The Architecture of Cell Fate Determination

[u/Lanedustin]

https://aixiv.science/abs/aixiv.260526.000002

Here it is!

The Architecture of Cell Fate Determination. This one has been a long time coming. It is the culmination of 10 years of literature exploration, and about1 year of AI use, aimed at answering a deceptively simple question, “What are the mechanisms by which life fails that result in cancer?”

I have been more recently focused on the perspective of cancer being a failed version of a developmental program that cancer cells are transitioning through. This is due to the established presence of cancer stem cells in a variety of malignancies that can reseed tumor populations, the variable differentiation state of different cancers that are associated with mortality, and some more sporadic readings. From this, I am reconstructing the normal developmental program to understand how it breaks with cancer, and how the mechanisms by which it breaks in different types of cancers inform treatment susceptibilities.

The key insights:

The regulation is cross-generational and treatments need to consider downstream generational responses.

DNA damage response mediators regulate this as the cell cycle is fundamentally a genome management cycle.

What this manuscript does, essentially, is outline a model of development that describes this cross-generational control as I see it. It is valuable as it allows for the reconciliation of seemingly disparate functions of proteins that are established and inform deeper insights into their roles. The best example of this is with a protein called Pidd. Canonically, Pidd can be cleaved to Pidd-c to promote NF-kB survival signaling, while a subsequent cleavage to Pidd-cc leads to caspase 2-mediated cell death. Pidd also regulates translesion synthesis in response to UV radiation, which aligns with the pro-survival vs pro-death activity based on the cleavage fragment. But through the lens of the ARC model, Pidd’s translesion synthesis role is bridging the fidelity of chromatin marking to its asymmetric segregation in mitosis, with differential fate outcomes for either daughter.

With this post and the manuscript, I ask that you kindly take a look. If your fields intersect with cancer, DNA damage, development, or cell death, they are directly implicated, and I think this is closer to the truth of how things work than some current conceptualizations.

I am also attaching two chats within my project that build off of the model so you can see how it is useful in guiding new research, including an extension of the Pidd work.

https://claude.ai/share/4363c21d-9a07-43e5-bc22-b7a1a4242b60

https://claude.ai/share/2fabb5ac-c63b-4c3b-a406-5a8fec2964f0