Basic and Laboratory Research

Cancer Biology

Proposed and confirmed important concepts about metastasis (that it is a non-random process) and tumor composition (that cells within a tumor have diverse properties and that not all cancer cells have the capacity to spread).

Fidler IJ. Selection of successive tumor lines for metastasis. Nature (New Biol). 1973;242(118):
148-149.

Fidler IJ, Kripke ML. Metastasis results from preexisting variant cells within a malignant tumor. Science. 1977;197(4306):893-895.

Talmadge JE, Wolman SR, Fidler IJ. Evidence for the clonal origin of spontaneous metastases. Science. 1982;217(4557):361-363.

Demonstrated that both the growth and metastasis of cancer cells depend in part on molecules provided by normal cells and other aspects of the microenvironment surrounding a cancer, suggesting a new approach to therapy that targets normal cells.

Hart IR, Fidler IJ. Role of organ selectivity in the determination of metastatic patterns of the B16 melanoma. Cancer Res. 1980;40(7):2281-2287.

Fidler IJ, Hart IR. Biological diversity in metastatic neoplasms: origins and implications. Science. 1982;217(4564):998-1003.

Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 2003;3(6):453-458.

Designed models of human cancers in which human cancer cells are grown in athymic mice in the organ from which the cancer was derived; these models are especially useful for studying new therapies for human cancers.

Fidler IJ. Biology of cancer metastasis. In: Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds. Clinical Oncology. 3rd ed. Philadelphia, PA: Elsevier Science; 2004:59-79.

Demonstrated in rats that a short exposure to environmental chemicals during development reprograms genes to become hyper-responsive to estrogen later in life, leading to a near-doubling in the incidence of uterine tumors in adult females.

Cook JD, Davis BJ, Cai SL, Barrett JC, Conti CJ, Walker CL. Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance. Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8644-9.

Walker CL, Stewart EA. Uterine fibroids: the elephant in the room. Science. 2005 Jun 10;308(5728):1589-92.

Developed a mouse model that mimics human psoriasis, and showed that the protein STAT3 must be present to initiate the disease. If new treatments can be developped to block the action of STAT3 in the human disease, this may open the door to more effective therapy.

Sano S, Chan KS, Carbajal S, Clifford J, Peavey M, Kiguchi K, Itami S, Nickoloff BJ, DiGiovanni J. Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model. Nature Medicine. 2005 Jan;11(1):43-9.

First to demonstrate that VEGF may be a target for therapy in patients with colorectal cancer. Anti-VEGF therapy is now standard of care for patients with metastatic colorectal cancer.

Takahashi Y, Kitadai Y, Bucana C, Cleary KR, Ellis LM. Expression of vascular endothelial growth factor and its receptor (KDR) correlates with vascularity, metastasis and proliferation of human colon cancer. Cancer Res, 55:3964-3968,1995.

Identified the role of the cannabinoid receptor, CB1, as a tumor-suppressor in human colorectal cancer.

Wang D, Wang H, Ning W, Backlund MF, Dey SK, DuBois RN. Loss of cannabinoid receptor 1 accelerates intestinal tumor growth. Cancer Res. 2008;68(15) 6468-6476.

First demonstration that tumors stimulate specific types of bone marrow cells to migrate into the tumor. These bone marrow cells help in the formation and expansion of the tumor vessels that bring oxygen and nutrients required for tumor growth. These bone marrow cells can help the tumor recover after anti-vascular therapy and may explain why tumors rebound after avastin (anti-VEGF) therapy.

Reddy K, Zhou Z, Jiao SF, Kleinerman ES. Specific bone marrow subsets differentiate into endothelial cells and pericytes and contribute to tumor vessel formation in Ewing’s sarcoma. Mol Cancer Res. 2008;6:929-936.

Genetics

Developed the C-banding technique for labeling chromosomes, enabling scientists to pinpoint the precise location of genes in various chromosomes.

Demonstrated that particular unstable sections of a DNA molecule can become deformed, producing mutations and chromosomal breaks in the absence of external chemical agents, thus discovering a new way that cancer-causing genes can be produced.

Wang G, Christensen LA, Vasquez KM. Z-DNA-forming sequences generate large-scale deletions in mammalian cells. Proc Natl Acad Sci U S A. 2006;103(8):2677-2682.

Wang G, Vasquez KM. Naturally occurring H-DNA-forming sequences are mutagenic in mammalian cells. Proc Natl Acad Sci U S A. 2004;101(37):13448-13453.

Demonstrated that p53, the most prevalent cancer-causing gene, acts differently depending on whether it is deleted or has specific mutations in its DNA sequence.

Lang GA, Iwakuma T, Suh YA, Liu G, Rao VA, Parant JM, Valentin-Vega YA, Terzian T, Caldwell LC, Strong LC, El-Naggar AK and Lozano G. Gain-of-function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell. 2004;119:861-872.

Discovered that colon cancers in patients from different geographic areas are different because different genes are being mutated or abnormally regulated.

Soliman AS, Bondy ML, El-Badawy SA, Mokhtar N, Eissa S, Bayoumy S, Seifeldin IA, Houlihan PS, Lukish JR, Watanabe T, Chan AO, Zhu D, Amos CI, Levin B, Hamilton SR. Contrasting molecular pathology of colorectal carcinoma in Egyptian and Western patients. Br J Cancer. 2001;85:1037-1046.

Chan AO, Soliman AS, Zhang Q, Rashid A, Bedeir A, Houlihan PS, Mokhtar N, Al-Masri N, Ozbek U, Yaghan R, Kandilci A, Omar S, Kapran Y, Dizdaroglu F, Bondy ML, Amos CI, Issa JP, Levin B, Hamilton SR. Differing DNA methylation patterns and gene mutation frequencies in colorectal carcinomas from Middle Eastern countries. Clin Cancer Res. 2005;11(23):8281-8287.

Discovered that a key DNA repair gene is turned off in half of all colon cancers and in surrounding non-cancerous colon cells as well, suggesting that the cancer occurred in a larger “field” of abnormal (but not yet malignant) colon cells.

Shen L, Kondo Y, Rosner GL, Xiao L, Hernandez NS, Vilaythong J, Houlihan PS, Krouse RS, Prasad AR, Einspahr JG, Buckmeier J, Alberts DS, Hamilton SR, Issa JP. MGMT promoter methylation and field defect in sporadic colorectal cancer. J Natl Cancer Inst. 2005;97(18): 1330-1338.

Issa JP. Epigenetic variation and human disease. J Nutr. 2002;132(8):2388S-2392S.

Demonstrated that specific precancerous (forerunner) genes are inactivated to stimulate early proliferation of premalignant cells in the development of bladder cancer.

Czerniak B, Li L, Chaturvedi V, Ro JY, Johnston DA, Hodges S, Benedict WF. Genetic modeling of human urinary bladder carcinogenesis. Genes Chromosomes Cancer. 2000;27(4):392-402.

Tuziak T, Jeong J, Majewski T, Kim MS, Steinberg J, Wang Z, Yoon DS, Kuang TC, Baggerly K, Johnston D, Czerniak B. High-resolution whole-organ mapping with SNPs and its significance to early events in carcinogenesis. Lab Invest. 2005;85(5):689-701.

Discovered the tumor suppressor gene PTEN and identified mutations that eliminate PTEN function.

Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH, Tavtigian SV. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997;15(4):356-362.

Discovered that UV-induced p53 mutations arise very early during skin cancer development and that inhibition of p53 mutations by sunscreens protects against skin cancer development.

Ananthaswamy HN, Ullrich SE, Mascotto RE, Fourtanier A, Loughlin SM, Khaskina P, Bucana CD, Kripke ML. Inhibition of solar simulator-induced p53 mutations and protection against skin cancer development in mice by sunscreens. J Invest Dermatol. 1999;112(5):763-768.

Ananthaswamy HN, Loughlin SM, Ullrich SE, Kripke ML. Inhibition of UV-induced p53 mutations by sunscreens: implications for skin cancer prevention. J Investig Dermatol Symp Proc. 1998;3(1):52-56.

Ananthaswamy HN, Loughlin SM, Cox P, Evans RL, Ullrich SE and Kripke ML. Sunlight and skin cancer: Inhibition of p53 mutations in UV-irradiated mouse skin by sunscreens. Nature Med. 3:510-513, 1997.

First to identify Bcr as a tumor suppressor gene in the leukemic effects caused by the Bcr-Abl oncoprotein in chronic myeloid leukemia.

Lin F, Liu J, Monaco G, Sun T, Liu ., Lin H, Stephens C, Belmont J, Arlinghaus RB. BCR gene expression blocks Bcr-Abl induced pathogenicity in a mouse model. Oncogene 20:1873-1881, 2001.

Hawk N, Sun T, Xie S, Wang Y, Wu Y, Liu J, Arlinghaus RB. Inhibition of the Bcr-Abl oncoprotein by Bcr requires phosphoserine 354. Cancer Research 62: 386-390, 2002.

Discovered the function of the p53 tumor suppressor gene as a transcriptional activator; demonstrated that common p53 mutations found in human cancers are transcriptionally inactive.

Raycroft L, Wu H and Lozano G. Transcriptional activation by wild-type but not transforming mutants of the p53 antioncogene. Science, 249:1049-1051, 1990.

Raycroft L, Schmidt JR, Yoas K, Hao M and Lozano G. Analysis of p53 mutants for transcriptional activity. Mol. Cell. Biol., 11:6067-6074, 1991.

Discovered the importance of dampening p53 function in normal tissues by two inhibitors Mdm2 and Mdm4. These inhibitors also suppress p53 activity in human cancers.

Montes de Oca Luna R, Wagner DS and Lozano G. Rescue of early embryonic lethality in mdm-2 deficient mice by deletion of p53. Nature, 378:203-206, 1995.

Parant J, Chavez-Reyes A, Little NA, Yan W, Reinke V, Jochemsen AG and Lozano G. Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a non-overlapping pathway with MDM2 to regulate p53. Nature Genet., 29:92-95, 2001.

Discovered a new gene called “Dead End” that modifies testicular cancers in mice.

Youngren K, Coveney D, Peng X, Bhattacharya C, Schmidt LS, Nickerson ML, Lamb B, Deng JM, Behringer RR, Capel B, Rubin E, Nadeau J and Matin A. The Ter mutation in the dead end gene causes germ cell loss and testicular germ cell tumours. Nature 435: 360-364, 2005.

Discovered the importance of two proteins, Pot1 and Pot2, in protecting the ends of the DNA (telomeres) from unraveling and becoming mutageneic.

Wu L, Multani AS, He H, Cosme-Blanco W, Deng Y, Deng JM, Bachilo O, Pathak S, Tahara H, Bailey SM, Deng Y, Behringer RR and Chang, S. Pot1 Deficiency Initiates DNA Damage Checkpoint Activation and Aberrant Homologous Recombination at Telomeres. Cell 126:49-62, 2006.

He H, Multani AS, Cosme-Blanco W, Tahara H, Ma J, Pathak S, Deng Y and Chang S. Pot2 Protects Telomeres From End-to-End Chromosomal Fusions and Aberrant Homologous Recombination. EMBO J, 25 (21): 5180-90, 2006.

Molecular Biology

Demonstrated that cell surface receptor molecules not only mediate traditional chemical signals activating proliferation but also travel to the nucleus, where they can act on genes and other nuclear proteins to regulate transcription, DNA repair and DNA synthesis.

Lin SY, Makino K, Xia W, Matin A, Wen Y, Kwong KY, Bourguignon L, Hung MC. Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nat Cell Biol. 2001;3(9):802-808.

Wang SC, Nakajima Y, Yu YL, Xia W, Chen CT, Yang CC, McIntush EW, Li LY, Hawke DH, Kobayashi R, Hung MC. Tyrosine phosphorylation controls protein stability of PCNA. Nature Cell Biol. 2006;8(12):1359-1368.

Lo HW, Hsu SC, Ali-Seyed M, Gunduz M, Xia W, Wei Y, Bartholomeusz G, Shih JY, Hung MC. Nuclear interaction of EGFR and STAT3 in the activation of iNOS/NO pathway. Cancer Cell. 2005;7(6):575-589.

Discovered MTA1s (metastatic tumor antigen 1, short version), a protein that is required for estrogen to exert its effects, including promotion of breast cancer, and demonstrated its abnormal activity in breast cancers.

Kumar R, Wang RA, Mazumdar A, Talukder AH, Mandal M, Yang Z, Bagheri-Yarmand R, Sahin A, Hortobagyi G, Adam L, Barnes CJ, Vadlamudi RK. A naturally occurring MTA1 variant sequesters estrogen receptor-alpha in the cytoplasm. Nature. 2002;418(6898):654-657.

Discovered Osterix, a molecule that binds to DNA and activates the expression of genes required for bone formation.

Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR, de Crombrugghe B. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell. 2002;108(1):17-29.

Koga T, Matsui Y, Asagiri M, Kodama T, de Crombrugghe B, Nakashima K, Takayanagi H. NFAT and Osterix cooperatively regulate bone formation. Nat Med. 2005;11(8):880-885.

Discovered a mechanism that enables cells to detect and degrade non-functional RNA, preventing these defective RNA molecules from encoding truncated and ineffective proteins.

Chang YF, Imam JS, Wilkinson MF. The nonsense-mediated decay RNA surveillance pathway. Annu Rev Biochem. 2007; 76: 51-74.

Chan WK, Huang L, Gudikote JP, Chang YF, Imam JS, MacLean JA, Wilkinson MF. An alternative branch of the nonsense-mediated decay pathway. EMBO J. 2007;26(7):1820-1830.

Gudikote JP, Imam JS, Garcia RF, Wilkinson MF. RNA splicing promotes translation and RNA surveillance. Nat Struct Mol Biol. 2005;12(9):801-809.

Discovered that EGFR, a receptor tyrosine kinase frequently overexpressed in human cancers, enhances the ability of cancer cells to utilize glucose. This novel activity empowers cancer cell survival under poor nutritional conditions and suggests that treatment may be enhanced by knocking down both kinase activity and glucose-related activity of EGFR.

Weihua Z, Tsan R, Huang WC, Wu Q, Chiu CH, Fidler IJ, Hung MC. Survival of cancer cells is maintained by EGFR independent of its kinase activity. Cancer Cell. 2008;13(5):385-393.

Developmental Biology

Demonstrated that adult stem cells isolated from muscle can be converted into functioning nerve cells, a concept now being explored in mouse models for treatment of Parkinsonism and spinal cord injury.

Watanabe Y, Kameoka S, Gopalakrishnan V, Aldape KD, Pan ZZ, Lang FF, Majumder S. Conversion of myoblasts to physiologically active neuronal phenotype. Genes Dev. 2004;18(8):889-900.

Demonstrated in preclinical models that adult stem cells of mesenchymal origin can be genetically modified to deliver anticancer molecules to the site of cancer.

Studeny M, Marini FC, Dembinski JL, Zompetta C, Cabreira-Hansen M, Bekele BN, Champlin RE, Andreeff M: Mesenchymal stem cells: Potential precursors for tumor stroma and targeted delivery vehicles of anti-cancer agents. J Natl Cancer Inst 96:1593-1603, 2004.

Kojima K, Konopleva M, Samudio IJ, Shikami M, Cabreira-Hansen M, McQueen T, Ruvolo V, Tsao T, Zeng Z, Vassilev LT, Andreeff M: MDM2 antagonists induce p53-dependent apoptosis in AML: Implications for leukemia therapy. Blood 106:3150-3159, 2005.

Demonstrated that the REST protein is a new member of an interconnected regulatory network used by embryonic stem cells to replicate themselves (self-renewal) and retain the capacity to differentiate into numerous cell types (pluripotency).

Singh SK, Kagalwala MN, Parker-Thornburg J, Adams H, Majumder S. REST maintains self- renewal and pluripotency of embryonic stem cells. Nature. 2008;453:223-227.

Demonstrated that mutations accumulating in DNA sequences that control gene expression within a population of animals may be a source of variation for the evolution of morphological differences between species.

Cretekos C, Wang Y, Green ED, Martin JF, Rasweilerr JJ, Behringer RR. Regulatory divergence modifies limb length between mammals. Genes Dev. 2008;22:141-151.

Immunology

Discovered that UV-irradiation causes systemic immunosuppression, contributing to carcinogenesis, and described the cellular and molecular mechanisms underlying UV-induced immunosuppression.

Ullrich SE. Mechanisms underlying UV-induced immune suppression [review]. Mutat Res. 2005;571(1-2):185-205.

Discovered the origin in the thymus gland of regulatory lymphocytes that police and protect the body by inhibiting T-cells that can cause autoimmune disease.

Watanabe N, Wang YH, Lee HK, Ito T, Wang YH, Cao W, Liu YJ. Hassall’s corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature. 2005;436(7054):1181-1185.

Characterized two functional receptors uniquely expressed by human plasmacytoid dendritic cells (pDCs) and discovered a major intracellular signaling pathway, through which pDC receptors modulate immune responses.

Cao W, Rosen DB, Ito T, Bover L, Bao M, Watanabe G, Zhang L, Lanier LL, Liu Y-J. Plasmacytoid Dendritic Cell-Specific Receptor ILT7/FcεRI Inhibits Toll-Like Receptor-Induced Interferon Production. J. Exp. Med. 203:1399-1405, 2006.

Cao W, Zhang L, Rosen DB, Bover L, Watanabe G, Bao M, Lanier LL, Liu Y-J. BDCA2/FceRIg Complex Signals through a Novel BCR-like Pathway in Human Plasmacytoid Dendritic Cells. PLoS Biology, in press, 2007.

Created a chimeric antigen receptor that can fully activate T-cells upon binding of antigen, leading to tumor-cell lysis, T-cell proliferation and cytokine production.

Kowolik CM, Topp MS, Gonzalez S, Pfeiffer T, Olivares S, Gonzalez N, Smith DD, Forman SJ, Jensen MC, Cooper LJ. CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. Cancer Res. 2006;66(22):10995-11004.

Gene therapy can improve the ability of T cells, a type of immune cell, to target human cancers. To safely insert desired genes into T cells, adapted a gene transfer system found in fish called Sleeping Beauty. Demonstrated that Sleeping Beauty can be used to efficiently introduce genes that will redirect the specificity of T cells for tumor cells. Achieved FDA approval to test Sleeping Beauty in clinical trials using T cells rendered specific for one type of lymphoma.

Singh H, Manuri PR, Olivares S, Dara N, Dawson MJ, Huls H, Hackett PB, Kohn DB, Shpall EJ, Champlin RE, Cooper LJ. Redirecting specificity of T-cell populations for CD19 using the sleeping beauty system. Cancer Res. 2008;68:2961-2971.

Preclinical Development of Novel Therapies

Identified and destroyed blood vessels providing circulation to tumors by attaching a small peptide to a toxic molecule that specifically targets the cells that form these blood vessels, providing proof-of-concept that peptides can be synthesized and directed to kill particular cancers.

Arap MA, Lahdenranta J, Mintz PJ, Hajitou A, Sarkis AS, Arap W, Pasqualini R. Cell surface expression of the stress response chaperone GRP78 enables tumor targeting by circulating ligands. Cancer Cell. 2004;6(3):275-284.

Established the feasibility of “anti-obesity therapy” based upon targeted induction of apoptosis in the vasculature of adipose tissue.

Kolonin MG, Saha PK, Chan L, Pasqualini R, Arap W. Reversal of obesity by targeted ablation of adipose tissue. Nat Med. 2004;10(6):625-632.

Discovered that a synthetic peptide corresponding to the envelope protein of HIV-1 can inhibit entry of the virus into human cells, making this peptide a candidate for therapeutic intervention for patients with HIV/AIDS.

Nehete PN, Vela EM, Hossain MM, Sarkar AK, Yahi N, Fantini J, Sastry KJ. A post-CD4-binding step involving interaction of the V3 region of viral gp120 with host cell surface glycosphingolipids is common to entry and infection by diverse HIV-1 strains. Antiviral Res. 2002;56(3):233-251.

Nehete PN, Arlinghaus RB, Sastry KJ. Inhibition of human immunodeficiency virus type 1 infection and syncytium formation in human cells by V3 loop synthetic peptides from gp120. J Virol. 1993;67(11):6841-6846.

Showed that PTEN activation contributes to tumor inhibition by trastuzumab (Herceptin) and that loss of PTEN predicts resistance to trastuzumab in HER2-positive breast cancer patients, leading to combination therapies to overcome Herceptin resistance.

Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Hortobagyi GN, Hung MC, Yu D. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004;6(2):117-127.

Identified cellular self digestion as a target for cancer therapy; identified potential compounds, such as the phenothiazines, to induce cellular self digestion, providing the first evidence of a mechanism for the role of nutrients and energy metabolism in cell survival.

Liang J, Shao SH, Xu ZX, Hennessy B, Ding Z, Larrea M, Kondo S, Dumont DJ, Gutterman JU, Walker CL, Slingerland JM, Mills GB. The energy sensing LKB1-AMOK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol. 2007;9:218-224.