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Joe Kissil, PhD

Vice Chair, Department of Molecular Oncology

Program: Molecular Oncology

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Overview


Associations

    • Molecular Oncology
    • Cancer Biology and Evolution Program

Education & Training

Fellowship:

  • Massachusetts Institute of Technology, -
Research

Research in the Kissil lab focuses on mechanistic understanding of mitogenic and developmental signaling pathways crosstalk in cancer and on identification of therapeutic targets. We employ a diverse toolkit which includes molecular and biochemical techniques, cellular biology and cutting-edge animal models of human cancer. In particular, we focus on understanding the molecular basis for lung cancer and neurofibromatosis type 2 (NF2). We employ in vivo models to dissect the function of different effectors in KRAS driven tumors in vivo. Examples include identifying the function of the small G-protein from the Rac/cdc42 family and Notch family receptors in KRAS-driven tumorigenesis. More recently, we have been developing and deploying advanced cell-based models to identify small molecules that are synthetic-lethal to oncogenic KRAS. These models involve the use of isogenic cell pairs and 3D culturing platforms, exploring novel chemical space utilizing functionalized fragment probes.  Our work on NF2 aims to understand the consequences of loss of the NF2 tumor suppressor gene. We identified and validated several therapeutic targets including the p21-activated kinases (PAKs) and the focal adhesion kinase (FAK). The latter identification stemmed from our work with the FDA approved drug Crizotinib, as a potential treatment for NF2 associated schwannoma. This work led to the initiation of a phase II clinical trial for NF2. More recently, we characterized the role and function of Hippo/Yap signaling in NF2, resulting in identification of previously unknown effectors in this pathway, the Angiomotins, and elucidated a mechanism through which Merlin, the product of the NF2 tumor suppressor gene, regulates multiple signaling pathways from cell junctions. This work also resulted in identification of novel functions for YAP, as a transcriptional repressor. We are interested in expanding the understanding of YAP function and are engaged in efforts to identify small-molecule inhibitors of YAP. These studies are conducted in collaboration with multidisciplinary teams with expertise in chemistry, proteomics and small-molecule screening.

Publications

  • Shepard A, Hoxha S, Troutman S, Harbaugh D, Kareta MS, Kissil JL. Transcriptional regulation of miR-30a by YAP impacts PTPN13 and KLF9 levels and Schwann cell proliferation. J Biol Chem. 2021 Aug.297(2):100962. Pubmedid: 34265306. Pmcid: PMC8348554.
  • Hoxha S, Shepard A, Troutman S, Diao H, Doherty JR, Janiszewska M, Witwicki RM, Pipkin ME, Ja WW, Kareta MS, Kissil JL. YAP-Mediated Recruitment of YY1 and EZH2 Represses Transcription of Key Cell-Cycle Regulators. Cancer Res. 2020 Jun.80(12):2512-2522. Pubmedid: 32409309. Pmcid: PMC7299785.
  • Shepard A, Kissil JL. The use of non-traditional models in the study of cancer resistance-the case of the naked mole rat. Oncogene. 2020 Jul.39(28):5083-5097. Pubmedid: 32535616.
  • Cui Y, Groth S, Troutman S, Carlstedt A, Sperka T, Riecken LB, Kissil JL, Jin H, Morrison H. The NF2 tumor suppressor merlin interacts with Ras and RasGAP, which may modulate Ras signaling. Oncogene. 2019 Sep.38(36):6370-6381. Pubmedid: 31312020. Pmcid: PMC6756068.
  • Carper MB, Troutman S, Wagner BL, Byrd KM, Selitsky SR, Parag-Sharma K, Henry EC, Li W, Parker JS, Montgomery SA, Cleveland JL, Williams SE, Kissil JL, Hayes DN, Amelio AL. An Immunocompetent Mouse Model of HPV16(+) Head and Neck Squamous Cell Carcinoma. Cell Rep. 2019 Nov.29(6):1660-1674.e7. Pubmedid: 31693903. Pmcid: PMC6870917.
  • Lyons J, Brubaker DK, Ghazi PC, Baldwin KR, Edwards A, Boukhali M, Strasser SD, Suarez-Lopez L, Lin YJ, Yajnik V, Kissil JL, Haas W, Lauffenburger DA, Haigis KM. Integrated in vivo multiomics analysis identifies p21-activated kinase signaling as a driver of colitis. Sci Signal. 2018 Feb.11(519). Pubmedid: 29487189. Pmcid: PMC6719711.
  • Kota S, Hou S, Guerrant W, Madoux F, Troutman S, Fernandez-Vega V, Alekseeva N, Madala N, Scampavia L, Kissil J, Spicer TP. A novel three-dimensional high-throughput screening approach identifies inducers of a mutant KRAS selective lethal phenotype. Oncogene. 2018 Aug.37(32):4372-4384. Pubmedid: 29743592. Pmcid: PMC6138545.
  • Chinthalapudi K, Mandati V, Zheng J, Sharff AJ, Bricogne G, Griffin PR, Kissil J, Izard T. Lipid binding promotes the open conformation and tumor-suppressive activity of neurofibromin 2. Nat Commun. 2018 Apr.9(1):1338. Pubmedid: 29626191. Pmcid: PMC5889391.
  • Moleirinho S, Hoxha S, Mandati V, Curtale G, Troutman S, Ehmer U, Kissil JL. Regulation of localization and function of the transcriptional co-activator YAP by angiomotin. Elife. 2017 May.6. Pubmedid: 28464980. Pmcid: PMC5415356.
  • Blakeley JO, Bakker A, Barker A, Clapp W, Ferner R, Fisher MJ, Giovannini M, Gutmann DH, Karajannis MA, Kissil JL, Legius E, Lloyd AC, Packer RJ, Ramesh V, Riccardi VM, Stevenson DA, Ullrich NJ, Upadhyaya M, Stemmer-Rachamimov A. The path forward: 2015 International Children's Tumor Foundation conference on neurofibromatosis type 1, type 2, and schwannomatosis. Am J Med Genet A. 2017 Jun.173(6):1714-1721. Pubmedid: 28436162.
  • Guerrant W, Kota S, Troutman S, Mandati V, Fallahi M, Stemmer-Rachamimov A, Kissil JL. YAP Mediates Tumorigenesis in Neurofibromatosis Type 2 by Promoting Cell Survival and Proliferation through a COX-2-EGFR Signaling Axis. Cancer Res. 2016 Jun.76(12):3507-3519. Pubmedid: 27216189. Pmcid: PMC4911274.
  • Troutman S, Moleirinho S, Kota S, Nettles K, Fallahi M, Johnson GL, Kissil JL. Crizotinib inhibits NF2-associated schwannoma through inhibition of focal adhesion kinase 1. Oncotarget. 2016 Aug.7(34):54515-54525. Pubmedid: 27363027. Pmcid: PMC5342359.
  • Widemann BC, Acosta MT, Ammoun S, Belzberg AJ, Bernards A, Blakeley J, Bretscher A, Cichowski K, Clapp DW, Dombi E, Evans GD, Ferner R, Fernandez-Valle C, Fisher MJ, Giovannini M, Gutmann DH, Hanemann CO, Hennigan R, Huson S, Ingram D, Kissil J, Korf BR, Legius E, Packer RJ, McClatchey AI, McCormick F, North K, Pehrsson M, Plotkin SR, Ramesh V, Ratner N, Schirmer S, Sherman L, Schorry E, Stevenson D, Stewart DR, Ullrich N, Bakker AC, Morrison H. CTF meeting 2012: Translation of the basic understanding of the biology and genetics of NF1, NF2, and schwannomatosis toward the development of effective therapies. Am J Med Genet A. 2014 Mar.164A(3):563-578. Pubmedid: 24443315. Pmcid: PMC4150212.
  • Moleirinho S, Guerrant W, Kissil JL. The Angiomotins--from discovery to function. FEBS Lett. 2014 Aug.588(16):2693-2703. Pubmedid: 24548561. Pmcid: PMC4112001.
  • Yi C, Shen Z, Stemmer-Rachamimov A, Dawany N, Troutman S, Showe LC, Liu Q, Shimono A, Sudol M, Holmgren L, Stanger BZ, Kissil JL. The p130 isoform of angiomotin is required for Yap-mediated hepatic epithelial cell proliferation and tumorigenesis. Sci Signal. 2013 Sep.6(291):ra77. Pubmedid: 24003254. Pmcid: PMC4175526.
  • Licciulli S, Maksimoska J, Zhou C, Troutman S, Kota S, Liu Q, Duron S, Campbell D, Chernoff J, Field J, Marmorstein R, Kissil JL. FRAX597, a small molecule inhibitor of the p21-activated kinases, inhibits tumorigenesis of neurofibromatosis type 2 (NF2)-associated Schwannomas. J Biol Chem. 2013 Oct.288(40):29105-29114. Pubmedid: 23960073. Pmcid: PMC3790009.
  • Licciulli S, Avila JL, Hanlon L, Troutman S, Cesaroni M, Kota S, Keith B, Simon MC, Puré E, Radtke F, Capobianco AJ, Kissil JL. Notch1 is required for Kras-induced lung adenocarcinoma and controls tumor cell survival via p53. Cancer Res. 2013 Oct.73(19):5974-5984. Pubmedid: 23943799. Pmcid: PMC3791518.
  • Avila JL, Kissil JL. Notch signaling in pancreatic cancer: oncogene or tumor suppressor?. Trends Mol Med. 2013 May.19(5):320-327. Pubmedid: 23545339. Pmcid: PMC3648591.
  • Avila JL, Troutman S, Durham A, Kissil JL. Notch1 is not required for acinar-to-ductal metaplasia in a model of Kras-induced pancreatic ductal adenocarcinoma. PLoS One. 2013 Jun.7(12):e52133. Pubmedid: 23284900. Pmcid: PMC3526595.
  • Zhou C, Licciulli S, Avila JL, Cho M, Troutman S, Jiang P, Kossenkov AV, Showe LC, Liu Q, Vachani A, Albelda SM, Kissil JL. The Rac1 splice form Rac1b promotes K-ras-induced lung tumorigenesis. Oncogene. 2013 Feb.32(7):903-909. Pubmedid: 22430205. Pmcid: PMC3384754.
  • Einheber S, Meng X, Rubin M, Lam I, Mohandas N, An X, Shrager P, Kissil J, Maurel P, Salzer JL. The 4.1B cytoskeletal protein regulates the domain organization and sheath thickness of myelinated axons. Glia. 2013 Feb.61(2):240-253. Pubmedid: 23109359. Pmcid: PMC3527682.
  • Vaira V, Faversani A, Martin NM, Garlick DS, Ferrero S, Nosotti M, Kissil JL, Bosari S, Altieri DC. Regulation of lung cancer metastasis by Klf4-Numb-like signaling. Cancer Res. 2013 Apr.73(8):2695-2705. Pubmedid: 23440423. Pmcid: PMC3695627.
  • Caino MC, Lopez-Haber C, Kissil JL, Kazanietz MG. Non-small cell lung carcinoma cell motility, rac activation and metastatic dissemination are mediated by protein kinase C epsilon. PLoS One. 2012 Aug.7(2):e31714. Pubmedid: 22384062. Pmcid: PMC3288050.
  • Coleman N, Kissil J. Recent advances in the development of p21-activated kinase inhibitors. Cell Logist. 2012 Apr.2(2):132-135. Pubmedid: 23162744. Pmcid: PMC3490963.
  • Fera D, Schultz DC, Hodawadekar S, Reichman M, Donover PS, Melvin J, Troutman S, Kissil JL, Huryn DM, Marmorstein R. Identification and characterization of small molecule antagonists of pRb inactivation by viral oncoproteins. Chem Biol. 2012 Apr.19(4):518-528. Pubmedid: 22520758. Pmcid: PMC3334872.
  • Jung Y, Kissil JL, McCarty JH. β8 integrin and band 4.1B cooperatively regulate morphogenesis of the embryonic heart. Dev Dyn. 2011 Jan.240(1):271-277. Pubmedid: 21181944.
  • Yi C, Troutman S, Fera D, Stemmer-Rachamimov A, Avila JL, Christian N, Persson NL, Shimono A, Speicher DW, Marmorstein R, Holmgren L, Kissil JL. A tight junction-associated Merlin-angiomotin complex mediates Merlin's regulation of mitogenic signaling and tumor suppressive functions. Cancer Cell. 2011 Apr.19(4):527-540. Pubmedid: 21481793. Pmcid: PMC3075552.
  • Yi C, Maksimoska J, Marmorstein R, Kissil JL. Development of small-molecule inhibitors of the group I p21-activated kinases, emerging therapeutic targets in cancer. Biochem Pharmacol. 2010 Sep.80(5):683-689. Pubmedid: 20302846. Pmcid: PMC2897962.
  • Licciulli S, Kissil JL. WT1: a weak spot in KRAS-induced transformation. J Clin Invest. 2010 Nov.120(11):3804-3807. Pubmedid: 20972324. Pmcid: PMC2965001.
  • Hanlon L, Avila JL, Demarest RM, Troutman S, Allen M, Ratti F, Rustgi AK, Stanger BZ, Radtke F, Adsay V, Long F, Capobianco AJ, Kissil JL. Notch1 functions as a tumor suppressor in a model of K-ras-induced pancreatic ductal adenocarcinoma. Cancer Res. 2010 Jun.70(11):4280-4286. Pubmedid: 20484026. Pmcid: PMC2880196.
  • Kissil JL, Blakeley JO, Ferner RE, Huson SM, Kalamarides M, Mautner VF, McCormick F, Morrison H, Packer R, Ramesh V, Ratner N, Rauen KA, Stevenson DA, Hunter-Schaedle K, North K. What's new in neurofibromatosis? Proceedings from the 2009 NF Conference: new frontiers. Am J Med Genet A. 2010 Feb.152A(2):269-283. Pubmedid: 20082461. Pmcid: PMC2818482.
  • Horresh I, Bar V, Kissil JL, Peles E. Organization of myelinated axons by Caspr and Caspr2 requires the cytoskeletal adapter protein 4.1B. J Neurosci. 2010 Feb.30(7):2480-2489. Pubmedid: 20164332. Pmcid: PMC2836844.
  • Mazumdar J, Hickey MM, Pant DK, Durham AC, Sweet-Cordero A, Vachani A, Jacks T, Chodosh LA, Kissil JL, Simon MC, Keith B. HIF-2alpha deletion promotes Kras-driven lung tumor development. Proc Natl Acad Sci U S A. 2010 Aug.107(32):14182-14187. Pubmedid: 20660313. Pmcid: PMC2922515.
  • Yi C, Kissil JL. Merlin in organ size control and tumorigenesis: Hippo versus EGFR?. Gene Dev. 2010 Aug.24(16):1673-1679. Pubmedid: 20713513. Pmcid: PMC2922497.
  • Santos AM, Jung J, Aziz N, Kissil JL, Puré E. Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice. J Clin Invest. 2009 Dec.119(12):3613-3625. Pubmedid: 19920354. Pmcid: PMC2786791.
  • Yi C, Wilker EW, Yaffe MB, Stemmer-Rachamimov A, Kissil JL. Validation of the p21-activated kinases as targets for inhibition in neurofibromatosis type 2. Cancer Res. 2008 Oct.68(19):7932-7937. Pubmedid: 18829550. Pmcid: PMC2707059.
  • Maksimoska J, Feng L, Harms K, Yi C, Kissil J, Marmorstein R, Meggers E. Targeting large kinase active site with rigid, bulky octahedral ruthenium complexes. J Am Chem Soc. 2008 Nov.130(47):15764-15765. Pubmedid: 18973295. Pmcid: PMC2654244.
  • Stedman W, Kang H, Lin S, Kissil JL, Bartolomei MS, Lieberman PM. Cohesins localize with CTCF at the KSHV latency control region and at cellular c-myc and H19/Igf2 insulators. Embo J. 2008 Feb.27(4):654-666. Pubmedid: 18219272. Pmcid: PMC2262040.
  • Kissil JL, Walmsley MJ, Hanlon L, Haigis KM, Bender Kim CF, Sweet-Cordero A, Eckman MS, Tuveson DA, Capobianco AJ, Tybulewicz VL, Jacks T. Requirement for Rac1 in a K-ras induced lung cancer in the mouse. Cancer Res. 2007 Sep.67(17):8089-8094. Pubmedid: 17804720.
  • Wong SY, Haack H, Kissil JL, Barry M, Bronson RT, Shen SS, Whittaker CA, Crowley D, Hynes RO. Protein 4.1B suppresses prostate cancer progression and metastasis. Proc Natl Acad Sci U S A. 2007 Jul.104(31):12784-12789. Pubmedid: 17640904. Pmcid: PMC1924789.
  • Aase K, Ernkvist M, Ebarasi L, Jakobsson L, Majumdar A, Yi C, Birot O, Ming Y, Kvanta A, Edholm D, Aspenström P, Kissil J, Claesson-Welsh L, Shimono A, Holmgren L. Angiomotin regulates endothelial cell migration during embryonic angiogenesis. Gene Dev. 2007 Aug.21(16):2055-2068. Pubmedid: 17699752. Pmcid: PMC1948860.
  • Kissil JL, Charest A. New tools for dissecting RON receptor tyrosine kinase oncogenic signaling. Cancer Biol Ther. 2006 Sep.5(9):1187-1188. Pubmedid: 17012849.
  • Kuns R, Kissil JL, Newsham IF, Jacks T, Gutmann DH, Sherman LS. Protein 4.1B expression is induced in mammary epithelial cells during pregnancy and regulates their proliferation. Oncogene. 2005 Sep.24(43):6502-6515. Pubmedid: 16007173.
  • Yi C, McCarty JH, Troutman SA, Eckman MS, Bronson RT, Kissil JL. Loss of the putative tumor suppressor band 4.1B/Dal1 gene is dispensable for normal development and does not predispose to cancer. Mol Cell Biol. 2005 Nov.25(22):10052-10059. Pubmedid: 16260618. Pmcid: PMC1280276.
  • Kim CF, Jackson EL, Kirsch DG, Grimm J, Shaw AT, Lane K, Kissil J, Olive KP, Sweet-Cordero A, Weissleder R, Jacks T. Mouse models of human non-small-cell lung cancer: raising the bar. Cold Spring Harb Symp Quant Biol. 2005 Dec.70:241-250. Pubmedid: 16869760.
  • Kissil JL, Wilker EW, Johnson KC, Eckman MS, Yaffe MB, Jacks T. Merlin, the product of the Nf2 tumor suppressor gene, is an inhibitor of the p21-activated kinase, Pak1. Mol Cell. 2003 Oct.12(4):841-849. Pubmedid: 14580336.
  • Johnson KC, Kissil JL, Fry JL, Jacks T. Cellular transformation by a FERM domain mutant of the Nf2 tumor suppressor gene. Oncogene. 2002 Sep.21(39):5990-5997. Pubmedid: 12203111.
  • Kissil JL, Johnson KC, Eckman MS, Jacks T. Merlin phosphorylation by p21-activated kinase 2 and effects of phosphorylation on merlin localization. J Biol Chem. 2002 Mar.277(12):10394-10399. Pubmedid: 11782491.
  • Inbal B, Shani G, Cohen O, Kissil JL, Kimchi A. Death-associated protein kinase-related protein 1, a novel serine/threonine kinase involved in apoptosis. Mol Cell Biol. 2000 Feb.20(3):1044-1054. Pubmedid: 10629061. Pmcid: PMC85221.
  • Cohen O, Inbal B, Kissil JL, Raveh T, Berissi H, Spivak-Kroizaman T, Feinstein E, Kimchi A. DAP-kinase participates in TNF-alpha- and Fas-induced apoptosis and its function requires the death domain. J Cell Biol. 1999 Jul.146(1):141-148. Pubmedid: 10402466. Pmcid: PMC2199731.
  • Kissil JL, Cohen O, Raveh T, Kimchi A. Structure-function analysis of an evolutionary conserved protein, DAP3, which mediates TNF-alpha- and Fas-induced cell death. Embo J. 1999 Jan.18(2):353-362. Pubmedid: 9889192. Pmcid: PMC1171130.
  • Kissil JL, Kimchi A. Death-associated proteins: from gene identification to the analysis of their apoptotic and tumour suppressive functions. Mol Med Today. 1998 Jun.4(6):268-274. Pubmedid: 9679246.
  • Lipschutz JH, Kissil JL. Expression of beta-catenin and gamma-catenin in epithelial tumor cell lines and characterization of a unique cell line. Cancer Lett. 1998 Apr.126(1):33-41. Pubmedid: 9563646.
  • Kissil JL, Feinstein E, Cohen O, Jones PA, Tsai YC, Knowles MA, Eydmann ME, Kimchi A. DAP-kinase loss of expression in various carcinoma and B-cell lymphoma cell lines: possible implications for role as tumor suppressor gene. Oncogene. 1997 Jul.15(4):403-407. Pubmedid: 9242376.
  • Kissil JL, Kimchi A. Assignment of death associated protein 3 (DAP3) to human chromosome 1q21 by in situ hybridization. Cytogenet Cell Genet. 1997 Jan.77(3-4):252. Pubmedid: 9284927.
  • Kissil JL, Deiss LP, Bayewitch M, Raveh T, Khaspekov G, Kimchi A. Isolation of DAP3, a novel mediator of interferon-gamma-induced cell death. J Biol Chem. 1995 Nov.270(46):27932-27936. Pubmedid: 7499268.

Grants

Title: A Chemical Proteomic Strategy for Mapping Codependency Pathways in KRAS Driven Lung Cancer
Sponsor: US Army
PI: Kissil, J.