Our Vision
Cancer is not an isolated process and its development is tightly associated with endocrine and metabolic changes in the body. As a lab sitting next to the Oncology Division, the bench and bedside are constantly intertwined. Therefore, we are not only focused on the patient's tumor, but know that the cancer disease is affected by many other factors. By investigating the complex interactions between the tumor, the received treatments and basic patient's characteristics, we are able to decipher novel endocrine aspects of malignancy and gain new insights into the development of cancer. This in turn uncovers vulnerabilities of the cancer and may aid in the development of novel treatments. Arkadi Hesin a link between longevity, metabolism and cancer Why do aging cells become more vulnerable to cancer? Our lab explores this fascinating connection through the hormone Klotho, a key regulator of longevity, metabolism, and cellular health. Our lab discovered that Klotho acts as a natural tumor suppressor and is often lost in cancer cells. Restoring Klotho can slow tumor growth and alter critical signaling and metabolic pathways that drive cancer progression. Today, we are working to better understand how Klotho protects the body from cancer and aging-related damage, and to translate these discoveries into innovative Klotho-based therapies for cancer treatment. mutations in breast cancer Our lab was the first to discover mutations in ESR1 that confer resistance to hormonal therapies in >40% of patients with metastatic breast cancer. We are trying to find the relationship between mutations and a more aggressive disease as well as finding new treatment strategies. We are tackling the role of specific mutations in mediating homing of cancer cells to specific organs. Using large patients’ databases and advanced bioinformatics we identify genes and pathways that coax homing of cancer cells to specific organs. Specifically, we are focusing on the relationship between the mutations and metabolic pathways. From The Press
Tami Rubinek - Google Scholar FOXM1 expression is induced by the brain microenvironment and supports CRC brain metastatic adaptation. Khair F, Greenberg I, Fuchs S, Shapira G, Zubkov A, Shomron N, Raz M, Wolf I, Rubinek T. Clin Exp Metastasis. 2026 Apr 27;43(3):22. doi: 10.1007/s10585-026-10397-y. PMID: 42036506 Free PMC article. The role of the SLC25A15 transporter in the formation of liver metastasis in ESR1-mutated breast cancer. Taya M, Fishman D, Kanani F, Zinger L, Merenbakh-Lamin K, Elfasi Sosner S, Shendge AK, Klein Goldberg A, Wolf U, Winkler G, Shifrut E, Cohen S, Wolf I, Sekler I, Rubinek T. Oncogene. 2026 Feb;45(5):603-619. doi: 10.1038/s41388-025-03640-5. Epub 2026 Jan 3. PMID: 41484388 IRS2 as a driver of brain metastasis in colorectal cancer: A potential target for novel therapeutic strategies. Greenberg I, Khair-Dabour F, Merenbakh-Lamin K, Sokol ES, Goldberg AK, Simkin D, Spitzer A, Benhamou M, Bar-Shira S, Raz M, Grossman R, Yeini E, Ofek P, Meirson T, Satchi-Fainaro R, Reuveni H, Wolf I, Rubinek T. Neuro Oncol. 2025 Sep 8;27(7):1729-1745. doi: 10.1093/neuonc/noaf028. PMID: 39888380 Glucagon-like peptide-1 analogs activate AMP kinase leading to reversal of the Warburg metabolic switch in breast cancer cells. Ligumsky H, Amir S, Arbel Rubinstein T, Guion K, Scherf T, Karasik A, Wolf I, Rubinek T. Med Oncol. 2024 May 6;41(6):138. doi: 10.1007/s12032-024-02390-w. PMID: 38705935 Revealing the tumor suppressive sequence within KL1 domain of the hormone Klotho. Abboud M, Merenbakh-Lamin K, Volkov H, Ben-Neriah S, Ligumsky H, Bronfeld S, Keren-Khadmy N, Giladi M, Shomron N, Wolf I, Rubinek T. Oncogene. 2024 Jan;43(5):354-362. doi: 10.1038/s41388-023-02904-2. Epub 2023 Dec 1. PMID: 38040805 The use of medical cannabis concomitantly with immune checkpoint inhibitors in non-small cell lung cancer: A sigh of relief? Waissengrin B, Leshem Y, Taya M, Meiri D, Merimsky O, Shamai S, Wolf I, Rubinek T. Eur J Cancer. 2023 Feb;180:52-61. doi: 10.1016/j.ejca.2022.11.022. Epub 2022 Nov 29. PMID: 36535195 Genomic alterations drive metastases formation in pancreatic ductal adenocarcinoma cancer: deciphering the role of CDKN2A and CDKN2B in mediating liver tropism. Journo S, Goldberg AK, Sokol ES, Zinger L, Pasmanik-Chor M, Sarvin B, Simkin D, Fuchs S, Shlomi T, Wolf I, Rubinek T. Oncogene. 2022 Mar;41(10):1468-1481. doi: 10.1038/s41388-022-02184-2. Epub 2022 Jan 22. PMID: 35064215 Klotho rewires cellular metabolism of breast cancer cells through alteration of calcium shuttling and mitochondrial activity. Shmulevich R, Nissim TB, Wolf I, Merenbakh-Lamin K, Fishman D, Sekler I, Rubinek T. Oncogene. 2020 Jun;39(24):4636-4649. doi: 10.1038/s41388-020-1313-5. Epub 2020 May 12. PMID: 32398866 Ligand-binding Domain-activating Mutations of ESR1 Rewire Cellular Metabolism of Breast Cancer Cells. Zinger L, Merenbakh-Lamin K, Klein A, Elazar A, Journo S, Boldes T, Pasmanik-Chor M, Spitzer A, Rubinek T, Wolf I. Clin Cancer Res. 2019 May 1;25(9):2900-2914. doi: 10.1158/1078-0432.CCR-18-1505. Epub 2019 Feb 7. PMID: 30733228 Klotho suppresses colorectal cancer through modulation of the unfolded protein response. Arbel Rubinstein T, Shahmoon S, Zigmond E, Etan T, Merenbakh-Lamin K, Pasmanik-Chor M, Har-Zahav G, Barshack I, Vainer GW, Skalka N, Rosin-Arbesfeld R, Varol C, Rubinek T, Wolf I. Oncogene. 2019 Feb;38(6):794-807. doi: 10.1038/s41388-018-0489-4. Epub 2018 Sep 19. PMID: 30232408 Klotho response to treatment with growth hormone and the role of IGF-I as a mediator. Rubinek T, Shahmoon S, Shabtay-Orbach A, Ben Ami M, Levy-Shraga Y, Mazor-Aronovitch K, Yeshayahu Y, Doolman R, Hemi R, Kanety H, Wolf I, Modan-Moses D. Metabolism. 2016 Nov;65(11):1597-1604. doi: 10.1016/j.metabol.2016.08.004. Epub 2016 Aug 14. PMID: 27733247 Alteration in serum klotho levels in anorexia nervosa patients. Wolf I, Stein D, Shahmoon S, Ziv SI, Hemi R, Kanety H, Rubinek T, Modan-Moses D. Clin Nutr. 2016 Aug;35(4):958-62. doi: 10.1016/j.clnu.2015.07.013. Epub 2015 Jul 18. PMID: 26243062 Reduced expression and growth inhibitory activity of the aging suppressor klotho in epithelial ovarian cancer. Lojkin I, Rubinek T, Orsulic S, Schwarzmann O, Karlan BY, Bose S, Wolf I. Cancer Lett. 2015 Jul 1;362(2):149-57. doi: 10.1016/j.canlet.2015.03.035. Epub 2015 Mar 28. PMID: 25827069 The aging suppressor klotho: a potential regulator of growth hormone secretion. Shahmoon S, Rubinfeld H, Wolf I, Cohen ZR, Hadani M, Shimon I, Rubinek T. Am J Physiol Endocrinol Metab. 2014 Aug 1;307(3):E326-34. doi: 10.1152/ajpendo.00090.2014. Epub 2014 Jun 17. PMID: 24939736 Free article. D538G mutation in estrogen receptor-α: A novel mechanism for acquired endocrine resistance in breast cancer. Merenbakh-Lamin K, Ben-Baruch N, Yeheskel A, Dvir A, Soussan-Gutman L, Jeselsohn R, Yelensky R, Brown M, Miller VA, Sarid D, Rizel S, Klein B, Rubinek T, Wolf I. Cancer Res. 2013 Dec 1;73(23):6856-64. doi: 10.1158/0008-5472.CAN-13-1197. Epub 2013 Nov 11. PMID: 24217577 Epigenetic silencing of the tumor suppressor klotho in human breast cancer. Rubinek T, Shulman M, Israeli S, Bose S, Avraham A, Zundelevich A, Evron E, Gal-Yam EN, Kaufman B, Wolf I. Breast Cancer Res Treat. 2012 Jun;133(2):649-57. doi: 10.1007/s10549-011-1824-4. Epub 2011 Oct 22. PMID: 22042362 The peptide-hormone glucagon-like peptide-1 activates cAMP and inhibits growth of breast cancer cells. Ligumsky H, Wolf I, Israeli S, Haimsohn M, Ferber S, Karasik A, Kaufman B, Rubinek T. Breast Cancer Res Treat. 2012 Apr;132(2):449-61. doi: 10.1007/s10549-011-1585-0. Epub 2011 Jun 3. PMID: 21638053 KL1 internal repeat mediates klotho tumor suppressor activities and inhibits bFGF and IGF-I signaling in pancreatic cancer. Abramovitz L, Rubinek T, Ligumsky H, Bose S, Barshack I, Avivi C, Kaufman B, Wolf I. Clin Cancer Res. 2011 Jul 1;17(13):4254-66. doi: 10.1158/1078-0432.CCR-10-2749. Epub 2011 May 13. PMID: 21571866 Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer. Wolf I, Levanon-Cohen S, Bose S, Ligumsky H, Sredni B, Kanety H, Kuro-o M, Karlan B, Kaufman B, Koeffler HP, Rubinek T. Oncogene. 2008 Nov 27;27(56):7094-105. doi: 10.1038/onc.2008.292. Epub 2008 Sep 1. PMID: 18762812 Highlight Publications
Genomic alterations drive metastases formation in pancreatic ductal adenocarcinoma cancer: deciphering the role of CDKN2A and CDKN2B in mediating liver tropism. Journo S, Goldberg AK, Sokol ES, Zinger L, Pasmanik-Chor M, Sarvin B, Simkin D, Fuchs S, Shlomi T, Wolf I, Rubinek T. Oncogene. 2022 Mar;41(10):1468-1481 Klotho rewires cellular metabolism of breast cancer cells through alteration of calcium shuttling and mitochondrial activity. Shmulevich R, Nissim TB, Wolf I, Merenbakh-Lamin K, Fishman D, Sekler I, Rubinek T. Ligand-binding domain-activating mutations of ESR1 rewire cellular metabolism of breast cancer cells. Zinger L, Merenbakh-Lamin K, Klein A, Elazar A, Journo S, Boldes T, Pasmanik-Chor M, Spitzer A, Rubinek T, Wolf I. A Transgenic Model Reveals the Role of Klotho in Pancreatic Cancer Development and Paves the Way for New Klotho-Based Therapy. Role of Klotho protein in tumor genesis, cancer progression, and prognosis in patients with high-grade glioma. Peshes-Yeloz N, Ungar L, Wohl A, Jacoby E, Fisher T, Leitner M, Nass D, Rubinek T, Wolf I, Cohen ZR. Klotho suppresses colorectal cancer through modulation of the unfolded protein response. Arbel Rubinstein T, Shahmoon S, Zigmond E, Etan T, Merenbakh-Lamin K, Pasmanik-Chor M, Har-Zahav G, Barshack I, Vainer GW, Skalka N, Rosin-Arbesfeld R, Varol C, Rubinek T, Wolf I. New somatostatin-drug conjugates for effective targeting pancreatic cancer. Ragozin E, Hesin A, Bazylevich A, Tuchinsky H, Bovina A, Shekhter Zahavi T, Oron-Herman M, Kostenich G, Firer MA, Rubinek T, Wolf I, Luboshits G, Sherman MY, Gellerman G. Klotho response to treatment with growth hormone and the role of IGF-I as a mediator. Rubinek T, Shahmoon S, Shabtay-Orbach A, Ben Ami M, Levy-Shraga Y, Mazor-Aronovitch K, Yeshayahu Y, Doolman R, Hemi R, Kanety H, Wolf I, Modan-Moses D. Alteration in serum klotho levels in anorexia nervosa patients. Wolf I, Stein D, Shahmoon S, Ziv SI, Hemi R, Kanety H, Rubinek T, Modan-Moses D. Klotho expression in cervical cancer: differential expression in adenocarcinoma and squamous cell carcinoma. Aviel-Ronen S, Rubinek T, Zadok O, Vituri A, Avivi C, Wolf I, Barshack I. Tumor suppressor activity of klotho in breast cancer is revealed by structure-function analysis. Ligumsky H, Rubinek T, Merenbakh-Lamin K, Yeheskel A, Sertchook R, Shahmoon S, Aviel-Ronen S, Wolf I. The effect of klotho treatment on atherogenesis, blood pressure, and metabolic parameters in experimental rodent models. Kamari Y, Fingrut O, Shaish A, Almog T, Kandel-Kfir M, Harats D, Rubinek T, Wolf I. Metab Res. 2016 Mar;48(3):196-200. Reduced expression and growth inhibitory activity of the aging suppressor klotho in epithelial ovarian cancer. Lojkin I, Rubinek T, Orsulic S, Schwarzmann O, Karlan BY, Bose S, Wolf I. Association between decreased klotho blood levels and organic growth hormone deficiency in children with growth impairment. Wolf I, Shahmoon S, Ben Ami M, Levy-Shraga Y, Mazor-Aronovitch K, Pinhas-Hamiel O, Yeshayahu Y, Hemi R, Kanety H, Rubinek T, Modan-Moses D. The aging suppressor klotho: a potential regulator of growth hormone secretion. Shahmoon S, Rubinfeld H, Wolf I, Cohen ZR, Hadani M, Shimon I, Rubinek T. Association between variants of 5-hydroxytryptamine receptor 3C (HTR3C) and chemotherapy-induced symptoms in women receiving adjuvant treatment for breast cancer. Pud D, Har-Zahav G, Laitman Y, Rubinek T, Yeheskel A, Ben-Ami S, Kaufman B, Friedman E, Symon Z, Wolf I. Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer. Jeselsohn R, Yelensky R, Buchwalter G, Frampton G, Meric-Bernstam F, Gonzalez-Angulo AM, Ferrer-Lozano J, Perez-Fidalgo JA, Cristofanilli M, Gómez H, Arteaga CL, Giltnane J, Balko JM, Cronin MT, Jarosz M, Sun J, Hawryluk M, Lipson D, Otto G, Ross JS, Dvir A, Soussan-Gutman L, Wolf I, Rubinek T, Gilmore L, Schnitt S, Come SE, Pusztai L, Stephens P, Brown M, Miller VA. D538G mutation in estrogen receptor-α: A novel mechanism for acquired endocrine resistance in breast cancer. Merenbakh-Lamin K, Ben-Baruch N, Yeheskel A, Dvir A, Soussan-Gutman L, Jeselsohn R, Yelensky R, Brown M, Miller VA, Sarid D, Rizel S, Klein B, Rubinek T, Wolf I. Epigenetic silencing of the tumor suppressor klotho in human breast cancer. Rubinek T, Shulman M, Israeli S, Bose S, Avraham A, Zundelevich A, Evron E, Gal-Yam EN, Kaufman B, Wolf I. KL1 internal repeat mediates klotho tumor suppressor activities and inhibits bFGF and IGF-I signaling in pancreatic cancer. Abramovitz L, Rubinek T, Ligumsky H, Bose S, Barshack I, Avivi C, Kaufman B, Wolf I. Functional variant of KLOTHO: a breast cancer risk modifier among BRCA1 mutation carriers of Ashkenazi origin. Wolf I, Laitman Y, Rubinek T, Abramovitz L, Novikov I, Beeri R, Kuro-O M, Koeffler HP, Catane R, Freedman LS, Levy-Lahad E, Karlan BY, Friedman E, Kaufman B. Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer. Wolf I, Levanon-Cohen S, Bose S, Ligumsky H, Sredni B, Kanety H, Kuro-o M, Karlan B, Kaufman B, Koeffler HP, Rubinek T. The Longevity Hormone Klotho is a New Player in the Interacion of the Growth Hormone/Insulin-Like Growth Factor 1 Axis. Rubinek T, Wolf I, Modan-Moses D. The Role of Alpha-Klotho as a Universal Tumor Suppressor. Rubinek T, Wolf I. Klotho and the Growth Hormone/Insulin-Like Growth Factor 1 Axis: Novel Insights into Complex Interactions. Rubinek T, Modan-Moses D. Endocrine resistance in breast cancer: focus on the phosphatidylinositol 3-kinase/akt/mammalian target of rapamycin signaling pathway. Hasson SP, Rubinek T, Ryvo L, Wolf I. Our Team
MD thesis
At The Lab
Research
Our Publications
Oncogene. 2020 Jun;39(24):4636-4649.
Clin Cancer Res. 2019 May 1;25(9):2900-2914.
Genomic alterations drive brain metastases formation in colorectal cancer: The role of IRS2. Greenberg I, S. E., Klein Goldberg A, Simkin D, Benhamou M, Bar-Shira S, Raz M, Grossman R, Yeini E, Ofer P, Liang B, Satchi-Fainaro R, Reuveni H, Rubinek T, Wolf I. Biorxiv Biorxiv/2022/495658 (2022).
Arbel Rubinstein T, Reuveni I, Hesin A, Klein-Goldberg A, Olauson H, Larsson TE, Abraham CR, Zeldich E, Bosch A, Chillón M, Hollander KS, Shabtay-Orbach A, Vainer GW, Wolf I, Rubinek T. Cancers (Basel). 2021 Dec 15;13(24):6297.
R269C variant of ESR1: high prevalence and differential function in a subset of pancreatic cancers. Boldes T, Merenbakh-Lamin K, Journo S, Shachar E, Lipson D, Yeheskel A, Pasmanik-Chor M, Rubinek T, Wolf I.
BMC Cancer. 2020 Jun 8;20(1):531.
World Neurosurg. 2019 Oct;130:e324-e332.
Oncogene. 2019 Feb;38(6):794-807.
Bioorg Med Chem. 2018 Jul 30;26(13):3825-3836.
Metabolism. 2016 Nov;65(11):1597-1604.
Clin Nutr. 2016 Aug;35(4):958-62.
J Clin Pathol. 2016 Jan;69(1):53-7.
Mol Cancer Res. 2015 Oct;13(10):1398-407.
Cancer Lett. 2015 Jul 1;362(2):149-57.
PLoS One. 2014 Sep 8;9(9):e107174.
Am J Physiol Endocrinol Metab. 2014 Aug 1;307(3):E326-34
Breast Cancer Res Treat. 2014 Feb;144(1):123-31.
Clin Cancer Res. 2014 Apr 1;20(7):1757-1767.
Cancer Res. 2013 Dec 1;73(23):6856-64.
Breast Cancer Res Treat. 2012 Jun;133(2):649-57.
Clin Cancer Res. 2011 Jul 1;17(13):4254-66.
Oncogene. 2010 Jan 7;29(1):26-33.
Oncogene. 2008 Nov 27;27(56):7094-105.
Pediatr Endocrinol Rev. 2016 Sep;14(1):9-18.
Vitam Horm. 2016;101:197-214.
Vitam Horm. 2016;101:85-118.
Breast Care (Basel). 2013 Aug;8(4):248-55.
Oncology Division Research Laboratory
The peptide-hormone glucagon-like peptide-1 activates cAMP and inhibits growth of breast cancer cells. Ligumsky H, Wolf I, Israeli S, Haimsohn M, Ferber S, Karasik A, Kaufman B, Rubinek T. Breast Cancer Res Treat. 2012 Apr;132(2):449-61.