We never tested explicitly this idea but it seems that the issue is not related to the amount of chromosome re-arrangements but on the kind..

It is very interesting question regarding transdifferentiation of cancer stem cell.

I would like to take the following steps for single cell (time-series RNA-Seq data) or population cell (time-series Microcarray data):

1.     Find out mechanism of how a stem cell/cells can make transdifferentiation in terms of critical dynamics point of views through investigation of the existence of a critical transition state.

2.     Find out critical difference between cancer-stem and stem cells from critical dynamics point of views (any difference of self-organization of overall expression such as critical states, and their temporal developments).

3.      Find out mechanism of how a cancer stem cell/cells could make transdifferentiation in terms of critical dynamics point of views through investigation of the existence of a critical transition state.

4.     These comparisons may provide some clues on cell-fate change in cancer-stem and stem cells.

Masa

It is an interesting consideration. I often paid attention to the epigenetic mechanisms of the appearance of cancer in my articles.

 Dear Alessandro, Messa, Georgi. Thank you for your replies to my query. I am absolutely intrigued by this line of inquiry. I agree that it the kind of chromosomal arrangements that could drive critical transition states and self-organization of cancer stem cell/progenitor/tumor cell populations not just random events. Some early thoughts, (some original, some not):

1. Chromosome breakage and reunion events are not stochastic (but more likely chaotic) due to fragile sites and many CHM rearrangements being incompatible with viability.

2. Only certain metabolic/bioenergetic dynamic states are favorable to tumor evolution (due to epigenetic effects in nDNA affecting transcriptomics, and proteomics) interacting with those rearrangements causing mitochondrial dysfunction. Many CHM rearrangements are neutral or even selected against contributing only noise to the system.

3. And lastly in addition to differentiation effects certain rearrangements (eg gene fusions) would generate entirely novel transcription and translation (non-human) products geneA fused to geneB generating a novel geneC contributing to differentiation states better described as those of a an emerging parasite rather than those of a human tissue. Anyway very interesting.

Yes!

Dear James

I think that   the issue is related to cells fate decision.

regards

Yes I agree.

My interest is to understand/decipher the existence of "epigenetic landscape", which should be equivalent to SOC control landscape in transdifferentiation of cancer stem cell.

Barry James Barclay: I wonder if cancer stem cells that shown numerous gross chromosomal rearrangements have transdifferentiation gene expression?

By definition - transdifferentiation is change of cell fate, usually transition between closely histlogically related cell types. In order to do that, the cell should first de-differentiate, in a more modern language - to become re-programmed. In order to reprogram, it must erase its epigenetic marks of histone and DNA modifications and  return to the embryonal stem cell state, even to totipotency of an egg.That is the case with the very malignant tumours and it is more or less known. What to do with mutations and chromosome aberrations? - they are stressy, while the epigenetic reprogramming is a general evolutionary adaptation to stress. The new epigenetics likely can overpass the mutations and aberrations and also have some instruments for restructuring the genomes, e.g. by chromothripsis. The best perspective of cancer transdifferentiation is induction of normalisation of reprogrammed cancer cells.  

Thanks Jekaterina. I agree completely and am thinking along these lines. Aberrations in one-carbon metabolism (genomic or epigenomic) that limit S-adenosylmethionine bioysynthesis with result in global hypomethylation over many cell divisions and consequential dedifferentiation. Aberrations in pyrimidine metabolism that cause increased DNA uracil incorporation and consequential gross chromosomal rearrangements will alter chromatin architecture greatly on many chromosomes and my argument is transdifferentiation as a consequence.

a good idea

Dear Barry,

What do you mean by transdifferentiation gene expression? - The capacity to change the tissue differentiation type? In principle, certainly yes, as they are de-differentiated  (in support of epigenetic model of carcinogenesis), while de-differentiation or reprogramming is a condition for transdifferentiation.

In the model I am proposing there are two molecular mechanisms that could affect dedifferentiation  redifferentiation and/or transdifferentiation in the same tumor population due to altered expression of the TYMS gene by deletion or amplification.

High TYMS activity would withdraw reduced folate away from S-adenosylmethionine biosynthesis and cause global hypomethylation and consequential dedifferentiation. Redifferention would occur after moderating events (eg loss of amplified TYMS genes on extrachromosomal elements) and subsequent global methylation.

The original question here though is how chromosomes are fragmented and rearranged in many tumors to such an extent that the cellular karyotype is hardly recognizable as human. I propose that this occurs continuously during tumor evolution in cells with low TYMS activity.

Consequential misrepair of DNA-uracil is clastogenic causing chromosome breakage and reunion with every cell division. The question is of course whether this complete genomic rearrangement causes transdifferentiation by numerous alterations in 3D chromatin architecture.

For continuation of discussions - see the methods on evaluating the genome plasticity and where a cancer cell is found - the the 2-cell wild mouse embryo attractor. Compare with 8-cell state. I attach this great article.