Neo-morphic missense mutant p53 proteins and the co-drivers promoting cell invasion
2019
Phenotypic and molecular profiling demonstrates a high
degree of heterogeneity in the breast tumors. TP53 tumor suppressor
is mutated in 30% of all breast tumors and the mutation frequency
in basal-like subtype is as high as 80% and co-exists with several
other somatic mutations in different genes. It was hypothesized
that tumor heterogeneity is a result of a combination of
neo-morphic functions of specific TP53 driver mutations and
distinct co-mutations or the co-drivers for each type of TP53
mutation. The 10 most common p53 missense mutant proteins found in
breast cancer patients were ectopically expressed in normal-like
mammary epithelial cells and phenotypes associated with various
hallmarks of cancer examined. Supporting the hypothesis, a wide
spectrum of phenotypic changes in cell survival, resistance to
apoptosis and anoikis, cell migration, invasion and polarity was
observed in the mutants compared to wildtype p53 expressing cells.
The missense mutants R248W, R273C and Y220C were most aggressive.
Integrated analysis of ChIP and RNA seq showed distinct promoter
binding profiles of the p53 mutant proteins different than wildtype
p53, implying altered transcriptional activity of mutant p53
proteins and the phenotypic heterogeneity of tumors. Enrichment and
model-based pathway analyses revealed dysregulated adherens
junction and focal adhesion pathways associated with the aggressive
p53 mutants. As several somatic mutations co-appear with mutant
TP53, we performed a functional assay to fish out the relevant
collaborating driver mutations, the co-drivers. When PTEN was
deleted by CRISPR-Cas9 in non-invasive p53-Y234C mutant cell, an
increase in cell invasion was observed justifying the concept of
co-drivers. A genome wide CRISPR library-based screen on p53-Y234C
and R273C cells identified separate candidate co-driver mutations
that promoted cell invasion. The top candidates included several
mutated genes in breast cancer patients harboring TP53 mutations
and were associated with cytoskeletal and apoptosis resistance
pathways. Overall, the combined approach of molecular profiling and
functional genomics screen highlighted distinct sets of co-driver
mutations that can lead to heterogeneous phenotypes and promote
aggressiveness in cells with different TP53 mutation background,
which can guide development of novel targeted
therapies.
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