Interested in the dynamics of cell-fate decisions & apoptosis resistance?
Read the full open-access article in npj Sys Biol & Appl: “Dynamical analysis of a model of BCL-2-dependent cellular decision making” @crmatematica.bsky.social @natureportfolio.nature.com

🔗 www.nature.com/articles/s41...

By mapping how BCL-2 network architecture encodes fate plasticity, the study offers a quantitative basis to design combination strategies that push cells irreversibly toward apoptosis.

These results provide a mechanistic and dynamical rationale for targeting BCL-2 family proteins in cancer and senescence-associated disease, where apoptosis resistance and senescent persistence are major obstacles.

This framework connects molecular measurements to emergent fate landscapes, making it easier to interpret perturbations such as BH3-mimetic therapies.

Hybrid models bridge detailed biochemical interactions with coarse-grained dynamical behaviours, clarifying which features of BCL-2 signalling are essential for multistability.

Comparing several mechanistic BCL-2 architectures, reveal that while standard architectures support bistability, robust tristability needs additional regulatory constraints, suggesting that physiological senescence likely relies on extra control layers to stabilise an intermediate fate.

Stochastic simulations indicate that noise in network components generates heterogeneous fate outcomes among genetically identical cells.
These fluctuations can delay/bias cell fate transitions, offering a quantitative explanation for fractional killing & variable drug responses.

A key finding: tristability requires coop binding between BH3-only & anti-apoptotic BCL-2 proteins beyond canonical interaction schemes that typically yield only bistability.
This cooperativity provides a dynamical mechanism for maintaining a metastable senescent-like state.

Bifurcation analysis shows how combinations of BCL-2 protein expression activity tune transitions between these states and determine whether cells commit to death or remain plastic.

The model reveals robust multistability in BCL-2-driven cell-fate dynamics, including regimes with three distinct stable states corresponding to survival, senescence-like arrest, and apoptosis.