Academic Appointments

Professional Education

  • Ph.D., Johns Hopkins University School of Medicine (2012)
  • M.Phil., University of Pennsylvania (2011)
  • Master of Arts, University of California Berkeley (2008)
  • B.A., University of California Berkeley (2006)

All Publications

  • The MYC oncogene - the grand orchestrator of cancer growth and immune evasion. Nature reviews. Clinical oncology Dhanasekaran, R., Deutzmann, A., Mahauad-Fernandez, W. D., Hansen, A. S., Gouw, A. M., Felsher, D. W. 2021


    The MYC proto-oncogenes encode a family of transcription factors that are among the most commonly activated oncoproteins in human neoplasias. Indeed, MYC aberrations or upregulation of MYC-related pathways by alternate mechanisms occur in the vast majority of cancers. MYC proteins are master regulators of cellular programmes. Thus, cancers with MYC activation elicit many of the hallmarks of cancer required for autonomous neoplastic growth. In preclinical models, MYC inactivation can result in sustained tumour regression, a phenomenon that has been attributed to oncogene addiction. Many therapeutic agents that directly target MYC are under development; however, to date, their clinical efficacy remains to be demonstrated. In the past few years, studies have demonstrated that MYC signalling can enable tumour cells to dysregulate their microenvironment and evade the host immune response. Herein, we discuss how MYC pathways not only dictate cancer cell pathophysiology but also suppress the host immune response against that cancer. We also propose that therapies targeting the MYC pathway will be key to reversing cancerous growth and restoring antitumour immune responses in patients with MYC-driven cancers.

    View details for DOI 10.1038/s41571-021-00549-2

    View details for PubMedID 34508258

  • Cancer Stem Cell Metabolism. Advances in experimental medicine and biology Alvina, F. B., Gouw, A. M., Le, A. 2021; 1311: 161-172


    Cancer stem cells (CSCs), also known as tumorinitiating cells (TICs), are a group of cells found within cancer cells. Like normal stem cells, CSCs can proliferate, engage in self-renewal, and are often implicated in the recurrence of tumors after therapy [1, 2]. The existence of CSCs in various types of cancer has been proven, such as in acute myeloid leukemia (AML) [3], breast [4], pancreatic [5], and lung cancers [6], to name a few. There are two theories regarding the origin of CSCs. First, CSCs may have arisen from normal stem/progenitor cells that experienced changes in their environment or genetic mutations. On the other hand, CSCs may also have originated from differentiated cells that underwent genetic and/or heterotypic modifications [7]. Either way, CSCs reprogram their metabolism in order to support tumorigenesis.

    View details for DOI 10.1007/978-3-030-65768-0_12

    View details for PubMedID 34014542

  • Mitochondrial copper depletion suppresses triple-negative breast cancer in mice. Nature biotechnology Cui, L., Gouw, A. M., LaGory, E. L., Guo, S., Attarwala, N., Tang, Y., Qi, J., Chen, Y., Gao, Z., Casey, K. M., Bazhin, A. A., Chen, M., Hu, L., Xie, J., Fang, M., Zhang, C., Zhu, Q., Wang, Z., Giaccia, A. J., Gambhir, S. S., Zhu, W., Felsher, D. W., Pegram, M. D., Goun, E. A., Le, A., Rao, J. 2020


    Depletion of mitochondrial copper, which shifts metabolism from respiration to glycolysis and reduces energy production, is known to be effective against cancer types that depend on oxidative phosphorylation. However, existing copper chelators are too toxic or ineffective for cancer treatment. Here we develop a safe, mitochondria-targeted, copper-depleting nanoparticle (CDN) and test it against triple-negative breast cancer (TNBC). We show that CDNs decrease oxygen consumption and oxidative phosphorylation, cause a metabolic switch to glycolysis and reduce ATP production in TNBC cells. This energy deficiency, together with compromised mitochondrial membrane potential and elevated oxidative stress, results in apoptosis. CDNs should be less toxic than existing copper chelators because they favorably deprive copper in the mitochondria in cancer cells instead of systemic depletion. Indeed, we demonstrate low toxicity of CDNs in healthy mice. In three mouse models of TNBC, CDN administration inhibits tumor growth and substantially improves survival. The efficacy and safety of CDNs suggest the potential clinical relevance of this approach.

    View details for DOI 10.1038/s41587-020-0707-9

    View details for PubMedID 33077961


    View details for DOI 10.1111/zygo.12594

    View details for Web of Science ID 000539449700010

  • THE CRISPR APPLE ON THE TREE OF KNOWLEDGE CONFERENCE HIGHLIGHTS: CRISPR IN SCIENCE, ETHICS, AND RELIGION with Arvin M. Gouw, "The CRISPR Apple on the Tree of Knowledge Conference Highlights: CRISPR in Science, Ethics, and Religion"; Arvin M. Gouw, "Introducing the Brave New CRISPR World"; Roger R. Adams, "Moral Decisions about Human Germ-line Modification"; Constance M. Bertka, "Navigating the Future in a Sea of CRISPR Uncertainty"; and Linda Groff, "CRISPR, CRISPR on My Mind." ZYGON Gouw, A. M. 2020; 55 (2): 409–20

    View details for DOI 10.1111/zygo.12591

    View details for Web of Science ID 000539449700009

  • Oncogene MYC regulates lipogenesis essential for neoplastic growth Margulis, K., Gouw, A., Liu, N., Felsher, D., Zare, R. AMER CHEMICAL SOC. 2019
  • The MYC Oncogene Cooperates with Sterol-Regulated Element-Binding Protein to Regulate Lipogenesis Essential for Neoplastic Growth. Cell metabolism Gouw, A. M., Margulis, K., Liu, N. S., Raman, S. J., Mancuso, A., Toal, G. G., Tong, L., Mosley, A., Hsieh, A. L., Sullivan, D. K., Stine, Z. E., Altman, B. J., Schulze, A., Dang, C. V., Zare, R. N., Felsher, D. W. 2019


    Lipid metabolism is frequently perturbed in cancers, but the underlying mechanism is unclear. We present comprehensive evidence that oncogene MYC, in collaboration with transcription factor sterol-regulated element-binding protein (SREBP1), regulates lipogenesis to promote tumorigenesis. We used human and mouse tumor-derived cell lines, tumor xenografts, and four conditional transgenic mouse models of MYC-induced tumors to show that MYC regulates lipogenesis genes, enzymes, and metabolites. We found that MYC induces SREBP1, and they collaborate to activate fatty acid (FA) synthesis and drive FA chain elongation from glucose and glutamine. Further, by employing desorption electrospray ionization mass spectrometry imaging (DESI-MSI), we observed invivo lipidomic changes upon MYC induction across different cancers, for example, aglobal increase in glycerophosphoglycerols. After inhibition of FA synthesis, tumorigenesis was blocked, and tumors regressed in both xenograft and primary transgenic mouse models, revealing the vulnerability of MYC-induced tumors to the inhibition of lipogenesis.

    View details for DOI 10.1016/j.cmet.2019.07.012

    View details for PubMedID 31447321

  • MYC regulates the HIF-2alpha stemness pathway via Nanog and Sox2 to maintain self-renewal in cancer stem cells versus non-stem cancer cells. Cancer research Das, B., Pal, B., Bhuyan, R., Li, H., Sarma, A., Gayan, S., Talukdar, J., Sandhya, S., Bhuyan, S., Gogoi, G., Gouw, A. M., Baishya, D., Gotlib, J. R., Kataki, A. C., Felsher, D. W. 2019


    Cancer stem cells (CSC) maintain both undifferentiated self-renewing CSCs and differentiated, non-self-renewing non-CSCs through cellular division. However, molecular mechanisms that maintain self-renewal in CSCs versus non-CSCs are not yet clear. Here, we report that in a transgenic mouse model of MYC-induced T cell leukemia, MYC maintains self-renewal in Sca1+ CSCs versus Sca-1- non-CSCs. MYC preferentially bound to the promoter and activated HIF-2alpha in Sca-1+ cells only. Further, the reprogramming factors Nanog and Sox2 facilitated MYC regulation of HIF-2alpha in Sca-1+ versus Sca-1- cells. Reduced expression of HIF-2alpha inhibited the self-renewal of Sca-1+ cells; this effect was blocked through suppression of reactive oxygen species (ROS) by N-acetyl cysteine (NAC) or the knock down of p53, Nanog or Sox2. Similar results were seen in ABCG2+ CSCs versus ABCG2- non-CSCs from primary human T cell lymphoma. Thus, MYC maintains self-renewal exclusively in CSCs by selectively binding to the promoter and activating the HIF-2alpha stemness pathway. Identification of this stemness pathway as a unique CSC determinant may have significant therapeutic implications.

    View details for DOI 10.1158/0008-5472.CAN-18-2847

    View details for PubMedID 31266772

  • The CRISPR Advent of Lulu and Nana THEOLOGY AND SCIENCE Gouw, A. 2019; 17 (1): 9–12
  • The glutathione redox system is essential to prevent ferroptosis caused by impaired lipid metabolism in clear cell renal cell carcinoma ONCOGENE Miess, H., Dankworth, B., Gouw, A. M., Rosenfeldt, M., Schmitz, W., Jiang, M., Saunders, B., Howell, M., Downward, J., Felsher, D. W., Peck, B., Schulze, A. 2018; 37 (40): 5435–50


    Metabolic reprogramming is a prominent feature of clear cell renal cell carcinoma (ccRCC). Here we investigated metabolic dependencies in a panel of ccRCC cell lines using nutrient depletion, functional RNAi screening and inhibitor treatment. We found that ccRCC cells are highly sensitive to the depletion of glutamine or cystine, two amino acids required for glutathione (GSH) synthesis. Moreover, silencing of enzymes of the GSH biosynthesis pathway or glutathione peroxidases, which depend on GSH for the removal of cellular hydroperoxides, selectively reduced viability of ccRCC cells but did not affect the growth of non-malignant renal epithelial cells. Inhibition of GSH synthesis triggered ferroptosis, an iron-dependent form of cell death associated with enhanced lipid peroxidation. VHL is a major tumour suppressor in ccRCC and loss of VHL leads to stabilisation of hypoxia inducible factors HIF-1α and HIF-2α. Restoration of functional VHL via exogenous expression of pVHL reverted ccRCC cells to an oxidative metabolism and rendered them insensitive to the induction of ferroptosis. VHL reconstituted cells also exhibited reduced lipid storage and higher expression of genes associated with oxidiative phosphorylation and fatty acid metabolism. Importantly, inhibition of β-oxidation or mitochondrial ATP-synthesis restored ferroptosis sensitivity in VHL reconstituted cells. We also found that inhibition of GSH synthesis blocked tumour growth in a MYC-dependent mouse model of renal cancer. Together, our data suggest that reduced fatty acid metabolism due to inhibition of β-oxidation renders renal cancer cells highly dependent on the GSH/GPX pathway to prevent lipid peroxidation and ferroptotic cell death.

    View details for PubMedID 29872221

    View details for PubMedCentralID PMC6173300

  • Genetic Virtue Program: An Unfeasible Neo-Pelagian Theodicy? THEOLOGY AND SCIENCE Gouw, A. M. 2018; 16 (3): 273–78
  • Engaging a Community for Rare Genetic Disease: Best Practices and Education From Individual Crowdfunding Campaigns. Interactive journal of medical research Ortiz, R. A., Witte, S. n., Gouw, A. n., Sanfilippo, A. n., Tsai, R. n., Fumagalli, D. n., Yu, C. n., Lant, K. n., Lipitz, N. n., Shepphird, J. n., Alvina, F. B., Cheng-Ho Lin, J. n. 2018; 7 (1): e3


    Genetic sequencing is critically important to diagnostic health care efforts in the United States today, yet it is still inaccessible to many. Meanwhile, the internet and social networking have made crowdfunding a realistic avenue for individuals and groups hoping to fund medical and research causes, including patients in need of whole exome genetic sequencing (WES).Amplify Hope is an educational program designed to investigate what factors affect the success of medical crowdfunding campaigns. We conducted a needs assessment, a series of 25 interviews concerning crowdfunding, and provided training on best practices identified through our assessment for 11 individuals hoping to run their medical crowdfunding campaigns to raise money for patients to access trio WES to identify the mutated proteins that caused their apparent inherited disease.The crowdfunding education was given in a 30-day training period with resources such as webinars, fact sheets and a crowdfunding training guide emailed to each participant. All campaigns were launched on the same date and were given 30 days to raise the same goal amount of US $5000. Reviewing the 4 crowdfunding campaigns that raised the goal amount within the 30-day period, we sought to identify features that made the 4 crowdfunding campaigns successful. In addition, we sought to assess which factors the resulting 75 donors report as influencing their decision to donate to a campaign. Finally, we investigated whether crowdfunding campaigns for exome sequencing had an impact on increasing applicant's and donors' knowledge of genomics.Of the 86 study inquiries, 11 participants submitted the required forms and launched their crowdfunding campaigns. A total of 4 of the 11 campaigns raised their goal amounts within 30 days.We found that social media played an important role in all campaigns. Specifically, a strong social media network, an active outreach process to networks, as well as engagement within the study all correlated with a higher success rate. Amplify Hope donors were more likely to support projects that were near their fundraising goals, and they found video far more effective for learning about genomics than any other medium.

    View details for DOI 10.2196/ijmr.7176

    View details for PubMedID 29402763

    View details for PubMedCentralID PMC5818677

  • Oncogene KRAS activates fatty acid synthase, resulting in specific ERK and lipid signatures associated with lung adenocarcinoma PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Gouw, A. M., Eberlin, L. S., Margulis, K., Sullivan, D. K., Toal, G. G., Tong, L., Zare, R. N., Felsher, D. W. 2017; 114 (17): 4300-4305


    KRAS gene mutation causes lung adenocarcinoma. KRAS activation has been associated with altered glucose and glutamine metabolism. Here, we show that KRAS activates lipogenesis, and this activation results in distinct proteomic and lipid signatures. By gene expression analysis, KRAS is shown to be associated with a lipogenesis gene signature and specific induction of fatty acid synthase (FASN). Through desorption electrospray ionization MS imaging (DESI-MSI), specific changes in lipogenesis and specific lipids are identified. By the nanoimmunoassay (NIA), KRAS is found to activate the protein ERK2, whereas ERK1 activation is found in non-KRAS-associated human lung tumors. The inhibition of FASN by cerulenin, a small molecule antibiotic, blocked cellular proliferation of KRAS-associated lung cancer cells. Hence, KRAS is associated with activation of ERK2, induction of FASN, and promotion of lipogenesis. FASN may be a unique target for KRAS-associated lung adenocarcinoma remediation.

    View details for DOI 10.1073/pnas.1617709114

    View details for PubMedID 28400509

  • Roles of estrogen receptor-alpha in mediating life span: the hypothalamic deregulation hypothesis. Physiological genomics Gouw, A. M., Efe, G. n., Barakat, R. n., Preecha, A. n., Mehdizadeh, M. n., Garan, S. A., Brooks, G. A. 2017; 49 (2): 88–95


    In several species caloric restriction (CR) extends life span. In this paper we integrate data from studies on CR and other sources to articulate the hypothalamic deregulation hypothesis by which estrogen receptor-alpha (ER-α) signaling in the hypothalamus and limbic system affects life span under the stress of CR in mammals. ER-α is one of two principal estrogen-binding receptors differentially expressed in the amygdala, hippocampus, and several key hypothalamic nuclei: the arcuate nucleus (ARN), preoptic area (POA), ventromedial nucleus (VMN), antero ventral periventricular nucleus (AVPV), paraventricular nucleus (PVN), supraoptic nucleus (SON), and suprachiasmatic nucleus (SCN). Estradiol signaling via ER-α is essential in basal level functioning of reproductive cycle, sexually receptive behaviors, physiological stress responses, as well as sleep cycle, and other nonsexual behaviors. When an organism is placed under long-term CR, which introduces an external stress to this ER-α signaling, the reduction of ER-α expression is attenuated over time in the hypothalamus. This review paper seeks to characterize the downstream effects of ER-α in the hypothalamus and limbic system that affect normal endocrine functioning.

    View details for DOI 10.1152/physiolgenomics.00073.2016

    View details for PubMedID 28011880

  • Correspondence: Oncogenic MYC persistently upregulates the molecular clock component REV-ERBα. Nature communications Altman, B. J., Hsieh, A. L., Gouw, A. M., Dang, C. V. 2017; 8: 14862

    View details for DOI 10.1038/ncomms14862

    View details for PubMedID 28332504

    View details for PubMedCentralID PMC5376640

  • Metabolic vulnerabilities of MYC-induced cancer ONCOTARGET Gouw, A. M., Toal, G. G., Felsher, D. W. 2016; 7 (21): 29879–80

    View details for PubMedID 26863454

  • MYC regulates the antitumor immune response through CD47 and PD-L1 SCIENCE Casey, S. C., Tong, L., Li, Y., Do, R., Walz, S., FitzGerald, K. N., Gouw, A. M., Baylot, V., Guetgemann, I., Eilers, M., Felsher, D. W. 2016; 352 (6282): 227-231


    TheMYConcogene codes for a transcription factor that is overexpressed in many human cancers. Here we show thatMYCregulates the expression of two immune checkpoint proteins on the tumor cell surface, the innate immune regulator, CD47 ( C: luster of D: ifferentiation 47) and the adaptive immune checkpoint, PD-L1 (programmed death-ligand 1). Suppression of MYC in mouse tumors and human tumor cells caused a reduction in the levels of CD47 and PD-L1 mRNA and protein. MYC was found to bind directly to the promoters of the CD47 and PD-L1 genes. MYC inactivation in mouse tumors down-regulated CD47 and PD-L1 expression and enhanced the anti-tumor immune response. In contrast, when MYC was inactivated in tumors with enforced expression of CD47 or PD-L1, the immune response was suppressed and tumors continued to grow. Thus MYC appears to initiate and maintain tumorigenesis in part through the modulation of immune regulatory molecules.

    View details for DOI 10.1126/science.aac9935

    View details for Web of Science ID 000373681600047

    View details for PubMedID 26966191

  • Crowdfunding for Personalized Medicine Research. Yale journal of biology and medicine Fumagalli, D. C., Gouw, A. M. 2015; 88 (4): 413-414


    Given the current funding situation of the National Institutes of Health, getting funding for rare disease research is extremely difficult. In light of the enormous potential for research in the rare diseases and the scarcity of research funding, we provide a case study of a novel successful crowdfunding approach at a non-profit organization called Rare Genomics Institute. We partner with biotechnology companies willing to donate their products, such as mouse models, gene editing software, and sequencing services, for which researchers can apply. First, we find that personal stories can be powerful tools to seek funding from sympathetic donors who do not have the same rational considerations of impact and profit. Second, for foundations facing funding restrictions, company donations can be a valuable tool in addition to crowdfunding. Third, rare disease research is particularly rewarding for scientists as they proceed to be pioneers in the field during their academic careers. Overall, by connecting donors, foundations, researchers, and patients, crowdfunding has become a powerful alternative funding mechanism for personalized medicine.

    View details for PubMedID 26604866

  • MYC Disrupts the Circadian Clock and Metabolism in Cancer Cells. Cell metabolism Altman, B. J., Hsieh, A. L., Sengupta, A., Krishnanaiah, S. Y., Stine, Z. E., Walton, Z. E., Gouw, A. M., Venkataraman, A., Li, B., Goraksha-Hicks, P., Diskin, S. J., Bellovin, D. I., Simon, M. C., Rathmell, J. C., Lazar, M. A., Maris, J. M., Felsher, D. W., Hogenesch, J. B., Weljie, A. M., Dang, C. V. 2015; 22 (6): 1009-1019

    View details for DOI 10.1016/j.cmet.2015.09.003

    View details for PubMedID 26387865

  • Targeted inhibition of tumor-specific glutaminase diminishes cell-autonomous tumorigenesis JOURNAL OF CLINICAL INVESTIGATION Xiang, Y., Stine, Z. E., Xia, J., Lu, Y., O'Connor, R. S., Altman, B. J., Hsieh, A. L., Gouw, A. M., Thomas, A. G., Gao, P., Sun, L., Song, L., Yan, B., Slusher, B. S., Zhuo, J., Ooi, L. L., Lee, C. G., Mancuso, A., McCallion, A. S., Le, A., Milone, M. C., Rayport, S., Felsher, D. W., Dang, C. V. 2015; 125 (6): 2293-2306


    Glutaminase (GLS), which converts glutamine to glutamate, plays a key role in cancer cell metabolism, growth, and proliferation. GLS is being explored as a cancer therapeutic target, but whether GLS inhibitors affect cancer cell-autonomous growth or the host microenvironment or have off-target effects is unknown. Here, we report that loss of one copy of Gls blunted tumor progression in an immune-competent MYC-mediated mouse model of hepatocellular carcinoma. Compared with results in untreated animals with MYC-induced hepatocellular carcinoma, administration of the GLS-specific inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) prolonged survival without any apparent toxicities. BPTES also inhibited growth of a MYC-dependent human B cell lymphoma cell line (P493) by blocking DNA replication, leading to cell death and fragmentation. In mice harboring P493 tumor xenografts, BPTES treatment inhibited tumor cell growth; however, P493 xenografts expressing a BPTES-resistant GLS mutant (GLS-K325A) or overexpressing GLS were not affected by BPTES treatment. Moreover, a customized Vivo-Morpholino that targets human GLS mRNA markedly inhibited P493 xenograft growth without affecting mouse Gls expression. Conversely, a Vivo-Morpholino directed at mouse Gls had no antitumor activity in vivo. Collectively, our studies demonstrate that GLS is required for tumorigenesis and support small molecule and genetic inhibition of GLS as potential approaches for targeting the tumor cell-autonomous dependence on GLS for cancer therapy.

    View details for DOI 10.1172/JCI75836

    View details for Web of Science ID 000355573900018

    View details for PubMedID 25915584

    View details for PubMedCentralID PMC4497742

  • MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Shroff, E. H., Eberlin, L. S., Dang, V. M., Gouw, A. M., Gabay, M., Adam, S. J., Bellovin, D. I., Tran, P. T., Philbrick, W. M., Garcia-Ocana, A., Casey, S. C., Li, Y., Dang, C. V., Zare, R. N., Felsher, D. W. 2015; 112 (21): 6539-6544


    The MYC oncogene is frequently mutated and overexpressed in human renal cell carcinoma (RCC). However, there have been no studies on the causative role of MYC or any other oncogene in the initiation or maintenance of kidney tumorigenesis. Here, we show through a conditional transgenic mouse model that the MYC oncogene, but not the RAS oncogene, initiates and maintains RCC. Desorption electrospray ionization-mass-spectrometric imaging was used to obtain chemical maps of metabolites and lipids in the mouse RCC samples. Gene expression analysis revealed that the mouse tumors mimicked human RCC. The data suggested that MYC-induced RCC up-regulated the glutaminolytic pathway instead of the glycolytic pathway. The pharmacologic inhibition of glutamine metabolism with bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide impeded MYC-mediated RCC tumor progression. Our studies demonstrate that MYC overexpression causes RCC and points to the inhibition of glutamine metabolism as a potential therapeutic approach for the treatment of this disease.

    View details for DOI 10.1073/pnas.1507228112

    View details for PubMedID 25964345

  • p19ARF is a critical mediator of both cellular senescence and an innate immune response associated with MYC inactivation in mouse model of acute leukemia ONCOTARGET Yetil, A., Anchang, B., Gouw, A. M., Adam, S. J., Zabuawala, T., Parameswaran, R., van Riggelen, J., Plevritis, S., Felsher, D. W. 2015; 6 (6): 3563-3577


    MYC-induced T-ALL exhibit oncogene addiction. Addiction to MYC is a consequence of both cell-autonomous mechanisms, such as proliferative arrest, cellular senescence, and apoptosis, as well as non-cell autonomous mechanisms, such as shutdown of angiogenesis, and recruitment of immune effectors. Here, we show, using transgenic mouse models of MYC-induced T-ALL, that the loss of either p19ARF or p53 abrogates the ability of MYC inactivation to induce sustained tumor regression. Loss of p53 or p19ARF, influenced the ability of MYC inactivation to elicit the shutdown of angiogenesis; however the loss of p19ARF, but not p53, impeded cellular senescence, as measured by SA-beta-galactosidase staining, increased expression of p16INK4A, and specific histone modifications. Moreover, comparative gene expression analysis suggested that a multitude of genes involved in the innate immune response were expressed in p19ARF wild-type, but not null, tumors upon MYC inactivation. Indeed, the loss of p19ARF, but not p53, impeded the in situ recruitment of macrophages to the tumor microenvironment. Finally, p19ARF null-associated gene signature prognosticated relapse-free survival in human patients with ALL. Therefore, p19ARF appears to be important to regulating cellular senescence and innate immune response that may contribute to the therapeutic response of ALL.

    View details for PubMedID 25784651

  • Alteration of the lipid profile in lymphomas induced by MYC overexpression. Proceedings of the National Academy of Sciences of the United States of America Eberlin, L. S., Gabay, M., Fan, A. C., Gouw, A. M., Tibshirani, R. J., Felsher, D. W., Zare, R. N. 2014; 111 (29): 10450-10455


    Overexpression of the v-myc avian myelocytomatosis viral oncogene homolog (MYC) oncogene is one of the most commonly implicated causes of human tumorigenesis. MYC is known to regulate many aspects of cellular biology including glucose and glutamine metabolism. Little is known about the relationship between MYC and the appearance and disappearance of specific lipid species. We use desorption electrospray ionization mass spectrometry imaging (DESI-MSI), statistical analysis, and conditional transgenic animal models and cell samples to investigate changes in lipid profiles in MYC-induced lymphoma. We have detected a lipid signature distinct from that observed in normal tissue and in rat sarcoma-induced lymphoma cells. We found 104 distinct molecular ions that have an altered abundance in MYC lymphoma compared with normal control tissue by statistical analysis with a false discovery rate of less than 5%. Of these, 86 molecular ions were specifically identified as complex phospholipids. To evaluate whether the lipid signature could also be observed in human tissue, we examined 15 human lymphoma samples with varying expression levels of MYC oncoprotein. Distinct lipid profiles in lymphomas with high and low MYC expression were observed, including many of the lipid species identified as significant for MYC-induced animal lymphoma tissue. Our results suggest a relationship between the appearance of specific lipid species and the overexpression of MYC in lymphomas.

    View details for DOI 10.1073/pnas.1409778111

    View details for PubMedID 24994904

  • Tumorigenicity of hypoxic respiring cancer cells revealed by a hypoxia-cell cycle dual reporter. Proceedings of the National Academy of Sciences of the United States of America Le, A. n., Stine, Z. E., Nguyen, C. n., Afzal, J. n., Sun, P. n., Hamaker, M. n., Siegel, N. M., Gouw, A. M., Kang, B. H., Yu, S. H., Cochran, R. L., Sailor, K. A., Song, H. n., Dang, C. V. 2014; 111 (34): 12486–91


    Although aerobic glycolysis provides an advantage in the hypoxic tumor microenvironment, some cancer cells can also respire via oxidative phosphorylation. These respiring ("non-Warburg") cells were previously thought not to play a key role in tumorigenesis and thus fell from favor in the literature. We sought to determine whether subpopulations of hypoxic cancer cells have different metabolic phenotypes and gene-expression profiles that could influence tumorigenicity and therapeutic response, and we therefore developed a dual fluorescent protein reporter, HypoxCR, that detects hypoxic [hypoxia-inducible factor (HIF) active] and/or cycling cells. Using HEK293T cells as a model, we identified four distinct hypoxic cell populations by flow cytometry. The non-HIF/noncycling cell population expressed a unique set of genes involved in mitochondrial function. Relative to the other subpopulations, these hypoxic "non-Warburg" cells had highest oxygen consumption rates and mitochondrial capacity consistent with increased mitochondrial respiration. We found that these respiring cells were unexpectedly tumorigenic, suggesting that continued respiration under limiting oxygen conditions may be required for tumorigenicity.

    View details for DOI 10.1073/pnas.1402012111

    View details for PubMedID 25114222

    View details for PubMedCentralID PMC4151727

  • Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell metabolism Le, A. n., Lane, A. N., Hamaker, M. n., Bose, S. n., Gouw, A. n., Barbi, J. n., Tsukamoto, T. n., Rojas, C. J., Slusher, B. S., Zhang, H. n., Zimmerman, L. J., Liebler, D. C., Slebos, R. J., Lorkiewicz, P. K., Higashi, R. M., Fan, T. W., Dang, C. V. 2012; 15 (1): 110–21


    Because MYC plays a causal role in many human cancers, including those with hypoxic and nutrient-poor tumor microenvironments, we have determined the metabolic responses of a MYC-inducible human Burkitt lymphoma model P493 cell line to aerobic and hypoxic conditions, and to glucose deprivation, using stable isotope-resolved metabolomics. Using [U-(13)C]-glucose as the tracer, both glucose consumption and lactate production were increased by MYC expression and hypoxia. Using [U-(13)C,(15)N]-glutamine as the tracer, glutamine import and metabolism through the TCA cycle persisted under hypoxia, and glutamine contributed significantly to citrate carbons. Under glucose deprivation, glutamine-derived fumarate, malate, and citrate were significantly increased. Their (13)C-labeling patterns demonstrate an alternative energy-generating glutaminolysis pathway involving a glucose-independent TCA cycle. The essential role of glutamine metabolism in cell survival and proliferation under hypoxia and glucose deficiency makes them susceptible to the glutaminase inhibitor BPTES and hence could be targeted for cancer therapy.

    View details for DOI 10.1016/j.cmet.2011.12.009

    View details for PubMedID 22225880

    View details for PubMedCentralID PMC3345194

  • Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proceedings of the National Academy of Sciences of the United States of America Le, A. n., Cooper, C. R., Gouw, A. M., Dinavahi, R. n., Maitra, A. n., Deck, L. M., Royer, R. E., Vander Jagt, D. L., Semenza, G. L., Dang, C. V. 2010; 107 (5): 2037–42


    As the result of genetic alterations and tumor hypoxia, many cancer cells avidly take up glucose and generate lactate through lactate dehydrogenase A (LDHA), which is encoded by a target gene of c-Myc and hypoxia-inducible factor (HIF-1). Previous studies with reduction of LDHA expression indicate that LDHA is involved in tumor initiation, but its role in tumor maintenance and progression has not been established. Furthermore, how reduction of LDHA expression by interference or antisense RNA inhibits tumorigenesis is not well understood. Here, we report that reduction of LDHA by siRNA or its inhibition by a small-molecule inhibitor (FX11 [3-dihydroxy-6-methyl-7-(phenylmethyl)-4-propylnaphthalene-1-carboxylic acid]) reduced ATP levels and induced significant oxidative stress and cell death that could be partially reversed by the antioxidant N-acetylcysteine. Furthermore, we document that FX11 inhibited the progression of sizable human lymphoma and pancreatic cancer xenografts. When used in combination with the NAD(+) synthesis inhibitor FK866, FX11 induced lymphoma regression. Hence, inhibition of LDHA with FX11 is an achievable and tolerable treatment for LDHA-dependent tumors. Our studies document a therapeutical approach to the Warburg effect and demonstrate that oxidative stress and metabolic phenotyping of cancers are critical aspects of cancer biology to consider for the therapeutical targeting of cancer energy metabolism.

    View details for DOI 10.1073/pnas.0914433107

    View details for PubMedID 20133848

    View details for PubMedCentralID PMC2836706

  • Insulin-like growth factor-1 receptor immunoreactive cells are selectively maintained in the paraventricular hypothalamus of calorically restricted mice. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience Saeed, O. n., Yaghmaie, F. n., Garan, S. A., Gouw, A. M., Voelker, M. A., Sternberg, H. n., Timiras, P. S. 2007; 25 (1): 23–28


    The mammalian lifespan is dramatically extended by both caloric restriction (CR) and insulin-like growth factor-1 (IGF-1) suppression. Both interventions involve neuroendocrine alterations directed by the hypothalamus. Yet, it remains unclear whether CR exerts its affects by altering central IGF-1 sensitivity. With this question in mind, we investigated the influence of CR and normal aging on hypothalamic IGF-1 sensitivity, by measuring the changes in IGF-1 receptor (IGF-1R) populations. Taking IGF-1 receptor (IGF-1R) immunoreactivity as an index of sensitivity to IGF-1, we counted IGF-1R immunoreactive and non-immunoreactive cells in the paraventricular nucleus (PVN) of Young-ad libitum fed (Young-Al, 6 weeks old), Old-ad libitum fed (Old-Al, 22 months old), and old calorically restricted (Old-CR, 22 months old) female B6D2F1 mice. An automated imaging microscopy system (AIMS) was used to generate cell counts for each cross-section of PVN hypothalamus. Ad libitum fed mice show a 37% reduction in IGF-1R immunoreactive cells and a 12% reduction in the total cell population of the PVN with aging. In comparison, caloric-restricted mice show a 33% reduction in IGF-1R immunoreactive cells and a notable 24% decrease in the total cell population with aging. This selective maintenance of IGF-1R expressing cells coupled with the simultaneous loss of non-immunoreactive cells, results in a higher percentage of IGF-1R immunoreactive cells in the PVNs of CR mice. Thus, the decline in the percentage of IGF-1 sensitive cells in the PVN with age is attenuated by CR.

    View details for DOI 10.1016/j.ijdevneu.2006.11.004

    View details for PubMedID 17194562

  • Age-related decline of sleep-dependent consolidation. Learning & memory (Cold Spring Harbor, N.Y.) Spencer, R. M., Gouw, A. M., Ivry, R. B. 2007; 14 (7): 480–84


    Sleep-dependent memory consolidation is observed following motor skill learning: Performance improvements are greater over a 12-h period containing sleep relative to an equivalent interval without sleep. Here we examined whether older adults exhibit sleep-dependent consolidation on a sequence learning task. Participants were trained on one of two sequence learning tasks. Performance was assessed after a 12-h break that included sleep and after a 12-h break that did not include sleep. Older and younger adults showed similar degrees of initial learning. However, performance of the older adults did not improve following sleep, providing evidence that sleep-dependent consolidation is diminished with age.

    View details for DOI 10.1101/lm.569407

    View details for PubMedID 17622650

  • Age-dependent loss of insulin-like growth factor-1 receptor immunoreactive cells in the supraoptic hypothalamus is reduced in calorically restricted mice. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience Yaghmaie, F. n., Saeed, O. n., Garan, S. A., Voelker, M. A., Gouw, A. M., Freitag, W. n., Sternberg, H. n., Timiras, P. S. 2006; 24 (7): 431–36


    Both life-long caloric restriction (CR) and the suppression of insulin-like growth factor-1 (IGF-1) signaling reliably extend the mammalian lifespan. The neuroendocrine system, regulated by the hypothalamus, remains the most convincing site of action for both these modes of life extension. Yet, determining whether CR actions are mediated by the modulation of neuroendocrine IGF-1 signaling remains unclear. Of the hypothalamic nuclei that express the IGF-1 receptor (IGF-1R), the cells of the supraoptic nucleus (SON) display some of the most robust IGF-1R expression. Taking IGF-1R immunoreactivity as an index of sensitivity to IGF-1, we counted IGF-1R immunoreactive and non-immunoreactive cells in the SON of young-ad-libitum fed (young-Al, 6 weeks), old-ad-libitum fed (Old-Al, 22 months), and old-calorie-restricted (Old-CR, 22 months) female B6D2F1 mice. An automated imaging microscopy system (AIMS) was used to generate cell counts for each section of supraoptic hypothalamus. Results show that while the total number of cells in the SON of ad-libitum fed mice does not change significantly with aging, a significant reduction in IGF-1R immunoreactive cells does occur in ad-libitum fed mice with aging. In contrast to this, calorie restricted mice show both a decline in the total number of cells and IGF-1R immunoreactive cells in the SON with age, but with the decrease in the latter being notably attenuated when compared to the degree of loss seen in ad-libitum fed mice. Thus, while CR induces greater loss in the total number of cells in the SON with age, it reduces the degree of age-dependent loss seen in IGF-1R expressing cells. As a result, when compared to Old-AL mice, the SON of Old-CR mice displays a greater proportion of IGF-1R cells and thus possibly enhanced IGF-1 sensitivity with aging.

    View details for DOI 10.1016/j.ijdevneu.2006.08.008

    View details for PubMedID 17034982