Honors & Awards

  • NIH Predoctoral Cancer Biology Training Grant, T32CA9054, National Cancer Institute (2009)
  • NIH Postdoctoral Molecular and Cellular Immunobiology Training Grant, 5T32AI07290, NIH (2012)
  • NIH NRSA for Individual Postdoctoral Fellows, 1F32CA177139, National Cancer Institute (2013)
  • Travel Award, Helena Anna Henzl-Gabor Young Women in Science Fund for Postdoctoral Scholars (2014)
  • Scholar-In-Training Award, American Association for Cancer Research (2014)

Professional Education

  • Bachelor of Science, University of California Los Angeles (2005)
  • Doctor of Philosophy, University of California Irvine (2012)

Stanford Advisors


All Publications

  • 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

  • Designing a broad-spectrum integrative approach for cancer prevention and treatment SEMINARS IN CANCER BIOLOGY Block, K. I., Gyllenhaal, C., Lowe, L., Amedei, A., Amin, A. R., Amin, A., Aquilano, K., Arbiser, J., Arreola, A., Arzumanyan, A., Ashraf, S. S., Azmi, A. S., Benencia, F., Bhakta, D., Bilsland, A., Bishayeen, A., Blain, S. W., Block, P. B., Boosani, C. S., Carey, T. E., Carnero, A., Carotenuto, M., Casey, S. C., Chakrabarti, M., Chaturvedi, R., Chen, G. Z., Chenx, H., Chen, S., Chen, Y. C., Choi, B. K., Ciriolo, M. R., Coley, H. M., Collins, A. R., Connell, M., Crawford, S., Curran, C. S., Dabrosin, C., Damia, G., Dasgupta, S., DeBerardinis, R. J., Decker, W. K., Dhawan, P., Diehl, A. M., Dong, J., Dou, Q. P., Drew, J. E., Elkord, E., El-Rayes, B., Feitelson, M. A., Felsher, D. W., Ferguson, L. R., Fimognari, C., Firestone, G. L., Frezza, C., Fujii, H., Fuster, M. M., Generali, D., Georgakilas, A. G., Gieseler, F., Gilbertson, M., Green, M. F., Grue, B., Guha, G., Halicka, D., Helferich, W. G., Heneberg, P., Hentosh, P., Hirschey, M. D., Hofseth, L. J., Holcombe, R. F., Honoki, K., Hsu, H., Huang, G. S., Jensen, L. D., Jiang, W. G., Jones, L. W., Karpowicz, P. A., Keith, W. N., Kerkar, S. P., Khan, G. N., Khatami, M., Ko, Y. H., Kucuk, O., Kulathinal, R. J., Kumar, N. B., Kwon, B. S., Le, A., Lea, M. A., Lee, H., Lichtor, T., Lin, L., Locasale, J. W., Lokeshwar, B. L., Longo, V. D., Lyssiotis, C. A., MacKenzie, K. L., Malhotra, M., Marino, M., Martinez-Chantar, M. L., Matheu, A., Maxwell, C., McDonnell, E., Meeker, A. K., Mehrmohamadi, M., Mehta, K., Michelotti, G. A., Mohammad, R. M., Mohammed, S. I., Morre, D. J., Muqbil, I., Muralidhar, V., Murphy, M. P., Nagaraju, G. P., Nahta, R., Niccolai, E., Nowsheen, S., Panis, C., Pantano, F., Parslow, V. R., Pawelec, G., Pedersen, P. L., Poore, B., Poudyal, D., Prakash, S., Prince, M., Raffaghello, L., Rathmell, J. C., Rathmell, W. K., Ray, S. K., Reichrath, J., Rezazadeh, S., Ribatti, D., Ricciardiello, L., Robey, R. B., Rodier, F., Rupasinghe, H. P., Russo, G. L., Ryan, E. P., Samadi, A. K., Sanchez-Garcia, I., Sanders, A. J., Santini, D., Sarkar, M., Sasada, T., Saxena, N. K., Shackelford, R. E., Kumara, H. M., Sharma, D., Shin, D. M., Sidransky, D., Siegelin, M. D., Signori, E., Singh, N., Sivanand, S., Sliva, D., Smythe, C., Spagnuolo, C., Stafforini, D. M., Stagg, J., Subbarayan, P. R., Sundin, T., Talib, W. H., Thompson, S. K., Tran, P. T., Ungefroren, H., Vander Heiden, M. G., Venkateswaran, V., Vinay, D. S., Vlachostergios, P. J., Wang, Z., Wellendx, K. E., Whelan, R. L., Yang, E. S., Yang, H., Yang, X., Yaswen, P., Yedjou, C., Yin, X., Zhu, J., Zollo, M. 2015; 35: S276-S304
  • Cancer prevention and therapy through the modulation of the tumor microenvironment. Seminars in cancer biology Casey, S. C., Amedei, A., Aquilano, K., Azmi, A. S., Benencia, F., Bhakta, D., Bilsland, A. E., Boosani, C. S., Chen, S., Ciriolo, M. R., Crawford, S., Fujii, H., Georgakilas, A. G., Guha, G., Halicka, D., Helferich, W. G., Heneberg, P., Honoki, K., Keith, W. N., Kerkar, S. P., Mohammed, S. I., Niccolai, E., Nowsheen, S., Vasantha Rupasinghe, H. P., Samadi, A., Singh, N., Talib, W. H., Venkateswaran, V., Whelan, R. L., Yang, X., Felsher, D. W. 2015; 35: S199-223


    Cancer arises in the context of an in vivo tumor microenvironment. This microenvironment is both a cause and consequence of tumorigenesis. Tumor and host cells co-evolve dynamically through indirect and direct cellular interactions, eliciting multiscale effects on many biological programs, including cellular proliferation, growth, and metabolism, as well as angiogenesis and hypoxia and innate and adaptive immunity. Here we highlight specific biological processes that could be exploited as targets for the prevention and therapy of cancer. Specifically, we describe how inhibition of targets such as cholesterol synthesis and metabolites, reactive oxygen species and hypoxia, macrophage activation and conversion, indoleamine 2,3-dioxygenase regulation of dendritic cells, vascular endothelial growth factor regulation of angiogenesis, fibrosis inhibition, endoglin, and Janus kinase signaling emerge as examples of important potential nexuses in the regulation of tumorigenesis and the tumor microenvironment that can be targeted. We have also identified therapeutic agents as approaches, in particular natural products such as berberine, resveratrol, onionin A, epigallocatechin gallate, genistein, curcumin, naringenin, desoxyrhapontigenin, piperine, and zerumbone, that may warrant further investigation to target the tumor microenvironment for the treatment and/or prevention of cancer.

    View details for DOI 10.1016/j.semcancer.2015.02.007

    View details for PubMedID 25865775

  • Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. Carcinogenesis Goodson, W. H., Lowe, L., Carpenter, D. O., Gilbertson, M., Manaf Ali, A., Lopez de Cerain Salsamendi, A., Lasfar, A., Carnero, A., Azqueta, A., Amedei, A., Charles, A. K., Collins, A. R., Ward, A., Salzberg, A. C., Colacci, A., Olsen, A., Berg, A., Barclay, B. J., Zhou, B. P., Blanco-Aparicio, C., Baglole, C. J., Dong, C., Mondello, C., Hsu, C., Naus, C. C., Yedjou, C., Curran, C. S., Laird, D. W., Koch, D. C., Carlin, D. J., Felsher, D. W., Roy, D., Brown, D. G., Ratovitski, E., Ryan, E. P., Corsini, E., Rojas, E., Moon, E., Laconi, E., Marongiu, F., Al-Mulla, F., Chiaradonna, F., Darroudi, F., Martin, F. L., van Schooten, F. J., Goldberg, G. S., Wagemaker, G., Nangami, G., Calaf, G. M., Williams, G., Wolf, G. T., Koppen, G., Brunborg, G., Kim Lyerly, H., Krishnan, H., Ab Hamid, H., Yasaei, H., Sone, H., Kondoh, H., Salem, H. K., Hsu, H., Park, H. H., Koturbash, I., Miousse, I. R., Scovassi, A. I., Klaunig, J. E., Vondrßcek, J., Raju, J., Roman, J., Wise, J. P., Whitfield, J. R., Woodrick, J., Christopher, J. A., Ochieng, J., Martinez-Leal, J. F., Weisz, J., Kravchenko, J., Sun, J., Prudhomme, K. R., Narayanan, K. B., Cohen-Solal, K. A., Moorwood, K., Gonzalez, L., Soucek, L., Jian, L., D'Abronzo, L. S., Lin, L., Li, L., Gulliver, L., McCawley, L. J., Memeo, L., Vermeulen, L., Leyns, L., Zhang, L., Valverde, M., Khatami, M., Romano, M. F., Chapellier, M., Williams, M. A., Wade, M., Manjili, M. H., Lleonart, M., Xia, M., Gonzalez, M. J., Karamouzis, M. V., Kirsch-Volders, M., Vaccari, M., Kuemmerle, N. B., Singh, N., Cruickshanks, N., Kleinstreuer, N., Van Larebeke, N., Ahmed, N., Ogunkua, O., Krishnakumar, P. K., Vadgama, P., Marignani, P. A., Ghosh, P. M., Ostrosky-Wegman, P., Thompson, P., Dent, P., Heneberg, P., Darbre, P., Sing Leung, P., Nangia-Makker, P., Cheng, Q. S., Robey, R. B., Al-Temaimi, R., Roy, R., Andrade-Vieira, R., Sinha, R. K., Mehta, R., Vento, R., Di Fiore, R., Ponce-Cusi, R., Dornetshuber-Fleiss, R., Nahta, R., Castellino, R. C., Palorini, R., Abd Hamid, R., Langie, S. A., Eltom, S., Brooks, S. A., Ryeom, S., Wise, S. S., Bay, S. N., Harris, S. A., Papagerakis, S., Romano, S., Pavanello, S., Eriksson, S., Forte, S., Casey, S. C., Luanpitpong, S., Lee, T., Otsuki, T., Chen, T., Massfelder, T., Sanderson, T., Guarnieri, T., Hultman, T., Dormoy, V., Odero-Marah, V., Sabbisetti, V., Maguer-Satta, V., Rathmell, W. K., Engstr÷m, W., Decker, W. K., Bisson, W. H., Rojanasakul, Y., Luqmani, Y., Chen, Z., Hu, Z. 2015; 36: S254-96


    Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.

    View details for DOI 10.1093/carcin/bgv039

    View details for PubMedID 26106142

  • The effect of environmental chemicals on the tumor microenvironment CARCINOGENESIS Casey, S. C., Vaccari, M., Al-Mulla, F., Al-Temaimi, R., Amedei, A., Barcellos-Hoff, M. H., Brown, D. G., Chapellier, M., Christopher, J., Curran, C., Forte, S., Hamid, R. A., Heneberg, P., Koch, D. C., Krishnakumar, P. K., Laconi, E., Maguer-Satta, V., Marongiu, F., Memeo, L., Mondello, C., Raju, J., Roman, J., Roy, R., Ryan, E. P., Ryeom, S., Salem, H. K., Scovassi, A. I., Singh, N., Soucek, L., Vermeulen, L., Whitfield, J. R., Woodrick, J., Colacci, A., Bisson, W. H., Felsher, D. W. 2015; 36: S160-S183


    Potentially carcinogenic compounds may cause cancer through direct DNA damage or through indirect cellular or physiological effects. To study possible carcinogens, the fields of endocrinology, genetics, epigenetics, medicine, environmental health, toxicology, pharmacology and oncology must be considered. Disruptive chemicals may also contribute to multiple stages of tumor development through effects on the tumor microenvironment. In turn, the tumor microenvironment consists of a complex interaction among blood vessels that feed the tumor, the extracellular matrix that provides structural and biochemical support, signaling molecules that send messages and soluble factors such as cytokines. The tumor microenvironment also consists of many host cellular effectors including multipotent stromal cells/mesenchymal stem cells, fibroblasts, endothelial cell precursors, antigen-presenting cells, lymphocytes and innate immune cells. Carcinogens can influence the tumor microenvironment through effects on epithelial cells, the most common origin of cancer, as well as on stromal cells, extracellular matrix components and immune cells. Here, we review how environmental exposures can perturb the tumor microenvironment. We suggest a role for disrupting chemicals such as nickel chloride, Bisphenol A, butyltins, methylmercury and paraquat as well as more traditional carcinogens, such as radiation, and pharmaceuticals, such as diabetes medications, in the disruption of the tumor microenvironment. Further studies interrogating the role of chemicals and their mixtures in dose-dependent effects on the tumor microenvironment could have important general mechanistic implications for the etiology and prevention of tumorigenesis.

    View details for DOI 10.1093/carcin/bgv035

    View details for Web of Science ID 000357048100009

    View details for PubMedID 26106136

  • 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 Web of Science ID 000355213200027

    View details for PubMedID 25964345

  • Pregnane X Receptor Knockout Mice Display Aging-Dependent Wearing of Articular Cartilage PLOS ONE Azuma, K., Casey, S. C., Urano, T., Horie-Inoue, K., Ouchi, Y., Blumberg, B., Inoue, S. 2015; 10 (3)


    Steroid and xenobiotic receptor (SXR) and its murine ortholog, pregnane X receptor (PXR), are nuclear receptors that are expressed at high levels in the liver and the intestine where they function as xenobiotic sensors that induce expression of genes involved in detoxification and drug excretion. Recent evidence showed that SXR and PXR are also expressed in bone tissue where they mediate bone metabolism. Here we report that systemic deletion of PXR results in aging-dependent wearing of articular cartilage of knee joints. Histomorphometrical analysis showed remarkable reduction of width and an enlarged gap between femoral and tibial articular cartilage in PXR knockout mice. We hypothesized that genes induced by SXR in chondrocytes have a protective effect on articular cartilage and identified Fam20a (family with sequence similarity 20a) as an SXR-dependent gene induced by the known SXR ligands, rifampicin and vitamin K2. Lastly, we demonstrated the biological significance of Fam20a expression in chondrocytes by evaluating osteoarthritis-related gene expression of primary articular chondrocytes. Consistent with epidemiological findings, our results indicate that SXR/PXR protects against aging-dependent wearing of articular cartilage and that ligands for SXR/PXR have potential role in preventing osteoarthritis caused by aging.

    View details for DOI 10.1371/journal.pone.0119177

    View details for Web of Science ID 000350689400055

    View details for PubMedID 25749104

  • Manufacturing doubt about endocrine disrupter science - A rebuttal of industry-sponsored critical comments on the UNEP/WHO report "State of the Science of Endocrine Disrupting Chemicals 2012". Regulatory toxicology and pharmacology : RTP Bergman, ┼., Becher, G., Blumberg, B., Bjerregaard, P., Bornman, R., Brandt, I., Casey, S. C., Frouin, H., Giudice, L. C., Heindel, J. J., Iguchi, T., Jobling, S., Kidd, K. A., Kortenkamp, A., Lind, P. M., Muir, D., Ochieng, R., Ropstad, E., Ross, P. S., Skakkebaek, N. E., Toppari, J., Vandenberg, L. N., Woodruff, T. J., Zoeller, R. T. 2015


    We present a detailed response to the critique of "State of the Science of Endocrine Disrupting Chemicals 2012" (UNEP/WHO 2013) by financial stakeholders, authored by Lamb et al. (2014). Lamb et al.'s claim that UNEP/WHO (2013) does not provide a balanced perspective on endocrine disruption is based on incomplete and misleading quoting of the report through omission of qualifying statements and inaccurate description of study objectives, results and conclusions. Lamb et al. define extremely narrow standards for synthesizing evidence which are then used to dismiss the UNEP/WHO 2013 report as flawed. We show that Lamb et al. misuse conceptual frameworks for assessing causality, especially the Bradford-Hill criteria, by ignoring the fundamental problems that exist with inferring causality from empirical observations. We conclude that Lamb et al.'s attempt of deconstructing the UNEP/WHO (2013) report is not particularly erudite and that their critique is not intended to be convincing to the scientific community, but to confuse the scientific data. Consequently, it promotes misinterpretation of the UNEP/WHO (2013) report by non-specialists, bureaucrats, politicians and other decision makers not intimately familiar with the topic of endocrine disruption and therefore susceptible to false generalizations of bias and subjectivity.

    View details for DOI 10.1016/j.yrtph.2015.07.026

    View details for PubMedID 26239693

  • Therapeutic targeting of BRCA1-mutated breast cancers with agents that activate DNA repair. Cancer research Alli, E., Solow-Cordero, D., Casey, S. C., Ford, J. M. 2014; 74 (21): 6205-6215


    Cancers due to germline mutations in the BRCA1 gene tend to lack targets for approved chemoprevention agents. This study aimed at a targeted chemoprevention strategy for BRCA1-associated malignancies. Mutant BRCA1 limits the base-excision DNA repair activity that addresses oxidative DNA damage, the accumulation of which heightens one's risk for cancer. Therefore, we conducted a high-throughput chemical screen to identify drug candidates that could attenuate the inhibitory effects of mutant BRCA1 on this repair activity, thereby describing a new class of DNA repair-activating chemopreventive agents. In the screen design, such drugs functioned by enhancing base-excision DNA repair of oxidative DNA damage in the presence of mutant BRCA1, with minimal cytotoxicity. We identified at least one new agent that decreased malignant properties associated with tumorigenesis, including anchorage-independent growth and tumor progression. This work offers a preclinical proof-of-concept for a wholly new approach to chemoprevention in carriers of BRCA1 mutations, as a strategy to reduce the prevalence of BRCA1-associated malignancy.

    View details for DOI 10.1158/0008-5472.CAN-14-1716

    View details for PubMedID 25217519

  • MYC through miR-17-92 Suppresses Specific Target Genes to Maintain Survival, Autonomous Proliferation, and a Neoplastic State CANCER CELL Li, Y., Choi, P. S., Casey, S. C., Dill, D. L., Felsher, D. W. 2014; 26 (2): 262-272


    The MYC oncogene regulates gene expression through multiple mechanisms, and its overexpression culminates in tumorigenesis. MYC inactivation reverses turmorigenesis through the loss of distinguishing features of cancer, including autonomous proliferation and survival. Here we report that MYC via miR-17-92 maintains a neoplastic state through the suppression of chromatin regulatory genes Sin3b, Hbp1, Suv420h1, and Btg1, as well as the apoptosis regulator Bim. The enforced expression of miR-17-92 prevents MYC suppression from inducing proliferative arrest, senescence, and apoptosis and abrogates sustained tumor regression. Knockdown of the five miR-17-92 target genes blocks senescence and apoptosis while it modestly delays proliferative arrest, thus partially recapitulating miR-17-92 function. We conclude that MYC, via miR-17-92, maintains a neoplastic state by suppressing specific target genes.

    View details for DOI 10.1016/j.ccr.2014.06.014

    View details for Web of Science ID 000340343800013

  • Inactivation of MYC reverses tumorigenesis JOURNAL OF INTERNAL MEDICINE Li, Y., Casey, S. C., Felsher, D. W. 2014; 276 (1): 52-60


    The MYC proto-oncogene is an essential regulator of many normal biological programmes. MYC, when activated as an oncogene, has been implicated in the pathogenesis of most types of human cancers. MYC overexpression in normal cells is restrained from causing cancer through multiple genetically and epigenetically controlled checkpoint mechanisms, including proliferative arrest, apoptosis and cellular senescence. When pathologically activated in the correct epigenetic and genetic contexts, MYC bypasses these mechanisms and drives many of the 'hallmark' features of cancer, including uncontrolled tumour growth associated with DNA replication and transcription, cellular proliferation and growth, protein synthesis and altered cellular metabolism. MYC also dictates tumour cell fate by enforcing self-renewal and by abrogating cellular senescence and differentiation programmes. Moreover, MYC influences the tumour microenvironment, including activating angiogenesis and suppressing the host immune response. Provocatively, brief or even partial suppression of MYC back to its physiological levels of activation can lead to the restoration of intrinsic checkpoint mechanisms, resulting in acute and sustained tumour regression associated with tumour cells undergoing proliferative arrest, differentiation, senescence and apoptosis, as well as remodelling of the tumour microenvironment, recruitment of an immune response and shutdown of angiogenesis. Hence, tumours appear to be addicted to the MYC oncogene because of both tumour cell intrinsic and host-dependent mechanisms. MYC is important for the regulation of both the initiation and maintenance of tumorigenesis. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/joim.12237

    View details for Web of Science ID 000337787500006

    View details for PubMedID 24645771

  • An essential role for the immune system in the mechanism of tumor regression following targeted oncogene inactivation IMMUNOLOGIC RESEARCH Casey, S. C., Li, Y., Felsher, D. W. 2014; 58 (2-3): 282-291


    Tumors are genetically complex and can have a multitude of mutations. Consequently, it is surprising that the suppression of a single oncogene can result in rapid and sustained tumor regression, illustrating the concept that cancers are often "oncogene addicted." The mechanism of oncogene addiction has been presumed to be largely cell autonomous as a consequence of the restoration of normal physiological programs that induce proliferative arrest, apoptosis, differentiation, and/or cellular senescence. Interestingly, it has recently become apparent that upon oncogene inactivation, the immune response is critical in mediating the phenotypic consequences of oncogene addiction. In particular, CD4(+) T cells have been suggested to be essential to the remodeling of the tumor microenvironment, including the shutdown of host angiogenesis and the induction of cellular senescence in the tumor. However, adaptive and innate immune cells are likely involved. Thus, the effectors of the immune system are involved not only in tumor initiation, tumor progression, and immunosurveillance, but also in the mechanism of tumor regression upon targeted oncogene inactivation. Hence, oncogene inactivation may be an effective therapeutic approach because it both reverses the neoplastic state within a cancer cell and reactivates the host immune response that remodels the tumor microenvironment.

    View details for DOI 10.1007/s12026-014-8503-6

    View details for Web of Science ID 000336333700015

    View details for PubMedID 24791942

  • Angiocrine factors deployed by tumor vascular niche induce B cell lymphoma invasiveness and chemoresistance. Cancer cell Cao, Z., Ding, B., Guo, P., Lee, S. B., Butler, J. M., Casey, S. C., Simons, M., Tam, W., Felsher, D. W., Shido, K., Rafii, A., Scandura, J. M., Rafii, S. 2014; 25 (3): 350-365


    Tumor endothelial cells (ECs) promote cancer progression in ways beyond their role as conduits supporting metabolism. However, it is unknown how vascular niche-derived paracrine factors, defined as angiocrine factors, provoke tumor aggressiveness. Here, we show that FGF4 produced by B cell lymphoma cells (LCs) through activating FGFR1 upregulates the Notch ligand Jagged1 (Jag1) on neighboring ECs. In turn, upregulation of Jag1 on ECs reciprocally induces Notch2-Hey1 in LCs. This crosstalk enforces aggressive CD44(+)IGF1R(+)CSF1R(+) LC phenotypes, including extranodal invasion and chemoresistance. Inducible EC-selective deletion of Fgfr1 or Jag1 in the E?-Myc lymphoma model or impairing Notch2 signaling in mouse and human LCs diminished lymphoma aggressiveness and prolonged mouse survival. Thus, targeting the angiocrine FGF4-FGFR1/Jag1-Notch2 loop inhibits LC aggressiveness and enhances chemosensitivity.

    View details for DOI 10.1016/j.ccr.2014.02.005

    View details for PubMedID 24651014

  • Activation of Cre recombinase alone can induce complete tumor regression. PloS one Li, Y., Choi, P. S., Casey, S. C., Felsher, D. W. 2014; 9 (9)


    The Cre/loxP system is a powerful tool for generating conditional genomic recombination and is often used to examine the mechanistic role of specific genes in tumorigenesis. However, Cre toxicity due to its non-specific endonuclease activity has been a concern. Here, we report that tamoxifen-mediated Cre activation in vivo induced the regression of primary lymphomas in p53-/- mice. Our findings illustrate that Cre activation alone can induce the regression of established tumors.

    View details for DOI 10.1371/journal.pone.0107589

    View details for PubMedID 25208064

  • Oncogene withdrawal engages the immune system to induce sustained cancer regression. Journal for immunotherapy of cancer Casey, S. C., Li, Y., Fan, A. C., Felsher, D. W. 2014; 2: 24-?


    The targeted inactivation of a single oncogene can induce dramatic tumor regression, suggesting that cancers are "oncogene addicted." Tumor regression following oncogene inactivation has been thought to be a consequence of restoration of normal physiological programs that induce proliferative arrest, apoptosis, differentiation, and cellular senescence. However, recent observations illustrate that oncogene addiction is highly dependent upon the host immune cells. In particular, CD4(+) helper T cells were shown to be essential to the mechanism by which MYC or BCR-ABL inactivation elicits "oncogene withdrawal." Hence, immune mediators contribute in multiple ways to the pathogenesis, prevention, and treatment of cancer, including mechanisms of tumor initiation, progression, and surveillance, but also oncogene inactivation-mediated tumor regression. Data from both the bench and the bedside illustrates that the inactivation of a driver oncogene can induce activation of the immune system that appears to be essential for sustained tumor regression.

    View details for DOI 10.1186/2051-1426-2-24

    View details for PubMedID 25089198

  • Noncanonical roles of the immune system in eliciting oncogene addiction CURRENT OPINION IN IMMUNOLOGY Casey, S. C., Bellovin, D. I., Felsher, D. W. 2013; 25 (2): 246-258


    Cancer is highly complex. The magnitude of this complexity makes it highly surprising that even the brief suppression of an oncogene can sometimes result in rapid and sustained tumor regression, illustrating that cancers can be 'oncogene addicted' [1-10]. The essential implication is that oncogenes may not only fuel the initiation of tumorigenesis, but in some cases must be excessively activated to maintain a neoplastic state [11]. Oncogene suppression acutely restores normal physiological programs that effectively overrides secondary genetic events and a cancer collapses [12,13]. Oncogene addiction is the description of the dramatic and sustained regression of some cancers upon the specific inactivation of a single oncogene [1-13,14(??),15,16(??)], that can occur through tumor intrinsic [1,2,4,12], but also host immune mechanisms [17-23]. Notably, oncogene inactivation elicits a host immune response that involves specific immune effectors and cytokines that facilitate a remodeling of the tumor microenvironment including the shut down of angiogenesis and the induction of cellular senescence of tumor cells [16(??)]. Hence, immune effectors are not only critically involved in tumor prevention, initiation [17-19], and progression [20], but also appear to be essential to tumor regression upon oncogene inactivation [21,22(??),23(??)]. Understanding how the inactivation of an oncogene elicits a systemic signal in the host that prompts a deconstruction of a tumor could have important implications. The combination of oncogene-targeted therapy together with immunomodulatory therapy may be ideal for the development of both robust tumor intrinsic and immunological responses, effectively leading to sustained tumor regression.

    View details for DOI 10.1016/j.coi.2013.02.003

    View details for Web of Science ID 000319369100018

  • State of the science of endocrine disrupting chemicals - 2012 UNEP, W. WHO/UNEP. 2013
  • Science and policy on endocrine disrupters must not be mixed: a reply to a "common sense" intervention by toxicology journal editors. Environ Health A, B., et al 2013; 12(1):69.: Aug 27;12(1):69.
  • Bisphenol A Diglycidyl Ether Induces Adipogenic Differentiation of Multipotent Stromal Stem Cells through a Peroxisome Proliferator-Activated Receptor Gamma-Independent Mechanism ENVIRONMENTAL HEALTH PERSPECTIVES Chamorro-Garcia, R., kirchner, s., Li, X., Janesick, A., Casey, S. C., Chow, C., Blumberg, B. 2012; 120 (7): 984-989


    Bisphenol A (BPA) and bisphenol A diglycidyl ether (BADGE), used in manufacturing coatings and resins, leach from packaging materials into food. Numerous studies suggested that BPA and BADGE may have adverse effects on human health, including the possibility that exposure to such chemicals can be superimposed on traditional risk factors to initiate or exacerbate the development of obesity. BPA is a suspected obesogen, whereas BADGE, described as a peroxisome proliferator-activated receptor gamma (PPAR?) antagonist, could reduce weight gain.We sought to test the adipogenic effects of BADGE in a biologically relevant cell culture model.We used multipotent mesenchymal stromal stem cells (MSCs) to study the adipogenic capacity of BADGE and BPA and evaluated their effects on adipogenesis, osteogenesis, gene expression, and nuclear receptor activation.BADGE induced adipogenesis in human and mouse MSCs, as well as in mouse 3T3-L1 preadipocytes. In contrast, BPA failed to promote adipogenesis in MSCs, but induced adipogenesis in 3T3-L1 cells. BADGE exposure elicited an adipogenic gene expression profile, and its ability to induce adipogenesis and the expression of adipogenic genes was not blocked by known PPAR? antagonists. Neither BADGE nor BPA activated or antagonized retinoid "X" receptor (RXR) or PPAR? in transient transfection assays.BADGE can induce adipogenic differentiation in both MSCs and in preadipocytes at low nanomolar concentrations comparable to those that have been observed in limited human biomonitoring. BADGE probably acts through a mechanism that is downstream of, or parallel to, PPAR?.

    View details for DOI 10.1289/ehp.1205063

    View details for Web of Science ID 000306035300023

    View details for PubMedID 22763116

  • The Steroid and Xenobiotic Receptor Negatively Regulates B-1 Cell Development in the Fetal Liver MOLECULAR ENDOCRINOLOGY Casey, S. C., Blumberg, B. 2012; 26 (6): 916-925


    The steroid and xenobiotic receptor (SXR) (also known as pregnane X receptor or PXR) is a broad-specificity nuclear hormone receptor that is well known for its role in drug and xenobiotic metabolism. SXR is activated by a wide variety of endobiotics, dietary compounds, pharmaceuticals, and xenobiotic chemicals. SXR is expressed at its highest levels in the liver and intestine yet is found in lower levels in other tissues, where its roles are less understood. We previously demonstrated that SXR(-/-) mice demonstrate elevated nuclear factor (NF)-?B activity and overexpression of NF-?B target genes and that SXR(-/-) mice develop lymphoma derived from B-1 lymphocytes in an age-dependent manner. In this work, we show that fetal livers in SXR(-/-) mice display elevated expression of NF-?B target genes and possess a significantly larger percentage of B-1 progenitor cells in the fetal liver. Furthermore, in utero activation of SXR in wild-type mice reduces the B-1 progenitor populations in the embryonic liver and reduces the size of the B-1 cell compartment in adult animals that were treated in utero. This suggests that activation of SXR during development may permanently alter the immune system of animals exposed in utero, demonstrating a novel role for SXR in the generation of B-1 cell precursors in the fetal liver. These data support our previous findings that SXR functions as a tumor suppressor in B-1 lymphocytes and establish a unique role for SXR as a modulator of developmental hematopoiesis in the liver.

    View details for DOI 10.1210/me.2011-1303

    View details for Web of Science ID 000304365100004

    View details for PubMedID 22496360

  • B-1 Cell Lymphoma in Mice Lacking the Steroid and Xenobiotic Receptor, SXR MOLECULAR ENDOCRINOLOGY Casey, S. C., Nelson, E. L., Turco, G. M., Janes, M. R., Fruman, D. A., Blumberg, B. 2011; 25 (6): 933-943


    The steroid and xenobiotic receptor (SXR) is a broad-specificity nuclear hormone receptor that is highly expressed in the liver and intestine, where its primary function is to regulate drug and xenobiotic metabolism. SXR is expressed at lower levels in other tissues, where little is known about its physiological functions. We previously linked SXR with immunity and inflammation by showing that SXR antagonizes the activity of nuclear factor (NF)-?B in vitro and in vivo. SXR(-/-) mice demonstrate aberrantly high NF-?B activity and overexpression of NF-?B target genes. Here we show that SXR(-/-) mice develop B cell lymphoma in an age-dependent manner. SXR(-/-) mice develop multiple hyperplastic lymphoid foci composed of B-1a cells in the intestine, spleen, lymph nodes, peritoneal cavity, and blood. In all circumstances, these lymphocytes possess cell surface and molecular characteristics of either chronic lymphocytic leukemia or non-Hodgkin's lymphoma originating from B-1 lymphocytes. These results demonstrate a novel and unsuspected role for SXR signaling in the B-1 cell compartment, establish SXR as a tumor suppressor in B-1 cells, and may provide a link between metabolism of xenobiotic compounds and lymphomagenesis.

    View details for DOI 10.1210/me.2010-0486

    View details for Web of Science ID 000290791600004

    View details for PubMedID 21436254

  • Pregnane X receptor knockout mice display osteopenia with reduced bone formation and enhanced bone resorption JOURNAL OF ENDOCRINOLOGY Azuma, K., Casey, S. C., Ito, M., Urano, T., Horie, K., Ouchi, Y., kirchner, s., Blumberg, B., Inoue, S. 2010; 207 (3): 257-263


    The steroid and xenobiotic receptor (SXR) and its murine ortholog pregnane X receptor (PXR) are nuclear receptors that are expressed mainly in the liver and intestine where they function as xenobiotic sensors. In addition to its role as a xenobiotic sensor, previous studies in our laboratories and elsewhere have identified a role for SXR/PXR as a mediator of bone homeostasis. Here, we report that systemic deletion of PXR results in marked osteopenia with mechanical fragility in female mice as young as 4 months old. Bone mineral density (BMD) of PXR knockout (PXRKO) mice was significantly decreased compared with the BMD of wild-type (WT) mice. Micro-computed tomography analysis of femoral trabecular bones revealed that the three-dimensional bone volume fraction of PXRKO mice was markedly reduced compared with that of WT mice. Histomorphometrical analysis of the trabecular bones in the proximal tibia showed a remarkable reduction in bone mass in PXRKO mice. As for bone turnover of the trabecular bones, bone formation is reduced, whereas bone resorption is enhanced in PXRKO mice. Histomorphometrical analysis of femoral cortical bones revealed a larger cortical area in WT mice than that in PXRKO mice. WT mice had a thicker cortical width than PXRKO mice. Three-point bending test revealed that these morphological phenotypes actually caused mechanical fragility. Lastly, serum levels of phosphate, calcium, and alkaline phosphatase were unchanged in PXRKO mice compared with WT. Consistent with our previous results, we conclude that SXR/PXR promotes bone formation and suppresses bone resorption thus cementing a role for SXR/PXR as a key regulator of bone homeostasis.

    View details for DOI 10.1677/JOE-10-0208

    View details for Web of Science ID 000284490300002

    View details for PubMedID 20876238

  • Prenatal Exposure to the Environmental Obesogen Tributyltin Predisposes Multipotent Stem Cells to Become Adipocytes MOLECULAR ENDOCRINOLOGY kirchner, s., Kieu, T., Chow, C., Casey, S., Blumberg, B. 2010; 24 (3): 526-539


    The environmental obesogen hypothesis proposes that pre- and postnatal exposure to environmental chemicals contributes to adipogenesis and the development of obesity. Tributyltin (TBT) is an agonist of both retinoid X receptor (RXR) and peroxisome proliferator-activated receptor gamma (PPARgamma). Activation of these receptors can elevate adipose mass in adult mice exposed to the chemical in utero. Here we show that TBT sensitizes human and mouse multipotent stromal stem cells derived from white adipose tissue [adipose-derived stromal stem cells (ADSCs)] to undergo adipogenesis. In vitro exposure to TBT, or the PPARgamma activator rosiglitazone increases adipogenesis, cellular lipid content, and expression of adipogenic genes. The adipogenic effects of TBT and rosiglitazone were blocked by the addition of PPARgamma antagonists, suggesting that activation of PPARgamma mediates the effect of both compounds on adipogenesis. ADSCs from mice exposed to TBT in utero showed increased adipogenic capacity and reduced osteogenic capacity with enhanced lipid accumulation in response to adipogenic induction. ADSCs retrieved from animals exposed to TBT in utero showed increased expression of PPARgamma target genes such as the early adipogenic differentiation gene marker fatty acid-binding protein 4 and hypomethylation of the promoter/enhancer region of the fatty acid-binding protein 4 locus. Hence, TBT alters the stem cell compartment by sensitizing multipotent stromal stem cells to differentiate into adipocytes, an effect that could likely increase adipose mass over time.

    View details for DOI 10.1210/me.2009-0261

    View details for Web of Science ID 000274929600005

    View details for PubMedID 20160124

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