme, A., and Czech, M. P. (2015) The Lipid Droplet Protein Hypoxia-inducible Gene 2 Promotes Hepatic Triglyceride Deposition by Inhibiting Lipolysis, J Biol Chem 290, 15175-15184.

Danai, L. V., Flach, R. J., Virbasius, J. V., Menendez, L. G., Jung, D. Y., Kim, J. H., Kim, J. K., and Czech, M. P. (2015) Inducible Deletion of Protein Kinase Map4k4 in Obese Mice Improves Insulin Sensitivity in Liver and Adipose Tissues, Mol Cell Biol 35, 2356-2365.

Li, Q., Li, S., Mana-Capelli, S., Roth Flach, R. J., Danai, L. V., Amcheslavsky, A., Nie, Y., Kaneko, S., Yao, X., Chen, X., Cotton, J. L., Mao, J., McCollum, D., Jiang, J., Czech, M. P., Xu, L., and Ip, Y. T. (2014) The conserved misshapen-warts-Yorkie pathway acts in enteroblasts to regulate intestinal stem cells in Drosophila, Dev Cell 31, 291-304.

Danai, L. V., Guilherme, A., Guntur, K. V., Straubhaar, J., Nicoloro, S. M., and Czech, M. P. (2013) Map4k4 suppresses Srebp-1 and adipocyte lipogenesis independent of JNK signaling, J Lipid Res 54, 2697-2707.

Stoffolano, J. G., Jr., Danai, L.*, and Chambers, J. (2013) Effect of channel blockers on the smooth muscle of the adult crop of the queen blowfly, Phormia regina, J Insect Sci 13, 97.

(* indicates high-school or undergraduate co-author)