LSI Challenge: Health

Triple negative breast cancer (TNBC) is a particularly agressive form of breast cancer which accounts for approximately 10–15% of all breast cancer cases. It is characterized by poor prognosis and a lack of effective targeted treatment options. The TP53 gene, a key regulator of cell cycle arrest and apoptosis, is mutated in 60–80% of TNBCs. While the transcriptional functions of p53 have been well studied, its non-transcriptional role—particularly in calcium (Ca²⁺)-mediated apoptosis—remains poorly understood.

Recent work from our group shows that TP53 mutations disrupt intracellular Ca²⁺ signalling, impairing apoptosis and contributing to chemoresistance. However, the mechanisms by which different TP53 mutations affect calcium homeostasis and apoptotic sensitivity are not well understood.

Hypothesis: Mutant TP53 disrupts transcriptional and non-transcriptional functions reducing apoptotic sensitivity to treatment through altered calcium regulation. Targeting calcium signalling in TP53 mutant TNBCs can restore chemotherapy sensitivity, representing a new treatment strategy.

Project Aim - Investigate how TP53 mutations impact both the transcriptional and non-transcriptional roles of p53 in modulating apoptotic sensitivity via calcium signalling. We aim is to identify TP53 mutant cohorts in TNBC that respond to targeting p53-calcium signalling to restore apoptotic sensitivity.

OBJECTIVES: We have identified two synergistic PhD projects that collectively investigate the transcriptional and non-transcriptional mechanisms of mutant TP53. Leveraging complementary expertise and a strong collaborative framework, the research will address four common objectives, outlined below (with specific aims detailed per project).

1. Mutant TP53 Models. Develop novel cell line models incorporating clinically relevant TP53 missense, frameshift, and stop mutations. These will be applied across both 2D cultures and advanced 3D tumour microenvironment (TME) on-chip co-culture systems.

2.Non-transcriptional calcium-mediated apoptosis. Determine how distinct TP53 mutations alter subcellular calcium dynamics and examine the downstream impact on apoptotic sensitivity and associated phenotypic changes.

3. Mapping P53 Binding Partners. Identify disrupted transcriptional and non-transcriptional pathways in mutant TP53 models that underlie calcium dysregulation and apoptotic resistance. Characterize novel p53 binding partners as candidate therapeutic targets.

4. Predictive signatures and therapeutic Screen. Assess calcium signalling profiles as potential predictive biomarkers and therapeutic targets for TP53-mutant TNBC. Extend findings to identify additional mutation-driven, treatment-resistant cancer subtypes.