Mutant p53 controls the tumor microenvironment
Outer-membrane -vesicles (OMVs) in host-pathogen interactions leading to cancer
Diffusing Alpha-emitting ratioation Therapy for solid metastatic tumors
TP53 mutants (mutp53) are involved in the pathogenesis of most human cancers. Specific mutp53 proteins gain oncogenic functions (GOF) distinct from the tumor suppressor of the wild-type p53. We found that specific mutp53 GOF proteins are capable of releasing a unique subset of exosomes leading to the reprogramming tumor-associated macrophages converting them to tumor supportive immune population in models of colon cancer and in patients.
We attempt to define the role of OMVs in driving inflammation-associated lung tumorigenesis in the presence of mutant p53. To that end, we determine the short RNAs (sRNAs) composition of OMVs shed by pathogenic bacteria invading the lung tissue and the specific transcriptional response of mutant p53 lung carcinoma cells to OMVs. We elucidate the modes of communications between invading bacteria and cancer cells and the effect of bacterial extracellular vesicles on the malignant process.
The DaRT technology is a unique form of brachytherapy based on short-lived atoms releasing alpha particles. We explore ways decipher molecular mechanisms fundamental for the spectrum of resistance to sensitivity of cancer cells to the treatment.
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Tomer Cooks, Ph.D.
My Ph.D. was conducted in the Tel-Aviv University after which I moved to the Weizmann Institute and later to the National Cancer Institute (NCI). My research interests are focused on extracellular vesicles (exosomes) and the intricate molecular relationship shared by the tumor, the host tissue and their microenvironment. Essentially, I wish to explore the emerging role of exosomes released by tumor cells giving rise to immuno-modulating changes in the microenvironment. Such cell-to-cell regulation is a key mechanism controlling the interplay between the innate immune system, the epithelial compartment and the microbial environment in inflammatory conditions driving toward tumorigenesis.
Bhatta B, Luz, I, Krueger K, Teo FX, Lane DP, Sabapathy K, Cooks T. Cancer Cells Shuttle Extracellular Vesicles Containing Oncogenic Mutant p53 Proteins to the Tumor Microenvironment . Cancers 2021, 13(12), 2985;, https://doi.org/10.3390/cancers13122985
Cooks T, Puzis R, Cohen O. Tissue resilience: lessons from social resilience. EMBO Rep 2021. e52926. doi: 10.15252/embr.202152926
Azulay EE, Cooks T, Elkabets M.. Potential oncogenic roles of mutant-p53-derived exosomes in the tumor-host interaction of head and neck cancers.. Cancer Immunol Immunother. 2020 doi: 10.1007/s00262-019-02450-5.
Cell Death Dis. 2019; 10(6):406. doi: 10.1038/s41419-019-1643-9.
Pateras IS1, Cooks T Determination of Polarization of Resident Macrophages and Their Effect on the Tumor Microenvironment. Methods Mol Biol. 2019;1928:101-112. doi: 10.1007/978-1-4939-9027-6_7.
Myrianthopoulos V, Evangelou K, Vasileiou PVS, Cooks T, Vassilakopoulos TP, Pangalis GA, Kouloukoussa M, Kittas C, Georgakilas AG, Gorgoulis VG. Senescence and senotherapeutics: a new field in cancer therapy. Pharmacol Ther. 2019. pii: S0163-7258(18)30144-X. doi: 10.1016/j.pharmthera.2018.08.006
Bhatta B, Cooks T. Reshaping the tumor microenvironment: extracellular vesicles as messengers of cancer cells. Carcinogenesis. 2020 doi: 10.1093/carcin/bgaa107.
Greathouse LK, White JR, Vargas AJ, Bliskovsky VV, Beck JA, Von Muhlinen N, Polley E, Bowman ED, Robles AI, Khan MA, Robles AI, Cooks T, Ryan BM, Dzutsev AH, Trinchieri G, Pineda MA, Bilke S, Meltzer PS, Hokenstad AN, Stickrod TM, Walther-Antonio MR, Earl JP, Mell JC, Krol JE, Balashov SV, Bhat AS, Ehrlich GD, Valm A, Deming C, Conlan S, Oh J, Segre JA, Harris CC. Microbiome-TP53 Gene Interaction in Human Lung Cancer. Genome Biol. 2018;19(1):123. doi: 10.1186/s13059-018-1501-6.
Cooks T, Pateras IS, Jenkins LM, Patel KM, Robles AI, Morris J, Forshew T, Appella E, Gorgoulis VG, Harris CC. Mutant p53 cancers reprogram tumor associated macrophages via exosomal miR-1246. Nature Comm. 2018;9(1):771. doi: 10.1038/s41467-018-03224-w.
Solomon H, Dinowitz N, Pateras IS, Cooks T, Shetzer Y, Molchadsky A, Charni M, Rabani S, Koifman G, Tarcic O, Porat Z, Kogan-Sakin I, Goldfinger N, Oren M, Harris CC, Gorgoulis VG, Rotter V. Mutant p53 gain of function underlies high expression levels of colorectal cancer stem cells markers.
Oncogene 2018. doi: 10.1038/s41388-017-0060-8.
Tarcic O, Pateras IS, Cooks T, Shema E, Kanterman J, Ashkenazi H, Boocholez H, Hubert A, Rotkopf R, Baniyash M, Pikarsky E, Gorgoulis VG, Oren M. RNF20 Links Histone H2B Ubiquitylation with Inflammation and Inflammation-Associated Cancer. Cell Rep. 2016;14(6):1462-76
Reitkopf-Brodutch S1, Confino H, Schmidt M, Cooks T, Efrati M, Arazi L, Rath-Wolfson L, Marshak G, Kelson I, Keisari Y. Ablation of experimental colon cancer by intratumoral 224Radium-loaded wires is mediated by alpha particles released from atoms which spread in the tumor and can be augmented by chemotherapy. Int J Radiat Biol 2015; 91(2):179-86.
Cooks T, Oren M, Harris CC. Caught in the cross fire: p53 in inflammation. Carcinogenesis. 35:1680-90, 2014.
Cooks T, Harris CC. p53 mutations and inflammation-associated cancer are linked through TNF signaling. Mol Cell. 2014;56(5):611-2.
Cooks T, Pateras IS, Gorgoulis VG. When mutant p53 fires up. Cancer cell & Microen. 1: e135, 2014.
Cooks T, Pateras IS, Tarcic O, Solomon H, Schetter AJ, Wilder S, Lozano GC, Pikarsky E, Forshew T, Rosenfeld 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. 2013; 23(5):634-46.
Lazarov E, Arazi L, Cooks T, Schmidt M, Keisari Y, Kelson I. Comparative in vitro microdosimetric study of murine and human-derived cancer cells exposed to alpha particles. Rad Res. 2012; 177(3):280-7.
Horev-Droroi G, Cooks T, Bittan H, Lazarov E, Schmidt M, Arazi L, Efrati M, Kelson I, Keisari Y. Local control of experimental malignant pancreatic tumors by treatment with a combination of chemotherapy and intratumoral 224Radium-loaded wires releasing alpha-emitting atoms. Translat. Res. 2012; 159(1):32-41.
Cooks T, Tal M, Raab S, Efrati M, Reitkopf S, Lazarov E, Etzyoni R, Schmidt M, Arazi L, Kelson I, Keisari Y. Intratumoral 224Ra-Loaded Wires Spread Alpha-Emitters Inside Solid Human Tumors in Athymic Mice Achieving Tumor Control. Anticancer Res. 2012; 32(12):5315-21.
Cooks T, Schmidt M, Bittan H, Lazarov E, Arazi L, Kelson I, Keisari Y. Local control of lung derived tumors by diffusing alpha-emitting atoms released from intratumoral wires loaded with Radium-224. Int J Radiat Oncol Biol Phys. 2009; 74(3):966-73.
Cooks T, Arazi L, Efrati M, Schmidt M, Marshak, G, Kelson I, Keisari Y. Treatment with interstitial wires releasing diffusing alpha-emitting atoms in combination with chemotherapy improved local tumor control and survival in squamous cell carcinoma bearing mice. Cancer 2009;115(8):1791-1801
Cooks T, Arazi L, Schmidt M, Marshak G, Kelson I, Keisari Y. Growth retardation and destruction of experimental Squamous cell carcinoma by interstitial radioactive wires releasing diffusing alpha-emitting atoms. Int J Cancer. 2008; 122(7):1657-64.
Arazi L, Cooks T, Schmidt M, Keisari Y, Kelson I. Treatment of solid tumours by interstitial release of recoiling short-lived alpha emitters. Phys. Med. Biol. 2007; 52 5025-5042.
Shalom-Feuerstein R, Cooks T, Raz A, Kloog Y. Galectin-3 regulates a molecular switch from N-Ras to K-Ras usage in human breast carcinoma cells. Cancer Res. 2005; 65(16): 7292-300.
Tomer Cooks Ph.D.
Ishai Luz Ph.D.
Maayan Vatarescu Ph.D.
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Ben-Gurion University of the Negev
Beer Sheva, 8410501, Israel
Building M6, Room 127