Poster Presentation 25th Lorne Cancer Conference 2013

Combined targeted expression of the Pik3caH1047R and Apc mutations in the gastrointestinal tract causes invasive adenocarcinomas (#199)

Lauren M Hare 1 , Karen G Montgomery 1 , Kevin Mills 1 , Toby J Phesse 2 , Mattias Ernst 2 , Rob G Ramsay 1 , Wayne A Phillips 1
  1. Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
  2. Cell Signalling and Cell Death, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia

The PI3K/Akt signalling cascade has an important role in critical cellular processes known to function aberrantly in pathological conditions, including cancer. Mutations in the PIK3CAgene, which encodes the p110α catalytic subunit of the PI3K enzyme, have been detected in up to 30% of colorectal cancers (CRCs). The majority of CRCs undergo a distinct multistage pathogenesis from aberrant crypts to adenomas and eventually invasive carcinomas and metastases. Yet, it is not known at which stage PIK3CAmutations occur. One common aberration is the Pik3caH1047R mutation for which we have developed a novel mouse model. This model possesses a conditional Cre recombinase (Cre) inducible Pik3caH1047R mutation.  Prior to excision, the wildtype allele is normally expressed however, upon the introduction of Cre, the wildtype allele is removed and the latent mutant allele is now expressed by the endogenous promoter and thus at physiologically relevant levels in otherwise wildtype cells.

This novel mouse model was used to assess the role of the Pik3caH1047R mutation at CRC initiation, progression and metastasis. Expression of the Pik3caH1047R mutation was targeted to the gastrointestinal tract using the RU486 inducible A33CrePR2 mouse whose Cre expression is under the control of the gastrointestinal specific gpa33 locus. The result is the induction of Pik3caH1047R in A33-expressing cells of the gastrointestinal tract. Expression of the Pik3caH1047R mutation alone was unable to initiate CRC. Using the Cre inducible Apc580D/580D mouse, expression of the Pik3caH1047R mutation in combination with loss of the Adenomatous Polyposis Coli (Apc) gene, known to cause colon adenomas, resulted in progression to invasive adenocarcinomas. This is the first mouse model of colorectal adenocarcinoma as a result of the endogenous expression of the Pik3caH1047R in synergism with Apc deletion and suggests that Pik3ca mutations have a role in the later stages of colorectal carcinogenesis.