The role of ANGEL2 in TP53-dependent tumor suppression

Project Summary ANGEL2 is an RNA-binding protein (RBP), and member of the catabolite repression 4 (CCR4) family of proteins, which are involved in the modulation of mRNA stability and translation. With clinical significance, decreased ANGEL2 expression across 17 different cancer types is correlated with both poor overall and

disease-free survival. However, the molecular mechanisms by which ANGEL2 modulates tumorigenesis have yet to be determined. Gene expression correlation analysis revealed a functional relationship between ANGEL2 and the tumor suppressor TP53. Consistently, ANGEL2 deficiency caused a substantial loss of TP53

expression and resulted in multicellular tumor spheroids adopting a stellate/invasive morphology. In addition, an ANGEL2-derived peptide increased TP53 expression and decreased multicellular tumor spheroid growth. TP53 is a transcription factor and stress sensor which plays an integral role in maintaining the genome.

Inactivation of TP53 occurs in more than 50% of human cancers, and is a hallmark of tumor progression and chemoresistance. It is therefore widely recognized that loss of wild-type TP53 expression/function is a driver of tumor progression. Consequently, determining the key modulators of TP53 is paramount for the understanding

of tumorigenesis and the development of the novel therapeutic approaches. This project aims to elucidate the role of ANGEL2 in TP53-dependent tumor suppression, and to determine if this pathway can be targeted to enhance wild-type TP53 expression and suppress tumor growth. Utilizing ANGEL2 knockout cell lines, coupled with xenograft and patient-derived organoid models, the effect of ANGEL2 on TP53

expression, and TP53-dependent tumor suppression will be determined. Moreover, the use of molecular and biophysical tools to design and modify ANGEL2-derived peptides to upregulate wild-type TP53 expression will be explored as a therapeutic approach for malignancies which carry wild-type TP53. These studies will guide the career development of Dr. Christopher Lucchesi by providing relevant

knowledge and skills obtained through collaborations and courses in molecular and biophysical techniques, 3D-organoid tumor modeling, peptide drug design, translational research and leadership skills. Dr. Lucchesi will also profit from the wealth of available resources at UC Davis to equip him with the necessary skillsets to

reach his career goals. Through training in this collaborative, ‘One Medicine’ environment, Dr. Lucchesi will be a competitive, independent investigator and a leader of a successful and productive research team.