A Hallmark-Integrated, Agent-Based Framework for Intratumor Heterogeneity in Melanoma Evolution.

Area of Science:

• Computational Biology
• Cancer Research
• Evolutionary Biology

Background:

• Intratumor heterogeneity (ITH) is a key factor in cancer progression and therapeutic resistance.
• Understanding the evolutionary dynamics driving ITH is crucial for developing effective cancer treatments.

Purpose of the Study:

• To develop a computational framework for studying ITH in melanoma.
• To investigate the interplay of genetic, immune, and spatial factors in shaping ITH.
• To model the emergence of distinct ITH modes and their impact on tumor behavior.

Main Methods:

• Development of a hallmark-integrated branching evolution process agent-based model (BEP-HI).
• Simulation of melanoma evolution under coupled selection pressures.
• Analysis of ITH modes, tumor growth kinetics, immune interactions, and cell motility.

Main Results:

• Identification of three distinct evolutionary ITH modes in melanoma.
• Demonstration of a mechanistic decoupling between tumor growth and heterogeneity.
• Immune recruitment identified as a primary driver of ITH via nonlinear immune-editing feedback.
• Melanoma cell motility shapes tumor morphology consistent with clinical observations.

Conclusions:

• The BEP-HI model provides a biologically grounded framework for studying ITH evolution.
• Interactions between cancer hallmarks significantly influence ITH.
• The model can generate virtual tumor cohorts linking genetic diversity to tumor behavior and treatment resistance.