E-Poster Presentation 33rd Lorne Cancer Conference 2021

Investigating the role of mutant TRP53 in the development and sustained growth of tumours (#127)

Elizabeth Lieschke 1 2 , Andrew Kueh 1 2 , Marco Herold 1 2 , Catherine Chang 1 , Gemma Kelly 1 2 3 , Andreas Strasser 1 2 3
  1. The Walter and Eliza Hall Institute, Parkville, VIC, Australia
  2. Medical Biology, The University of Melbourne, Melbourne
  3. GK and AS contributed equally to this work,

Mutations in the tumour suppressor gene, TP53, occur in ~50% of all human cancers. Many of these mutations cause TP53 protein to be stabilised abnormally and accumulate in cells. It has been proposed that mutant TP53 exhibits functions that are different from those of wild-type TP53. It is still unclear what impact these functions have on a cell undergoing neoplastic transformation, if they are impacted by cell type, and presence of other oncogenic lesions. Furthermore, it is unknown if these functions are required for sustained tumour growth, and response to anti-cancer therapies. Given its high mutation rate, and the increased difficulty in treating these cancers, the thought of targeting mutant TP53 for cancer therapy has been an exciting prospect. However, answers to the above questions are required for effective treatments to be designed.

 

In this study, using CRISPR-based genome editing, we have generated a switchable mutant Trp53 (Trp53 is TP53 in mice) mouse model that encodes wild-type TRP53 in all cells of the body from conception. After FLP-mediated gene recombination, expression of mutant TRP53 protein is switched on in specifically targeted cells. Following CRE recombination wild-type TRP53 protein expression can be restored. This allows us to investigate the role of a mutant TRP53 in both tumorigenesis and sustained tumour growth.

We are currently investigating the role of this Trp53 mutation in the development of lymphomas by crossing this mouse model onto an Eµ-Myc background, where mice spontaneously develop lymphomas that are accelerated by loss or mutation of Trp53. We will also expand these studies to other cancer models, including lung cancer.

This switchable mutant Trp53 mouse model has the potential to answer some of the most important open questions in the field, such as whether deleting mutant TRP53 protein or restoring wild-type TRP53 function will have an effect on tumour growth; the answers to which will inform on the development of novel, improved therapies for cancers with defects in TRP53.