Data driven network inference and longitudinal transcriptomics unveil dynamic regulation in Chronic Lymphocytic...

Area of Science:

• Cancer Biology
• Immunology
• Computational Biology

Background:

• The tumor microenvironment (TME) significantly influences cancer cell behavior, yet the specific regulatory changes within cancer cells interacting with immune cells are not fully understood.
• This knowledge gap hinders effective treatment strategies for diseases like Chronic Lymphocytic Leukaemia (CLL).

Purpose of the Study:

• To investigate the dynamic regulatory mechanisms governing Chronic Lymphocytic Leukaemia (CLL) cell behavior in response to immune cell interactions within the TME.
• To develop and apply a computational framework for analyzing time-series transcriptomic data to infer gene regulatory networks (GRNs).

Main Methods:

• Utilized time-series transcriptomics on CLL patient samples cultured in a reconstituted in vitro TME over five time points (14 days).
• Employed data-driven GRN inference from transcription factor activity to capture temporal and patient-specific regulatory interactions.
• Analyzed gene expression profiles to identify gene modules associated with immune-cancer cell interactions.

Main Results:

• Identified patient-specific and temporally resolved GRNs, demonstrating how immune signals modulate CLL cell phenotype.
• Revealed distinct gene modules linked to cytokine signaling, metabolic reprogramming, and differentiation, crucial for immune-cancer cell crosstalk.
• Found that while immune cells influence CLL cell activation, intrinsic cellular features predominantly dictate survival.

Conclusions:

• Immune cell presence significantly impacts CLL cell activation and phenotypic changes through specific regulatory networks.
• CLL cell survival is primarily governed by intrinsic factors, independent of immune cell interactions.
• The study provides a robust computational framework for integrating time-series transcriptomics and GRN inference to study dynamic cellular behaviors.