Group Keizer

Areas of expertise uitklapper, klik om te openen

The aim of Peter de Keizer’s group is to unravel the molecular mechanisms that cause cells to become senescent and to identify how these cells drive aging and age-related diseases. The role of senescence in late-stage therapy-resistant cancer is a major component of this research. The research has a strong translational component and a spearpoint of the group is to develop methods to target the deleterious effects of senescent and senescent-like cancer cells, for instance by eliminating them altogether.

In 2004, Peter obtained his MSc in Biomolecular Science form Utrecht University. The final part of his training was performed at Harvard Medical School / Massachusetts General Hospital in Boston, USA. Here, he focused on therapy-resistant Glioblastoma, the most lethal form of brain cancer, something which is now on of the focus areas of the group.

In 2009, Peter obtained his PhD from UMC Utrecht on the regulation of FOXO proteins under conditions of stress and their role in tumor suppression. During these years, he identified FOXOs as targets in oncogene and damage-induced senescence (e.g. PhD thesis 2009 and de Keizer et al., Cancer Research 2010). Being highly intrigued by cellular senescence, he joined the lab of a pioneer in the field, Prof. dr. Judith Campisi, at the Buck Institute for Research on Aging, in Novato, CA, USA. As a fellow of the Dutch Cancer Society, he focused on the molecular regulation of senescence, identified senescence heterogeneity and generated the first and second generation of compounds to eliminate senescent and therapy-resistant cancer cells (e.g. patent US20130288981 A1; 2012).

In 2012, Peter joined the Erasmus Medical Center in Rotterdam, where he designed the third generation of anti-senescence drugs: the FOXO4-DRI peptide, aka Proxofim. This proved to be effective in counteracting signs of chemotoxicity and, excitingly, was able to restore certain healthspan features in models for fast and natural aging, e.g. fur density, behavior and renal function. (Baar et al., Cell, 2017). This research received worldwide media attention, including coverage in numerous TV and radio shows, newspapers and blogs.

In January 2018, Peter joined the University Medical Center Utrecht as assistant professor, where his group will be focused on identifying the molecular variation in individual senescence phenotypes and how senescence dictates (cancer) stemness, cancer metastases and therapy resistance. In parallel the group is highly dedicated to develop the next generation of anti-senescence drugs with an improved safety profile to allow for human translation.

Patents uitklapper, klik om te openen

2016 -  de Keizer PLJ Anti-senescence compounds and uses thereof.

PCT/NL2016/050057, P106664NL00

2013 - de Keizer PLJ, Laberge RM, Campisi J. TARGETING SENESCENT AND CANCER CELLS FOR SELECTIVE KILLING BY INTERFERENCE WITH FOXO4 (No: 13/830,790)

2013 - de Keizer PLJ, Laberge RM, Campisi J. TARGETING SENESCENT CELLS AND CANCER CELLS BY INTERFERENCE WITH JNK AND/OR FOXO4 (No: 13/830,846)

Research lines/group uitklapper, klik om te openen

The role of senescent cells in aging and cancer
Healthy cells can become senescent when they experience a persistent damage response. This can be caused by the actual damage that is accumulated on a daily basis, but also due to telomere shortening, metabolic overdrive by oncogenic mutations, or chromatin remodeling, all of which mimic the damage response. Consequently, senescent cells are permanently withdrawn from the cell cycle. This is favorable as they are no longer able to cause mischief. Unfortunately, senescent cells also secrete a wide range of factors that influence the tissue microenvironment. In time, this 'signaling noise' causes neighboring cells to misfunction. We aim to understanding what makes cells become senescent, what regulates their secretion profile and how these cells impair healthspan.


Regulation of stemness, EMT and therapy resistance by senescent cells
There is a close connection between cellular senescence and markers of stemness in neighboring cells. We have theorized that such signaling can lead to a 'senescence - stem lock' (de Keizer, Trends in Molecular Medicine, 2017), in which senescent cell cause a persistent start of pluripotency in their local environment, thereby impairing rejuvenation at times of need. A goal of our research is to identify the responsible mechanisms and to identify how this lock could be reversed.

Heterogeneity in senescence
We identified that seemingly homogeneous populations of senescent cells express senescence markers in very heterogenic patterns. This is important, since for some diseases certain SASP factors are deleterious, whereas this may be completely different for others. We employ molecular imaging  and sorting techniques to study identify the biology of senescent cells, their heterogeneity, their effect on tissues and their weak spots for effective elimination.

Translational efforts to eliminate senescent and senescent-like late stage cancer cells
Ultimately, the aim is to optimize compounds that effectively eliminate the most dangerous senescent cells in human. For this, we teamed up with experts from pharma and drug development, optimize our most potent anti-senescence lead compounds in a professional manner for actual clinical translation. For more information see de website of Cleara Biotech, a UMC Utrecht-based biotech company.

Group members

• Marjolein Baar (Postdoc)
• Johannes Lehmann (Postdoc)
• Rana Özdeslik (Postdoc)
• Diana Putavet (PhD student)
• Thomas Brandt (PhD Student)
• Maidina Tuohetahuntila (Technician)
• Esmée Bouma (Technician)
• Tim Leyten (MSc student)
• Damon Hofman (MSc student)
• Veerle de Goederen (MSc student)
• Ivar van Galen (MSc student)
• Beatriz Subtil (MSc student)
   

Key publications uitklapper, klik om te openen

1. Marjolein P. Baar, Renata M.C. Brandt, Diana A. Putavet, Julian D.D. Klein, Kasper W.J. Derk, Benjamin R. M. Bourgeois, Sarah Stryeck, Yvonne Rijksen, Hester van Willigenburg, Danny A. Feijtel, Ingrid van der Pluijm, Jeroen Essers, Wiggert A. van Cappellen, Wilfred F.J. van IJcken, Adriaan B. Houtsmuller, Joris Pothof, Ron W.F. de Bruin, Tobias Madl, Jan H.J. Hoeijmakers, Judith Campisi, Peter L.J. de Keizer. Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell (2017). Impact factor 28.71.

2. Peter L.J. de Keizer. The Fountain of Youth by Targeting Senescent Cells? Trends Mol. Med. (2017) Impact factor: 9.292.

3. Kruiswijk F, Hasenfuss S, Sivapatham R, Naipal K, van den Broek NJF, Kruit W, van der Spek P, van Gent D, Brenkman A.B, Campisi J, Burgering BMT, Hoeijmakers JHJ and de Keizer PLJ. Targeted inhibition of metastatic melanoma through interference with Pin1-FOXM1 signaling.

Oncogene, (2016) Impact factor 8.459.

4. Laberge RM, Zhou L, Sarantos MR, Rodier F, Freund A, de Keizer PL, Liu S, Demaria M, Cong YS, Kapahi P, Desprez PY, Hughes RE, Campisi J. Glucocorticoids Suppress Selected Components of the Senescence-Associated Secretory Phenotype. Aging Cell. (2012). Impact Factor: 6.34.

5. de Keizer P, Burgering B, Dansen TB. FOXO as a sensor, mediator and regulator of redox signaling. Antioxid. Redox Signal. (2011) Impact Factor: 7.407.

6. de Keizer PL, Laberge RM, Campisi J. p53: Pro-aging or pro-longevity? Aging (Albany NY). (2010) Impact Factor: 5.127.

7. de Keizer PLJ, Riedl-Polderman PE, Szypowska AA, Packer LM, van den Broek NJF, Dansen TB, Marais R, Brenkman AB, Burgering,BMT. Activation of FOXO transcription factors by oncogenic BRAF promotes p21cip1-dependent senescence. Cancer Res. (2010) Impact Factor: 9.329.

8. Brenkman AB, van den Broek NJF, de Keizer PLJ, van Gent D, Burgering BMT. The DNA damage repair protein Ku70 interacts with FOXO4 to coordinate a conserved cellular stress response. FASEB J. (2010) Impact Factor: 5.043.

9. Dansen TB, Smits AM, van Triest MH, de Keizer PLJ, van Leenen D, Groot Koerkamp M, Szypowska AA, Meppelink A, Brenkman AB, Yodoi J, Holstege FCP, Burgering BMT. Redox-sensitive cysteines bridge p300-mediated acetylation and FoxO4 activity. Nat. Chem. Biol. (2009) Impact Factor: 13.217.

10. de Keizer PL*, Brenkman AB*, van den Broek NJ, van der Groep P, van Diest PJ, van der Horst A, Smits AM, Burgering BM * These authors contributed equally; reverse in Pubmed. The peptidyl-isomerase Pin1 regulates p27kip1 expression through inhibition of Forkhead box O tumor suppressors. * equal contribution. Reverse order in PubMed. Cancer Res. (2008) Impact Factor: 9.329.

11. Brenkman AB, de Keizer PL, van den Broek NJ, Jochemsen AG, Burgering BM. Mdm2 induces mono-ubiquitination of FOXO4. PLoS. ONE. (2008) Impact Factor: 3.234.

Contact information uitklapper, klik om te openen

Visiting address:
Stratenum 3.217
Universiteitsweg 100
3584 CG Utrecht
The Netherlands

Secretariat:
Cristina Arpesella or Marianne van der Heiden
m.c.arpesella@umcutrecht.nl / a.m.vanderheiden@umcutrecht.nl

PRESS officers uitklapper, klik om te openen

Press UMC Utrecht:
+31 88 75 55000

Additional information - in the media uitklapper, klik om te openen

• Nieuwsplatform UMC Utrecht, Gezond ouder worden door aanpak roestcellen, Woensdag 24 april 2019.
• AvroTros TV, Dokters van Morgen, 8 januari 2019. Verjongen van cellen in je DNA, hoe werkt dat dan? Peter de Keizer geeft uitleg.
• Vrij Nederland. Dertig jaar langer leven? Technisch gezien is het al mogelijk. 21 oktober 2018. Al-Jazeera, Dutch scientists test anti-ageing molecule, Sunday 20th May 2018. Scientists in the Netherlands are working on a drug that could reverse certain aspects of ageing. A rejuvenating molecule tested in mice managed to extend their lifespan by 25 percent. Human trials have not yet started, but replicas of the molecule are already being sold on the internet. Al Jazeera's Fleur Launspach visited the research team at the UMC Utrecht in the Netherlands.
• LeafScience.org, An interview with dr. Peter de Keizer,  maandag 16 juli 2018.
• Funx radio, Er bestaat een stofje dat veroudering tegen gaat, maandag 16 juli.
• Radio 538, Evers staat op, bioloog Peter de Keizer over anti-verouderingsmedicijn, vrijdag 13 juli 2018.
• Algemeen Dagblad, 'Levenselixer' voor het eerst op mensen getest, en het werkt!', vrijdag 12 juli 2018.
• Radio 1, Nieuwsweekend, Menselijke proefkonijnen tegen veroudering, zaterdag 7 april 2018.
• BNR Nieuwsradio. Gezond ouder worden, woensdag 4 april 2018.
• De Volkskrant, podcast Hoe dicht zijn we bij de sleutel tot eeuwig leven? woensdag 4 april 2018.
• De Volkskrant, Het Rotterdamse experiment met de muis die 113 werd, vrijdag 30 maart 2018
• De Volkskrant, Nederlands 'levenselixer' inspireert futuristen, bodybuilders en kattenliefhebbers, donderdag 29 maart 2018.
• Meet-Up VPRO Tegenlicht 'De Onsterfelijken': A discussion on the future of aging (starting @36:07), woensdag 7 maart 2018.
• A movie with the MouseAge consortium to ask for awareness of aging as a major health problem in the future and how we should tackle it, februari 2018.

Profile Peter de Keizer on Researchgate