The goal of Reuven Agami's research is to generate a better
understanding of the molecular processes leading to human cancer.
His strategy is to identify essential cancer genes and pathways,
and he is particularly interested in the role of RNA. RNA is a
versatile molecule and the human genome expresses many different
types. Interestingly, only a small fraction of these encodes for
proteins, while most regulate protein production and therefore
control cell behavior. His group develops and utilizes novel RNA
tools to alter gene expression and thereby influence cancer cell
fate. They hope to generate knowledge that can be used to develop
more effective therapeutic strategies for treating cancer.
Jacqueline Jacobs began her research group at the NKI in 2008,
and investigates the mechanisms that preserve cell viability and
protect against cancer development. Cells with unstable genomes are
at high risk of becoming cancerous, and her group is particularly
interested in the detection and repair of DNA lesions, which
maintain genome integrity. These mechanisms are prevented from
operating at natural chromosome ends by unique nucleoprotein
structures, called telomeres.
However, telomeres shorten with every cell division, eventually
compromising telomere protection and leading to cell death,
senescence or genomic instability, which have important
consequences for aging and the development of cancer.
Wilbert Zwart joined the NKI as a junior group leader in 2011.
He is interested in the biology underlying breast cancer,
endometrial cancer and prostate cancer, and how this links with
patient response to treatment in the clinic. These three cancer
types share one major characteristic: tumor induction and/or tumor
cell proliferation is dependent on hormonal regulation. Drug
treatment is often directed at inhibiting hormonal action, but
resistance is common. Therefore, an understanding of the molecular
wiring of hormonal regulation in these tumor types essential, both
under drug sensitive as well as resistant conditions. His group
combines cell biology, genomics, endocrinology and molecular
pathology, which are directly correlated with clinical analyses, to
determine which patients would benefit the most from a specific
With his senior post-doc Koen van de Wetering, Borst is trying
to identify the natural substrates of a class of drug transporters,
called Multidrug Resistance-associated Proteins (MRPS or ABCCs). A
recent focus has been on MRP5 and MRP6. The main approach is to
compare body fluids of WT and KO mice by LC/MS and verify by
vesicular transport whether the compounds altered in the KO are
transported by the missing MRP. The function of MRP5 (ABCC5) was
long unknown, but we recently found that it transports
neurotransmitter - like compounds and an entirely new class of
compounds not known in mammals before. The absence of MRP6 (ABCC6)
causes an inborn error, PXE, and identification of the natural
substrate of MRP6 may allow substitution therapy of PXE. Up to 2013
Borst also worked on mechanisms of drug resistance in cancer cells
and on biosynthesis and function of base J, a new base in the DNA
of parasites discovered in the Borst lab.
The resistance project is continued by Sven Rottenberg in the
NKI; the base J project is continued by Peter Myler (Seattle, US).
Borst remains an adviser in both projects.