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Studies on Memo: a novel protein with a role in cancer and aging

English title Studies on Memo: a novel protein with a role in cancer and aging
Applicant Hynes Nancy E.
Number 138674
Funding scheme Project funding (Div. I-III)
Research institution Friedrich Miescher Institute for Biomedical Research
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Molecular Biology
Start/End 01.01.2012 - 30.04.2014
Approved amount 377'832.00
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All Disciplines (3)

Discipline
Molecular Biology
Cellular Biology, Cytology
Biochemistry

Lay Summary (English)

Lead
Lay summary

Lay Abstract

 

In the female population, breast cancer is the second cause of cancer- related deaths, behind the biggest killer, lung cancer. There are different treatment options for breast cancer patients, including endocrine agents, the ErbB2 receptor targeted antibody, trastuzumab, as well as standard chemotherapeutics. Despite improvement in response to each of these options, likely related to early detection and better treatment, once a primary tumor has metastasized, it is essentially incurable. Thus, studies of the mechanisms and proteins that contribute to metastasis are of utmost importance for increasing the anti-cancer arsenal of drugs.  In my lab we are working on breast cancer metastasis with our goal being to uncover novel protein players essential for this process. We discovered the protein Memo (mediator of ErbB2 driven cell motility) while screening for ErbB2 interacting proteins with essential roles in cancer cell motility. Memo is encoded by a gene that found in all kingdoms of life (bacteria, fungi and mammals) and is highly conserved. The function of Memo was not known in any species when we uncovered it in our initial screen.  As the name suggests, Memo is important for cancer cell motility induced, not only by ErbB2 activation, but also by activation of other receptors such as the fibroblast growth factor receptor (FGFR) and the platelet derived growth factor receptor (PDGFR), suggesting that Memo has a general role in migration induced by extracellular cues.

 

Based on these initial results, using funds generously supplied by the SNF, we initiated a large project with three main goals: 1) To test if Memo has an essential role in metastasis, using in vivo models of breast cancer growing in mice; 2) To uncover the normal physiological role of Memo, using mouse genetics combined with biochemical approaches; 3) To use the model organism S. cerevisiae to characterize the Memo-homologue, Mho1, and to investigate its function in yeast.  We have been relatively successful in all three goals, although as is usual for science, our results have raised many more questions, which is so aptly summed up in the quote “Science is an endless frontier” from the famous engineer Vannevar Bush.

 

I will briefly summarize our most important results. 1)  We have found that Memo is essential for in vivo metastasis formation. For these studies we used a technology which allows the knock-down of the Memo protein in breast cancer cell lines, termed KD cells.  The Memo KD tumor cells and the parental cells that express Memo were injected into the mammary gland of NOD/SCID mice where they both grew into tumors. Importantly, the Memo KD tumors gave rise to significantly fewer lung metastases. These results suggest that Memo is important for tumor cell migration and in the formation of metastasis. We have partially elucidated the molecular mechanisms responsible for these effects.  2) To uncover Memo’s normal physiological role, full-body Memo knock-out (KO) mice were generated. Surprisingly, these animals display rapid onset of a premature aging phenotype, including small stature, hair graying, hair loss, and curvature of the back.  They also exhibit increased insulin sensitivity and alteration of vitamin D metabolism, with increased levels of serum vitamin D and calcium. The features of the Memo KO mice recapitulate some features of mice lacking FGF23 or its receptor, Klotho.  Since this ligand and its receptor have important roles in the kidney, controlling circulating level of Vitamin D, we looked for a role for Memo down-stream of FGFR. For these studies we used cell culture models and examined the effects of FGF in Memo WT and KO cell lines. Our results show that Memo does have important function downstream of FGF-induced signaling; in the absence of Memo the strength and duration of FGFR signaling is impaired. Whether Memo plays a role in normal aging in humans awaits further studies that would have to be done in collaboration with population geneticists. 3) In yeast, MHO1 expression is induced by stress conditions. Since invasive growth is also stress-induced, we tested Mho1’s role in this response. We found that overexpression of Mho1 blocked the invasive ability of yeast cells, suggesting that Mho1 might be acting in a dominant negative manner.  Thus, considering the results in yeast and in human cancer cells, a role for Memo in cell motility/invasion appears to be conserved across species.

 

 

 

 

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Loss of Memo, a novel FGFR regulator, results in reduced lifespan
Haenzi Barbara (2014), Loss of Memo, a novel FGFR regulator, results in reduced lifespan, in The FASEB Journal, 28(1), 327-336.
Memo has a novel role in S1P signaling and crucial for vascular development
Kondo Sshunya (2014), Memo has a novel role in S1P signaling and crucial for vascular development, in PLOS ONE, 9(4), e94114-e94114.
Memo Is a Copper-Dependent Redox Protein with an Essential Role in Migration and Metastasis
MacDonald G Nalvarte I Smirnova T Vecchi M Aceto N Doelemeyer A Frei A Lienhard S Wyckoff, Hess D Seebacher J Keusch J Gut H Salaun D Mazzarol G Disalvatore D Bentires-Alj M Di Fiore, PP Badache A Hynes NE (2014), Memo Is a Copper-Dependent Redox Protein with an Essential Role in Migration and Metastasis, in Science Signaling, 7(329), ra56 1-ra56 13.
MHO1, an evolutionarily conserved gene, is synthetic lethal with PLC1; Mho1p has a role in invasive growth
Schlatter Ivan (2012), MHO1, an evolutionarily conserved gene, is synthetic lethal with PLC1; Mho1p has a role in invasive growth, in PLoS ONE, 7(3), e32501-e32501.

Collaboration

Group / person Country
Types of collaboration
Dr. M. Murakami, NIBR Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. A. Badache, Centre de Recherche en Cancerologie de Marseille (CRCM) France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Drs. R. Movva & D. Hoepfner, NIBR Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Dr. M. Bentires-Alj, Friedrich Miescher Institute Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Dr. A. Huwiler, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. A. Dolemeyer, NIBR Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Drs. S. Spiegel & J. Allegood, Virginia Commonwealth University School of Medicine United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. M. Kuro-o, University of Texas Southwestern Medical Center United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Dr. M. Vecchi, European Institute of Oncology Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Alfred Nordheim, University of Tuebingen Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dr. P.P. Di Fiore, IFOM-IEO Campus, Milan Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. O. Bonny, University of Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
105th Annual Meeting of the American Association for Cancer Research Talk given at a conference Insight into Mechanisms of Breast Cancer Metastasis 05.04.2014 San Diego, CA, United States of America Hynes Nancy E.;
Life Sciences Switzerland (LS2) Annual Meeting Poster Involvement of the novel protein Memo in the regulation of SphK1-S1P pathway 31.01.2014 Basel, Switzerland Kondo Shunya; Hynes Nancy E.;
Epidermal Growth Factor Receptor-Future Directions: Joint Conference of the Israeli Institute for Advanced Studies and The Israeli Science Foundation Talk given at a conference Grand challenges in breast cancer research 17.11.2013 Jerusalem, Israel Hynes Nancy E.;
Signal Transduction Society: Signal Transduction Receptors, Mediators and Genes Talk given at a conference Receptor tyrosine kinases in breast cancer: from mechanisms to therapeutic targeting 04.11.2013 Weimar, Germany Hynes Nancy E.;
Molecular Mechanisms of Cell Signaling International PhD Program Symposium Talk given at a conference Receptor tyrosine kinases in breast cancer: from mechanisms to therapeutic targeting 05.06.2013 Vienna, Austria Hynes Nancy E.;
Ludwig Boltzmann Canter for Cancer Research Meeting: From Cancer Modelling to New Therapies Talk given at a conference Targeting signaling Pathways in Breast Cancer 14.04.2013 Obergurgl, Austria Hynes Nancy E.;
Institut Curie Individual talk Targeting signaling pathways in breast cancer 12.04.2013 Paris, France Hynes Nancy E.;
17th International AEK Cancer Congress Talk given at a conference Receptor Tyrosine Kinases in Breast Cancer: From Mechanisms to Therapeutic Targeting 19.03.2013 Heidelberg, Germany Hynes Nancy E.;
The Biotechnology Centre of Oslo, University of Oslo Individual talk Receptor tyrosine kinases in breast cancer-from mechanisms to therapeutic targeting 15.01.2013 Oslo, Norway Hynes Nancy E.;
Spanish National Cancer Research Center (CNIO) Individual talk Receptor tyrosine kinases in breast cancer-from mechanisms to therapeutic targeting 14.12.2012 Madrid, Spain Hynes Nancy E.;
CTRC-AACR San Antonio Breast Cancer Symposium Talk given at a conference Inhibition of RTKs in combination with endocrine therapy impacts on migration and metastasis 04.12.2012 San Antonio, TX, United States of America Hynes Nancy E.;
Baylor College of Medicine Individual talk Receptor tyrosine kinases in breast cancer-from mechanisms to therapeutic targeting 03.12.2012 Houston, TX, United States of America Hynes Nancy E.;
University of Copenhagen Individual talk Receptor tyrosine kinases in breast cancer-from mechanisms to therapeutic targeting 05.11.2012 Copenhagen, Denmark Hynes Nancy E.;
IDIBELL, Barcelona Individual talk Receptor tyrosine kinases in breast cancer-from mechanisms to therapeutic targeting 30.10.2012 Barcelona, Spain Hynes Nancy E.;
Dana Farber Cancer Institute, Harvard Medical School Individual talk Receptor tyrosine kinases in breast cancer-from mechanisms to therapeutic targeting 09.10.2012 Boston , United States of America Hynes Nancy E.;
The 4th EMBO Meeting-Advancing Life Sciences Talk given at a conference Receptor Tyrosine Kinases in Breast Cancer: From Mechanisms to Therapeutic Targeting 22.09.2012 Nice, France Hynes Nancy E.;
SSSTC Stepping Stone Symposium Talk given at a conference Receptor Tyrosine Kinases in Breast Cancer: 20.06.2012 Zurich, ETH, Switzerland Hynes Nancy E.;
EuroMEMBRANE International Conference 2012; “Membrane Dynamics in Physiology and Disease” Poster Involvement of the novel protein Memo in the regulation of SphK1-S1P pathway 05.06.2012 Basel, Switzerland Kondo Shunya; Hynes Nancy E.;
EMBO Conference – Cellular signaling & Molecular Medicine Talk given at a conference Targeting Receptor Tyrosine Kinases in Cancer: from mechanisms to therapeutic targeting 25.05.2012 Cavtat, Croatia Hynes Nancy E.;
Elena Timofeeff-Ressovsky Seminar, Max Delbruck Center Individual talk Targeting Receptor Tyrosine Kinases in Cancer: Response & Resistance 25.04.2012 Berlin, Max Delbruck Center, Germany Hynes Nancy E.;
28th International Association for Breast Cancer Conference Poster Studies on Memo in breast cancer invasion and metastasis 15.04.2012 Manchester, Great Britain and Northern Ireland MacDonald Gwen; Hynes Nancy E.;
Annual ENBDC Workshop: Methods in mammary gland biology & breast cancer, Talk given at a conference Targeting Receptor Tyrosine Kinases in Cancer: from mechanisms to therapeutic targeting 13.04.2012 Weggis, Switzerland Hynes Nancy E.;
Symposium on Signal Transduction in Cancer & Infectious Diseases:Prevention, Diagnostics & Therapy Talk given at a conference Targeting Receptor Tyrosine Kinases in Cancer: Response & Resistance 15.03.2012 Okayama University , Okayama, Japan Hynes Nancy E.;


Associated projects

Number Title Start Funding scheme
121574 Studies on Memo: a novel protein with a role in cancer and aging 01.01.2009 Project funding (Div. I-III)

Abstract

STUDIES ON MEMO: A NOVEL PROTEIN WITH A ROLE IN CANCER AND AGINGSUMMARYMemo is encoded by a unique gene that is found in all branches of life, from bacteria to humans. Memo is widely expressed during embryogenesis and Memo null embryos die during the last third of gestation (E13.5 to E18.5). Memo is expressed in adult mice, in all examined organs. To probe for Memo’s role in normal physiology a strain allowing an inducible Memo deletion in all organs was generated. Surprisingly, loss of Memo led to the rapid onset of a premature aging phenotype accompanied by alterations in insulin and glucose metabolism. Our current hypothesis is that Memo has a general, essential role in normal physiology and in cancer, a function that goes beyond our original work showing that Memo has a role in cancer cell migration. Based on this hypothesis, the proposal has two major aims. 1) We will test if Memo protects cells from stress, using Memo null and Memo wild type fibroblasts. Cells treated with different stress inducers will be monitored for survival. Moreover, oncogene-transformed tumor models, which are matched for Memo-expressing and Memo-null, will be tested in vivo for sensitivity to chemotherapy. The impact of Memo on biochemical and molecular signaling pathways will also be examined. 2) We will continue to study the role of Memo in breast cancer, asking questions about Memo expression levels and patient prognosis. Memo’s role in invasion and metastasis will be studied in breast cancer models with decreased Memo expression.
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