Grant: Project Grant

Cellular senescence is a key tumor-suppressive program activated by diverse cellular stressors. Yet, how different forms of stress converge on this shared pathway remains poorly understood. Our data show that senescence induction leads to widespread chromatin opening, particularly in non-coding regions, driven by a network of senescence-activated transcription factors. We hypothesize that oncogenic stress is sensed through the aberrant activation of these transcription factors, which in turn open specific non-coding genomic regions to trigger the senescence response. Tumor cells may evade this barrier by engaging mechanisms that prevent or reverse such chromatin opening. This proposal aims to test this hypothesis by precisely mapping the non-coding chromatin regions opened during senescence and altered in human cancers. We will develop tools to genetically modulate these elements-using engineered transcription factor variants or CRISPR-based approaches-and assess their role in senescence induction in response to oncogenes or cancer therapies. Finally, we will evaluate the therapeutic potential of chromatin-opening strategies by testing drugs that reopen chromatin to restore or reinforce senescence, using pancreatic cancer cell lines, patient-derived organoids, and xenograft models in mice. This work will reveal a novel role for the non-coding genome in senescence and cancer and open a new avenue for therapy based on chromatin-opening agents to strengthen tumor suppression.