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Researchers
  • Prof.  Eli Pikarsky
Prof Eli Pikarsky
 
Introduction
Our group is interested in studying the role of heterotypic cellular interactions in the development of cancer. We are particularly interested in the role of immune cells in tumorigenesis, the bidirectional cross talk between immune and epithelial cells and how this cross talk affects tissue homeostasis and carcinogenesis. We maintain that cancer is critically dependent on its microenvironment and that these interactions not only shape the course of disease but also constitute a vulnerable trait which should be used for therapeutic purposes. The nature of our studies necessitates the use of sophisticated mouse models of cancer and state of the art analysis tools. The link between inflammation and cancer is now established, yet the underlying molecular mechanisms are unresolved. As tumors progress, they modulate the inflammatory cells towards a protumorigenic phenotype. We have shown that the inflammatory cells reciprocate by sculpting the parenchymal epithelial cells. We hypothesize that these reciprocal interactions lie at the heart of the link between inflammation and cancer.
 
Hepatocellular carcinoma (HCC), one of the deadliest tumors, is a prototype of inflammation induced cancer. Using models of human HCC we revealed several unique forms of inflammation, taking parts in different pathogenetic processes that precede and promote HCC.
 
We employ several strategies to analyze the changes that occur in inflammatory cells before and after tumor emergence, based on our findings showing that changes in inflammatory cells precede tumorigenesis. We are comprehensively mapping the changing inflammatory microenvironment using mouse models of inflammation induced HCC. Using genetic manipulation strategies, coupled to cell isolation techniques, we are delineating the molecular cues that mediate these changes and are analyzing the functional role of key mediators of these processes in the malignant process. Furthermore, drawing on our findings that a recurring tumor amplicon drives HCC progression by modulating the microenvironment, we are working towards the identification of additional similar amplicons to define the key effectors of the microenvironment. Of special importance, heterotypic cell interactions that play key roles in both cancer initiation and progression, present ideal therapeutic targets, which are easily accessible and less amenable to mutational selection.
 
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Specific Projects
Heterotypic cell interactions in chronic hepatitis and hepatocellular carcinoma
The link between inflammation and cancer is now established, yet the underlying molecular mechanisms are unresolved. As tumors progress, they modulate the inflammatory cells towards a protumorigenic phenotype. We have shown that the inflammatory cells reciprocate by sculpting the parenchymal epithelial cells. I hypothesize that these reciprocal interactions lie at the heart of the link between inflammation and cancer.

This team employs a two-fold strategy to analyze the changes that occur in inflammatory cells before and after tumor emergence, based on our preliminary findings showing that changes in inflammatory cells precede tumorigenesis. First, we will perform comprehensive mapping of the changing inflammatory microenvironment in a mouse model of inflammation induced HCC. We will employ genetic manipulation strategies, coupled to cell isolation techniques to delineate the molecular cues that mediate these changes and then will analyze the functional role of key mediators of these processes in the malignant process. Microfluidics approaches will give us a highthroughput quantitative view of these heterotypic interactions. The same approaches will be harnessed to identify the interactions that form the liver stem cell niche which dramatically expands in states of chronic inflammation.
 
 
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Funded by the ERC (1,490,000 Euro, 2011-2016)
 
 
Epithelial p53 and the microenvironment – a continuous cross talk
p53 is a central hub in preventing cancer: it is regulated by multiple cellular signaling pathways and biochemical events and in turn regulates the expression of multiple target genes and can execute several cellular outcomes. However, as cancer develops in tissues it is only logical to assume that p53 could be regulated by, and in turn regulate, tissue level phenomena which transcend the cellular level. Indeed, we have recently noted that p53 regulates the crosstalk between gut epithelial cells and the underlying lamina propria, to preserve tissue boundaries. We will explore the hypothesis that inflammation, injury or repair change the amplitude or the spectrum of the p53 response in epithelial cells. We expect that tissue danger lowers the threshold for p53 activation and thus adds extra-protection. Furthermore, by modulating the nature of the p53 response, the tissue could adapt better to the changing environment. We will study the reciprocal hypothesis that p53 in epithelial cells modulates the state of the microenvironment in disease states. Thus, it is conceivable that genotoxic stress occurring in multiple epithelial cells (leading to p53 activation), should alter inflammatory processes, to modulate inflammation so that the latter will not increase cancer risk.

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Funded by the ISF as part of a Center Of Excellence program (2,124,000 NIS 2012-2016)
Untangling the role of the NF-κB response in cancer tissues
We have shown that inhibiting NF-κB in vivo blocks tumorigenesis in mouse models of cancer. Surprisingly, it is now evident that in some cases, particularly in mouse liver and skin cancers, NF-κB blockade paradoxically facilitates carcinogenesis. These opposing actions of NF-κB, even in a particular organ system, hinder the implementation of NF-κB inhibition in human studies. It is therefore important to decipher the pathogenetic mechanisms that underlie these opposing outcomes. To this end, we have developed 3 different animal models of liver cancer, based on chronic inflammation, carcinogen administration or dietary modification, in which we can inhibit NF-κB specifically in hepatocytes in a timed and reversible manner. We have also constructed genetically modified mice in which we can activate the NF-κB pathway in hepatocytes. We found that NF-κB exerts its opposing effects at different time points in the malignant process, possibly through activation of different cellular responses. Taken together, we expect that these multilevel studies of the NF-κB pathway will facilitate the design of patient-tailored NF-κB-based therapeutics in cancer prevention and treatment.
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Funded by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (ongoing support so far totaling $1,400,000 over 8 years)
 
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Collaborations
Our group is involved in multiple collaborations which enhance our ability to achieve our goals and assist our collaborators in exploring the in vivo relevance of their findings in both humans and mice. Our key collaborators at our campus are the Ben-Neriah, Bergman and Katzav-Shapira groups. Other collaborators in Israel include Moshe Oren and Varda Rotter as part of the ISF center of excellence and Ciechanover, Shiloh and Yarden as part of the AMRF center of excellence. We also enjoy the collaboration with multiple scientists abroad, including among others Peter Angel (Heidelberg), Mathias Heikenwalder (Munich), Yujin Hoshida (USA), Michael Karin (USA), Ben Stanger (USA), Luigi Terracciano (Basel) and Arndt Vogel (Hanover).
 
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Lab Members
 
Eli Pikarsky Nina Mayorek Ilan Stein Einat Cinnamon
Eli Pikarsky, MD PhD
Researcher
Nina Mayorek, PhD
Research Associate
Ilan Stein, PhD
Research Associate
Einat Cinnamon, PhD
Research Associate
Eti Avraham Shafika Al Kawasmi
Eti Avraham
Lab Technician
Mohamed Juma
Histotechnician
 Hiba Kanaan
Lab technician
Shafika Al-Kawasmi
Lab Technician
all lab members together
Shlomi Finkin David Knigin
Shlomi Finkin
PhD Student
David Knigin
PhD Student
Efi Weitman Ela Nazirov Yoga Krishnamoorthy Yousef Mansour
Efi Weitman
DMD PhD Student
Ela Nazirov
PhDStudent
Yoga Krishnamoorthy
PhD student
Yousef Mansour
MSc Student
 
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Selected Publications
Pikarsky, E. & Peretz, T. Bone marrow metastases in breast cancer. N Engl J Med 343, 577-8 (2000).
 
Gidekel, S., Pizov, G., Bergman, Y. & Pikarsky, E. Oct-3/4 is a dose-dependent oncogenic fate determinant. Cancer Cell 4, 361-70 (2003).
   ✓ Highlighted in Cancer Cell
 
Lavon I*, Pikarsky E*, Gutkovich E, Goldberg I, Bar J, Oren M & Ben-Neriah Y. Nuclear factor-kappaB protects the liver against genotoxic stress and functions independently of p53. Cancer Res 63, 25-30 (2003).
 
Pikarsky, E#, Porat, R.M., Stein, I., Abramovitch, R., Amit, S., Kasem, S., Gutkovich-Pyest, E., Urieli-Shoval, S., Galun, E. & Ben-Neriah, Y. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461-6 (2004).
    ✓ Highlighted in Nature, Science, Cell, Nature Reviews Cancer, Faculty of 1000 and others
 
Pikarsky E, Ronen A, Abramowitz J, Levavi-Sivan B, Hutoran M, Shapira Y, Steinitz M, Perelberg A, Soffer D & Kotler M. Pathogenesis of acute viral disease induced in fish by carp interstitial nephritis and gill necrosis virus. J Virol 78, 9544-51 (2004).
 
Yutkin, V., Pode, D., Pikarsky, E.# & Mandelboim, O. The Expression Level of Ligands for Natural Killer Cell Receptors Predicts Response to Bacillus Calmette-Guerin Therapy: A Pilot Study. J Urol, 178, 2660-4. (2007)
   ✓ Highlighted in Journal of Urolog
 
Németh J, Stein I, Haag D, Longerich T, Riehl A, Breuhahn K, Gebhardt C, Hahn M, Ben Neriah Y, Pikarsky E, Angel P, Hess J. S100A8 and S100A9 are novel NF-B target genes during malignant progression of liver carcinogenesis. Hepatology 50:1251-62 (2009)
 
Gluschneider U., Hides G., Cojucaru G., Ben-Neriah Y. and Pikarsky E. β-TrCP inhibition reduces prostate cancer cell growth via upregulation of the Arylhydrocarbon receptor. PLoS ONE. 5:e9060 (2010).
 
Barash H, R Gross E, Edrei Y, Ella E, Israel A, Cohen I, Corchia N, Ben-Moshe T, Pappo O, Pikarsky E, Goldenberg D, Shiloh Y, Galun E, Abramovitch R. Accelerated carcinogenesis following liver regeneration is associated with chronic inflammation-induced double-strand DNA breaks. Proc Natl Acad Sci U S A. 107:2207-12 (2010).
 
Gielchinsky Y, Laufer N, Abramovitch R, Granot Z, Bergman Y & Pikarsky E. Pregnancy restores the regenerative capacity of the aged liver via activation of an mTOR-controlled hyperplasia/hypertrophy switch. Genes Dev 24:543-48 (2010).
    Highlighted in Nature, Faculty of 1000
 
Zaaroor-Regev D, de Bie P, Scheffner M, Noy T, Shemer R, Heled M, Stein I, Pikarsky E & Ciechanover A. Regulation of the polycomb protein Ring1B by self-ubiquitination or by E6-AP may have implications to the pathogenesis of Angelman syndrome. Proc Natl Acad Sci U S A. 107:6788-93 (2010).
 
Demaria S, Pikarsky E, Karin M, Coussens LM, Chen YC, El-Omar EM, Trinchieri G, Dubinett SM, Mao JT, Szabo E, Krieg A, Weiner GJ, Fox BA, Coukos G, Wang E, Abraham RT, Carbone M & Lotze MT. Cancer and inflammation: promise for biologic therapy. J Immunother. 33:335-51 (2010)
 
Finkin S & Pikarsky E. NF-kappaB in Liver Cancer: The Plot Thickens. Curr Top Microbiol Immunol. 349:185-96 (2011)
 
Elyada E, Pribluda A, Goldstein RE, MorgensternY, Brachya G, Cojocaru G, Snir-Alkalay I, Burstain I, Haffner-Krausz R, Jung S, Wiener Z, Alitalo K, Oren M, Pikarsky E# & Ben-Neriah Y. CKIalpha ablation highlights a critical role of p53 in invasiveness control. Nature 470:409-13 (2011)
    Highlighted in Faculty of 1000
 
Biton M, Levin A, Slyper M, Alkalay I, Horwitz E, Mor H, Cojocaru G, Zreik F, Bentwich Z, Poy MN, Artis D, Hornstein E, Pikarsky E# & Ben-Neriah Y. Epithelial microRNAs regulate gut mucosal immunity via epithelium-T cell crosstalk. Nature Immunology 12:239-46 (2011)
  ✓ Highlighted in Faculty of 1000
 
Perets R, Kaplan T, Stein I, Hidas G, Tayeb S, Avraham E, Ben-Neriah Y, Simon I & Pikarsky E. Genome-Wide Analysis of Androgen Receptor Targets Reveals COUP-TF1 as a Novel Player in Human Prostate Cancer. PLoS One. 7(10):e46467. doi: 10.1371/journal.pone.0046467 (2012)
 
Cooks T, Pateras IS, Tarcic O, Solomon H, Schetter AJ, Wilder S, Lozano G, Pikarsky E, Forshew T, Rozenfeld N, Harpaz N, Itzkowitz S, Harris CC, Rotter V, Gorgoulis VG & Oren M. Mutant p53 Prolongs NF-κB Activation and Promotes Chronic Inflammation and Inflammation-Associated Colorectal Cancer. Cancer Cell 23:634-46 (2013)
   Highlighted in "Cancer Cell top 10 for 2013", Nature Reviews Cancer
 
Pribluda A, Elyada E, Wiener Z, Hamza H, Goldstein RE, Biton M, Burstain I, Morgenstern Y,  Brachya G, Billauer H, Biton S, Snir-Alkalay I, Vucic D, Schlereth K, Mernberger M, Stiewe T, Oren M, Alitalo K, Pikarsky E# & Ben-Neriah Y, A senescence-inflammatory switch from cancer-inhibitory to cancer-promoting mechanism. Cancer Cell 24:242-56 doi: 10.1016/j.ccr.2013.06.005 (2013)
   Highlighted in "Cancer Cell top 10 for 2013"
 
Kanarek N, Grivennikov SI, Leshets M, Lasry A, Alkalay I, Horwitz E, Shaul YD, Stachler M, Voronov E, Apte RN, Pagano M, Pikarsky E, Karin M, Ghosh S, Ben-Neriah Y, Critical role for IL-1β in DNA damage-induced mucositis. Proc Natl Acad Sci U S A. 111:E702-11. doi: 10.1073/pnas.1322691111 (2014)
 
Horwitz E, Stein I, Andreozzi M, Nemeth J, Shoham  A, Pappo  O, Schweitzer  N, Tornillo L, Kanarek  K, Quagliata  L, Zreik  F, Porat  RM, Finkelstein R, Reuter  H, Koschny R, Ganten T, Mogler C, Shibolet O, Hess J, Breuhahn K, Grunewald M, Schirmacher P, Vogel A, Terracciano L, Angel P, Ben-Neriah Y & Pikarsky E. Human and mouse VEGFA-amplified hepatocellular carcinomas are highly sensitive to sorafenib treatment. Cancer Discovery, 4:730-43 (2014)
   Highlighted in Cancer Cell, Cancer Discovery, Molecular and Cellular Oncology
 
Yanger K*, Knigin D*, Zong Y,  Maggs L, Gu G, Akiyama H, Pikarsky E & Stanger BZ. Adult hepatocytes are formed by self-duplication rather than stem-cell differentiation. Cell Stem Cell, 15:340-9. (2014)
 ​  Highlighted in Cell Stem Cell
 
Hefetz-Sela S, Stein I, Klieger Y, Porat R, Sade-Feldman M, Zreik F, Nagler A, Pappo O, Eferl R, Wagner EF, Ben-Neriah Y, Baniyash M, Pikarsky E. Acquisition of an Immunosuppressive Pro-Tumorigenic Macrophage Phenotype Depends on c-Jun Phosphorylation.  Proc Natl Acad Sci U S A. 111:17582-7 (2014)
 
Kravtsova-Ivantsiv Y, Shomer I, Cohen-Kaplan V, Snijder B, Superti-Furga g, Gonen H, Sommer T, Ziv T, Admon A, Naroditsky I, Jbara M, Brik A, Normand R, Shen-Orr SS, Pikarsky E, Doweck I, and Ciechanover A. The Ubiquitin Ligase KPC1 Promotes Processing of p105 NF-κB1 to p50, Eliciting Strong Tumor Suppression. Cell, In press.  
 
# Corresponding author
* Equal contribution
 
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