We have previously alluded to the use of the Turing model
for demonstrating the propagation of melanoma in humans. We have further
demonstrated a model of metastatic propagation and the interaction of ligand
and receptors in a spatial manner similar to that of Turing. We have further
demonstrated that from the recent literature that benign normal cell can
actually then be used to reinforce the growth of the metastatic malignant
cells. This then leads us to seek experimental evidence to this effect. To that
end we look at the zebra fish and melanoma related to that model.
In a recent paper by Ceol et al they authors state[1]:
The most common mutation in human melanoma, BRAF(V600E),
activates the serine/threonine kinase BRAF and causes excessive activity in the
mitogen-activated protein kinase pathway BRAF(V600E) mutations are also present
in benign melanocytic naevi, highlighting the importance of additional genetic
alterations in the genesis of malignant tumours. Such changes include recurrent
copy number variations that result in the amplification of oncogenes. For
certain amplifications, the large number of genes in the interval has precluded
an understanding of the cooperating oncogenic events.
Here we have used a zebrafish melanoma model to test
genes in a recurrently amplified region of chromosome 1 for the ability to
cooperate with BRAF(V600E) and accelerate melanoma. SETDB1, an enzyme that
methylates histone H3 on lysine 9 (H3K9), was found to accelerate melanoma
formation significantly in zebrafish. Chromatin immunoprecipitation coupled
with massively parallel DNA sequencing and gene expression analyses uncovered
genes, including HOX genes, that are transcriptionally dysregulated in response
to increased levels of SETDB1. Our studies establish SETDB1 as an oncogene in
melanoma and underscore the role of chromatin factors in regulating
tumorigenesis.
In a more details general write up, Science Daily states[2]:
Craig Ceol, PhD, assistant professor of molecular
medicine at the University of Massachusetts Medical School, and collaborators
at several institutions, used zebrafish to identify a new gene responsible for
promoting melanoma. In a paper featured on the cover of the March 24 issue of Nature, Dr. Ceol and colleagues
describe the melanoma-promoting gene SETDB1.
"We've known for some time that there are a number
of genes that are responsible for the promotion and growth of melanoma,"
said Ceol, who completed the research while a postdoctoral fellow in the lab of
Howard Hughes Medical Institute investigator Leonard Zon, MD, at Children's
Hospital Boston. "With existing methods, it had been difficult to identify
what those genes are. By developing the new approach described in this paper,
we were able to isolate SETDB1 as one of those genes."
Cases of melanoma, an aggressive form of skin cancer,
have been on the rise in the United States: in 2009 alone, 68,000 new cases
were diagnosed and 8,700 people died of the disease. Though it accounts for
less than 5 percent of all skin cancers, it is responsible for the majority of
deaths from skin cancers and has a poor prognosis when diagnosed in its advanced
stages. Early signs of melanoma include changes to the shape or color of
existing moles or the appearance of a new lump anywhere on the skin.
The article then continues as follows:
Painstakingly analyzing more than 2,100 tumors from more
than 3,000 zebrafish, researchers found that in fish with the SETDB1 gene,
melanoma not only appeared earlier, but grew faster and invaded more deeply
into the neighboring muscle and spinal tissue. With this new information, researchers
screened 100 human melanomas for the SETDB1 gene. In 70 percent of the sample
tumors, SETDB1 was present at high levels, indicating that SETDB1 may be
involved in the formation of a majority of human melanomas."
Further analysis showed that SETDB1 produces an enzyme
that turns other genes on or off and is overrepresented in other forms of
cancer, such as ovarian, breast and liver cancer. "It's clear that SETDB1
is up-regulated and that it's altering the activity levels of other
genes," said Ceol. "Because SETDB1 regulates several genes, we still
don't know which of its targets promote melanoma."
Thus another gene is identified in the melanoma chain. The
last comment as to what specifically is regulated is concerning yet progress is
being made.
Now how does this relate to Turing? In a more recent paper
by Eom et al[3]
the authors state:
Remarkably, these interactions meet the predictions of
Turing models of pattern formation that rely on dynamics driven by processes of
reaction diffusion with lateral inhibition. Nevertheless, the molecular
mechanisms that drive cellular behaviors during stripe formation have remained
obscure.
Namely connecting these two we have further evidence that
melanoma, using a zebra fish model, can follow the Turing approach we discussed
several years ago.
We believe that this is a significant nexus between models
and reality and is worthy of additional effort.
[1]
Ceol, et al, The histone methyltransferase
SETDB1 is recurrently amplified in melanoma and accelerates its onset, Nature, 71, 513–517,
(24 March 2011) ,http://www.nature.com/nature/journal/v471/n7339/full/nature09806.html
[3]
Eom, D., et al, Melanophore Migration and
Survival during Zebrafish Adult Pigment Stripe Development Require the
Immunoglobulin Superfamily Adhesion Molecule Igsf11, PLoS Genet 8(8): e1002899.
doi:10.1371/journal.pgen.1002899, http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002899
Posts
