David A. Foster, Rosalyn Yalow Professor
413 East 69th Street
New York, NY 10021
Mail Box 180
- A.B., 1976, University of California, Berkeley
- M.A., 1978, Columbia University
- Ph.D., 1982, Columbia University
- Postdoc., 1982-1986, The Rockefeller University
- Cancer Biology
Our lab has two major research focuses. The first is the promotion of cancer cell survival by the generation of the oncometabolite phosphatidic acid (PA). PA is generated by several different mechanisms including - de novo membrane phospholipid biosynthesis, diacylglycerol kinase (DGK), and phospholipase D (PLD). PA is critical for the activation of mTOR – the mammalian target of rapamycin – a critical integrator of both growth factor and nutrient signals. Since PA is the product of glycolysis and fatty acid synthesis, it is proposed that PA requirement of mTOR represents a key nutrient input to mTOR indicating that there is sufficient glucose and lipids available for a dividing cell to double its mass and form two daughter cells. The generation of PA by DGK and PLD likely evolved as a means to regulate PA levels and mTOR via growth factor signals. In this regard, it is significant that PLD activity is elevated in virtually all cancer cells where it has been investigated. The second major focus of the lab is the metabolic control of cell cycle progression. A major hallmark of cancer is the dysregulation of G1 cell cycle checkpoints. We have identified several late G1 checkpoints that are sensitive to the presence of – essential amino acids, the “conditionally” essential amino acid glutamine, lipids and another mediated by mTOR. Importantly, KRas-driven cancer cells override the glutamine checkpoint and arrest in S-phase rather than G1 when deprived of glutamine. The S-phase arrest makes KRas-driven cancers (about 30% of human cancer) sensitive to S-phase-specific cytoxic drugs, including rapamycin. In this way, we are exploiting metabolic vulnerabilities of cancer cells to develop strategies to target specifically the cancer cells. These two major focuses of the lab – dysregulated cell cycle progression and PA metabolism – intersect at mTOR, which has been referred to as the most dysregulated signaling node in human cancer.
Selected Publications (from 120):
Jiang H, Luo JQ, Urano T, Frankel P, Lu Z, Foster DA*, and Feig LA. (1995). Involvement of Ral GTPase in v-Src-induced phospholipase D activation. Nature. 378, 409-412, (*corresponding author).
Spiegel S, Foster DA. and Kolesnick R. (1996). Signal transduction through lipid second messengers. Curr. Op. Cell Biol. 8, 159-167.
Lu, Z., Liu, D., Hornia, A., Devonish, W., Pagano, M., and Foster, D.A. (1998). Activation of protein kinase C triggers its ubiquitination and degradation. Mol. Cell. Biol. 18, 839-845. PMCID: PMC108795
Luo, J.-Q., Liu, X., Frankel, P., Rotunda, T., Ramos, M., Flom, J., Jiang, H., Feig, L.A., Morris, A, Kahn, R.A. and Foster, D.A. (1998). Functional association between RalA and Arf in active phospholipase D complexes. Proc. Natl. Acad. Sci. USA. 95, 3632-3637. PMCID: PMC19887
Hornia, A., Lu, Z., Sukezane, T., Zhong, M. Joseph, T., Frankel, P., and Foster, D.A. (1999). Antagonistic effects of protein kinase Ca and d on both transformation and phospholipase D activity mediated by the EGF receptor. Mol. Cell. Biol. 19, 7672-7680. PMCID: PMC84804
Lu, Z., Hornia, A., Joseph, T., Sukezane, T., Frankel, P., (Zhong et al., 2003), M., Bychenok, S., Xu, L., Feig, L.A., and Foster, D.A. (2000). Phospholipase D and RalA cooperate with the EGF receptor to transform 3Y1 rat fibroblasts. Mol. Cell. Biol. 20, 462-467. PMCID: PMC85102
Shen, Y., Xu, L., and Foster, D.A. (2001). Role for phospholipase D in receptor-mediated endocytosis. Mol. Cell. Biol. 21, 595-602. PMCID: PMC86627
Xu, L., Frankel, P., Jackson, D., Rotunda, T., Boshans, R.L., D’Souza-Schorey, C., and Foster, D.A. (2003). Elevated phospholipase D activity in H-Ras-, but not K-Ras-transformed cells by the synergistic action of RalA and Arf6. Mol. Cell. Biol. 23, 645-654. PMCID: PMC151535
Chen, Y., Zheng, Y., and Foster, D.A. (2003). Phospholipase D confers rapamycin resistance in human breast cancer cells. Oncogene. 22, 3937-3942.
Foster, D.A. and Xu, L. (2003). Phospholipase D in cell proliferation and cancer. Mol. Cancer Res. 1, 789-800.
Jackson, D., and Foster, D.A. (2004). The enigmatic protein kinase Cd: Complex roles in cell proliferation and survival. FASEB J. 18, 627-636.
Hui, L., Abbas, T., Pielak, R., Joseph, T., Bargonetti, J. and Foster, D.A. (2004). Phospholipase D elevates the level of MDM2 and suppresses DNA damage-induced increases in p53. Mol. Cell. Biol. 24, 5677-5688. PMCID: PMC480910
Chen, Y., Rodrik, V. and Foster, D.A. (2005). Alternative phospholipase D / mTOR survival signal in human breast cancer cells. Oncogene, 24, 672-679.
Rodrik, V., Zheng, Y., Harrow, F., Chen, Y., and Foster, D.A. (2005). Survival signals generated by estrogen and phospholipase D in MCF-7 breast cancer cells are dependent on Myc. Mol. Cell. Biol. 25, 7917-7925. PMCID: PMC1190308
Hui, L., Rodrik, V., Pielak, R.M., Zheng, Y., and Foster, D.A. (2005). mTOR-dependent suppression of protein phosphatase 2A is critical for phospholipase D survival signals in human breast cancer cells. J. Biol. Chem. 280, 35829-35835.
Cai, D., Zhong, M., Wang, R., Netzer, W.J., Shields, D., Zheng, H., Sisodia, S.S., Foster, D.A., Gorelick, F.S., Xu, H., and Greengard, P. (2006). Phospholipase D1 corrects impaired βAPP trafficking and neurite outgrowth in FAD-linked PS1 mutant neurons. Proc. Natl. Acad. Sci. USA, 103, 1936-1940. PMCID: PMC1413666
Cai, D., Netzer, W.J., Zhong, M., Lin, Y., Guangwei Du, G., Frohman, M., Foster, D.A., Sisodia S.S., Xu, H., Gorelick, F.S., and Greengard, P. (2006). Presenilin-1 (PS1) utilizes phospholipase D1 as a negative regulator of β-amyloid formation. Proc. Natl. Acad. Sci. USA, 103, 1941-1946. PMCID: PMC1413665
Zheng, Y., Rodrik, V., Toschi, A., Shi, M., Hui. L., Shen, Y., and Foster, D.A. (2006). Phospholipase D couples survival and migration signals in response to stress in human breast cancer cells. J. Biol. Chem. 281, 15862-15868.
Hui, L., Zheng, Y., Yan, Y., Bargonetti, J., and Foster, D.A. (2006). Mutant p53 in MDA-MB-231 breast cancer cells is stabilized by elevated phospholipase D activity and contributes to survival signals generated by phospholipase D. Oncogene 25, 7305-7310.
Foster DA. (2007). Regulation of mTOR by phosphatidic acid? Cancer Res. 67, 1-4.
Mor, A., Campi, G., Du, G., Zheng, Y., Foster, D.A., Dustin, M.L., and Philips, M., (2007). The lymphocyte function associated-1 receptor co-stimulates plasma membrane Ras via phospholipase D2. Nature Cell Biol. 9, 713-719.
Gadir, N., Lee, E., Garcia, A., Toschi, A., and Foster, D.A. (2007). Suppression of TGF-b signaling by phospholipase D. Cell Cycle 6, 2840-2845 (Featured on Journal Cover).
Gadir, N., Jackson, D., Lee, E., and Foster, D.A. (2008). Defective TGF-β signaling sensitizes human cancer cells to rapamycin. Oncogene 27, 1055-1062.
Toschi, A., Edelstein, J., Rockwell, P., Ohh, M., and Foster, D.A. (2008). HIFa expression in VHL deficient renal cell carcinoma cells is dependent on phospholipase D. Oncogene, 27, 2746-2753.
Garcia, A., Zheng, Y., Zhao, C., Toschi, A., Fan, J., Schreibman, N., Brown, H.A., Bar-Sagi, D., Foster, D.A.*, and Arbiser, J. (2008). Honokiol suppresses survival signals mediated by Ras-dependent phospholipase D activity in human cancer cells. Clinical Cancer Res. 14, 4267-4274. PMCID: PMC2759181 *Corresponding Author.
Toschi, A., Lee, E., Gadir, N., Ohh, M., and Foster, D.A. (2008). *Differential dependence of HIF1a and HIF2a on mTORC1 and mTORC2. J. Biol. Chem. 283, 34495-34499. PMCID: PMC2596400 *Accelerated Publication
Toschi A, Lee E, Xu L, Garcia A, Gadir N, and Foster DA. (2009). Regulation of mTORC1 and mTORC2 complex assembly by phosphatidic acid – a competition with rapamycin. Mol. Cell. Biol. 29, 1411-1420. PMCID: PMC2648237
Foster DA, and Toschi A. (2009). Targeting mTOR with Rapamycin: One dose does not fit all. Cell Cycle. 8, 1026-1029. PMCID: PMC2778016 (Invited Review)
Foster DA. (2009). Phosphatidic acid signaling to mTOR: Signals for the survival of human cancer cells. Biochem. Biophys. Acta. 1791, 949-955. PMCID: PMC2759177 (Invited Review)
Foster DA, and Darnell JE Jr. Obituary: Hidesaburo Hanafusa (1929-2009) (2009). Nature. 458, 718.
Foster DA. (2010). Reduced mortality and moderate alcohol consumption: The phospholipase D-mTOR connection. Cell Cycle. 9, 1291-1294. PMCID: PMC2957519
Foster DA, Yellen P, Xu L. and Saqcena M. (2010). Regulation of G1 cell cycle progression: Distinguishing the restriction point from a nutrient-sensing cell growth checkpoint. Genes and Cancer. 1, 1124-1131. PMCID: PMC3092273
Xu L, Salloum D, Saqcena M, Yellen P, Medlin PS, Perrella B, and Foster DA. (2011). Phospholipase D mediates nutrient input to mTORC1. J. Biol. Chem. 286, 25477-25486. PMCID: PMC3138251
Yellen P, Saqcena M, Salloum D, Feng J, Preda A, Xu L, Rodrik-Outmezguine V, and Foster DA. (2011). High-dose rapamycin induces apoptosis in human cancer cells by dissociating mTOR complex 1 and suppressing phosphorylation of 4E-BP1. Cell Cycle 10, 3948-3956. PMCID: PMC3266120
Yellen P, Chatterjee A, Preda A, and Foster DA. (2013). Inhibition of S6 kinase suppresses the apoptotic effect of eIF4E ablation by inducing TGF-b-dependent G1 cell cycle arrest. Cancer Lett. 333, 239-243. PMCID: PMC3640435
LeGendre O, Sookdeo A, Duliepre S-A, Utter M, Frias M, and Foster DA. (2013). Suppression of AKT phosphorylation restores rapamycin-mediated synthetic lethality in SMAD4-defective pancreatic cancer cells. Mol Cancer Res. 11, 474-481. PMCID: PMC3640435
Foster DA. (2013). Phosphatidic acid and lipid sensing by mTOR. Trends Endocrin Metab 24, 272-278. PMCID: PMC3669661
Saqcena M, Menon D, Patel D, Mukhopadhyay S, Chow V, and Foster DA. (2013). Distinct nutrient-dependent metabolic checkpoints in mammalian G1 cell cycle. PLoS-One. 8, e71457. PMCID: PMC3747087
Salloum D, Mukhopadhyay S, Tung K, Polonetskaya A, and Foster DA. (2014). Mutant Ras elevates dependence on serum lipids and creates a synthetic lethality for rapamycin. Mol Cancer Ther. 13, 733-741. PMCID: PMC4001122
Foster DA, Salloum D, Menon D, and Frias M. (2014). Phospholipase D and the maintenance of phosphatidic acid levels for regulation of mTOR. J Biol Chem. 289, 22583-22588. PMCID: PMC4132766
Foster DA. (2014). Obituary: Geoffrey Louis Zubay (1931-2014): Pioneer in cell-free gene expression studies and molecular genetics. Trends Biochem Sci. 39, 505-506. PMCID: PMC3669661
Foster DA. (2014). Metabolic vulnerability of K-Ras-driven cancer cells. Mol Cell Oncology. 1, e963445. PMCID:PMC4655600
Saqcena M, Mukhopadhyay S, Hosny, C, Alhamed AA, Chatterjee A, and Foster DA. (2015). Blocking anaplerotic entry of glutamine to TCA cycle sensitizes K-Ras mutant cancer cells to cytotoxic drugs. Oncogene. 34, 2672-2680. PMCID: PMC4418945 Epub Jul 2014.
LeGendre O, Breslin P, and Foster DA. (2015). Oleocanthal rapidly and selectively induces cell death in cancer cells via lysosomal membrane permeabilization (LMP). Mol Cell Oncology. 2, e1006077. PMCID: PMC4568762
Mukhopadhyay S, Saqcena M, Chatterjee A, Garcia A, Frias MA, and Foster, DA. (2015). Reciprocal regulation of AMPK and phospholipase D. J Biol Chem. 290, 6986-6993. PMCID: PMC4358122
Chatterjee A, Mukhopadhyay S, Tung K, Patel D, and Foster DA. (2015). Rapamycin employs TGF-β and Rb pathways to cause cell cycle arrest. Cancer Lett. 360, 134-140. PMCID: PMC4415112
Saqcena, M, Patel D, Menon D, Mukhopadhyay S, and Foster DA. (2015). Apoptotic effects of high dose rapamycin occur in S-phase of the cell cycle. Cell Cycle. 14, 2285-2292. PMCID: PMC4614271
Mukhopadhyay S, Chatterjee A, Kogan D, Patel D, and Foster, DA. (2015). 5-Aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) enhances the efficacy of rapamycin in human cancer cells. Cell Cycle, 14, 3331-3339. PMCID: PMC4825547
Mukhopadhyay S, Saqcena M, and Foster DA. (2015). Synthetic lethality in KRas-driven cancer cells created by glutamine deprivation. Oncoscience, 2, 807-808. PMCID: PMC4671930
Mukhopadhyay S, Frias MA, Chatterjee A, Yellen P, and Foster DA. (2016). The enigma of rapamycin dosage. Mol Cancer Ther. 15, 347-353. PMCID: PMC4783198
Patel D, Menon D, Bernfeld S, Mroz V, Kalan S, Loayza D, Foster DA. (2016). Aspartate rescues S-phase arrest caused by suppression of glutamine utilization in KRas-driven cancer cells. J. Biol Chem. 291, 9322-9329. PMCID: PMC4861495