Metastatic prostate cancer cells that spread throughout the
patient's body reactivate a DNA program responsible for fetal
prostatic development, new research shows. Cancer researchers led
by Wilbert Zwart of the Netherlands Cancer Institute and Oncode
Institute, and Matthew Freedman of the Harvard Dana-Farber Cancer
Institute in Boston, demonstrated this process in tissue samples
taken from hundreds of surgically removed prostate tumors.
This reactivation of an embryonic DNA program during metastasis
has never before been documented in cancer research.
The researchers have published their findings on July 20, 2020,
in the scientific journal Nature Genetics. Yanyun Zhu, PhD
researcher at the Netherlands Cancer Institute, is one of the
MM Pomerantz et al., Prostate
cancer resurrects developmental epigenomic programs during
metastatic progression, Nature Genetics 20 July 2020. DOI:
Microscopic image of prostate cancer that has spread to a
patient's lymph node.
Back in time
"Once prostate cancer metastasizes, the tumor cell travels back
in time to the embryonic state, when the prostate develops in
utero," says research leader Wilbert Zwart, endowed professor at
the Eindhoven University of Technology and specialist in
hormone-sensitive cancers, such as prostate cancer.
During fetal development, the formation of the prostate is
facilitated by several activated DNA programs in specific
locations. Once the prostate is "done", these programs are turned
off. And they remain off, even in patients with prostate tumors.
Until the tumor metastasizes.
This "organ development" DNA program in prostate cells appears
to retain a memory of its previous activity. As fellow research
leader Matthew Freedman states, the activity seems to have left
behind some sort of molecular footprint. The tumor "abuses" this
slumbering memory when spreading throughout the body.
All metastatic prostate tumors
Wilbert Zwart: "This turned out to be the case in every
metastasis we studied. Every tumor is unique, but all metastatic
tumors shared this one trait: the metastatic tumor cells
reactivated DNA that has been inactive since fetal development, in
order to metastasize. This is a tremendously valuable discovery! As
a potential follow-up question, we could consider whether this
process is unique to prostate cancer, or whether other tumor types
also use this embryogenesis-specific program to metastasize." The
researchers hope that this new knowledge will lead to the
development of new treatment options.
Cooperation of many patients
Among the researchers involved in this study were medical
specialists André Bergman and Henk van der Poel of the Netherlands
Cancer Institute, both specialized in prostate cancer. Metastases
often make cancer incurable. Bergman: "Thanks to this important
step in our understanding of the development of metastatic cancer,
we are one step closer to potential preventative measures. We owe
our discovery to the many patients who chose to cooperate with our
research, and the development of new treatment options."
Zwart: "During our research, we found multiple proteins that are
involved in the DNA programs for organ development that appear to
be hijacked by metastatic prostate cancer. By using drugs to
inhibit these proteins, we want to try and block tumor metastasis.
We are currently initiating these experiments at our lab, and hope
to eventually translate our findings into medical practice."
In order to conduct their research, the researchers from
Amsterdam and Boston compiled the world's biggest database of DNA
regulating ("epigenetic") processes in healthy prostate tissue and
tumor tissue. They analyzed DNA regulation in hundreds of
surgically removed prostate samples showing the transition between
healthy prostate tissue and cancer, and between non-metastatic
prostate cancer and metastatic tumors. This led to the discovery of
the patterns that lie at the root of metastases.
This research was made possible through the support of:
- Dutch Cancer Society/Alpe d'HuZes
- Oncode Institute
- Prostate Cancer Foundation (US)
- NIH (US)