Dissecting cross-lineage tumourigenesis under p53 inactivation through single-cell multi-omics and spatial...

Area of Science:

• Cancer Biology
• Genomics
• Cellular Homeostasis

Background:

• TP53 (p53) is a critical tumour suppressor gene.
• Germline TP53 mutations cause Li-Fraumeni syndrome, a hereditary cancer predisposition.
• The precise tumour-suppressive mechanisms of p53 are not fully understood.

Purpose of the Study:

• Investigate how p53 inactivation disrupts cellular homeostasis and promotes tumourigenesis.
• Explore these disruptions across different cell types.
• Elucidate context-dependent tumour-suppressive mechanisms of p53.

Main Methods:

• Utilized a Trp53 (mouse p53) knockout model.
• Integrated multi-omics analyses: single-cell transcriptomics, ATAC-seq, spatial transcriptomics, whole genome sequencing, CUT&Tag.
• Employed deep learning for p53 regulatory network reconstruction and in silico perturbation simulations.

Main Results:

• Revealed transitional cell dynamics from normal to p53-deficient and tumourigenic states.
• Identified critical pathways (cell cycle, stress response, metabolism, immune modulation) with shared and specific features.
• Discovered tumour-prone cells with high differentiation plasticity and early ribosomal protein gene upregulation.
• Uncovered chromatin disruptions in p53-loss-driven thymic T-cell clusters.
• Decoded p53 regulatory networks and simulated inactivation effects at single-cell resolution.

Conclusions:

• Elucidated multiscale consequences of p53 inactivation.
• Provided insights into tumour predisposition linked to TP53 mutations.
• Generated valuable resources for developing clinical interception strategies.