Cancer-A story of condensates, feedback loops and the epigenome ?

 

Cancer_Hypothesis

1.Probably the epigenome of a cell is modified by an oncogenic mutation. Phenotypic plasticity/tumor heterogeneity occurs in this process.

2. This modified epigenome overrides the inhibitory signaling of tumor microenvironment via activating stemness networks. Chaos ensues.

3. The above (2) breaks cell cell interactions leading to tumor cells release from primary site and spread i.e. invasion.

4. Altered epigenome leads to epithelial mesenchymal transition.

5. Tumor cells at secondary site  undergo mesenchymal epithelial transition due to restored epigenome in a new microenvironment.

6. As critical threshold of oncogenic protein/signaling activity is breached (1) happens again.

7. A vicious cycle of tumor growth and spread ensues.

8. Altered expression/phenotype of tumor cells  containing oncogenic mutation occurs via phase transition. Mutant oncogenic proteins form multiple aggregates with their target sustrates forming numerous biomolecular condensates. Sustained oncogenic signaling occurs in biomolecular condensates which are resistant to negative feedback loops.  Membranes of such biomolecular condensates could prevent access of inhibitors to oncogenic signaling. This sustained signaling acts like a siren activating stress response pathways. Such stress response pathways could activate suppressive epigenomic enzymes in a negative feedback loop. The reason being that suppressive epigenomic enzymes such as histone deacetylases can suppress both tumor suppressor and oncogene transcription, but in a tumor it is the tumor suppressor that is silenced, but not the mutant oncogene levels. Ultimately it is cell survival regulating these feedback loops.

9. Since, the unpredictable component is how the epigenome is altered from a normal one to a cancerous one via the  oncogenic mutation,the oncogenic mutation via aberrant signaling could downregulate promoter activity of tumor suppressors via activating suppressive epigenome enzymes  like methylases.  The oncogenic mutation re-inforces its own activity positively since although the promoter of the mutant oncogene can be silenced by methylation, the methyl groups at promoters of mutant oncogenes are removed by demethylases as cell survival is the ultimate goal.

Stemness plays a role when downregulation of a tumor suppressor activates the uncontrolled  self-renewal activity of stemness networks, probably by activating oncogenic transcription factors of stemness networks that function in self-renewal.

The analogy with an Enzymatic Reaction:

Initiator-Oncogenic mutation, Epigenome alteration/Ist hit

Catalyst-Altered Tumor Microenvironment /2nd hit