Thursday, August 16, 2012

Melanoma, Zebra Fish, and Alan Turing

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) ,

[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,