Nuclear inclusion bodies of mutant and wild-type p53 in cancer: a hallmark of p53 inactivation and proteostasis remodeling by p53 aggregation.

Smet F, Rubio MS, Hompes D, Naus E, De Baets G, Langenberg T, Hipp MS, Houben B, Claes F, Charbonneau S, Blanco JD, Plaisance S, Ramkissoon S, Ramkissoon L, Simons C, van den Brandt P, Weijenberg M, Van England M, Lambrechts S, Amant F, D'Hoore A, Ligon KL, Sagaert X, Schymkowitz J, Rousseau F; J Pathol. 2016 Dec 30;:

Although p53 protein aggregates have been observed in cancercell lines and tumour tissue, their impact in cancer remains largely unknown.Here, we extensively screened for p53 aggregationphenotypes in tumour biopsiesand identified nuclear inclusion bodies (nIBs) of transcriptionally inactivemutant or wild-type p53 as the most frequent aggregation-like phenotype across sixdifferent cancer types. p53-positive nIBs co-stained with nuclear aggregationmarkers and shared molecular hallmarks of nIBs commonly found inneurodegenerative disorders. In cellculture, tumour-associated stress was a stronginducer of p53 aggregation and nuclear inclusion body formation. This wasmost prominent for mutant p53, but could also be observed in wild-type p53 celllines for which nIB formation correlated to the loss of p53s transcriptionalactivity. Importantly, protein aggregation also fueled the dysregulation of theproteostasis network inthe tumour cell by inducing a hyper-activated, oncogenicheat-shock response to which tumours are commonly addicted, and by overloadingthe proteasomal degradation system, anobservation that was most pronouncedfor structurally destabilized mutant p53. Patients exhibiting tumours with p53-positivenIBs suffered from a poor clinical outcome similar to loss-of-p53-expression,and tumour biopsies displayed a differential proteostatic expression profileassociated to p53-nIBs. p53-positive nIBs therefore highlight a malignant stateof the tumour thatresults from the interplay between (i) the functionalinactivation of p53 through mutation and/or aggregation and (ii)microenvironmental stress, a combination that catalyses proteostaticdysregulation. This study highlights severalunexpected clinical, biologicaland therapeutically unexplored parallelsbetween cancer and neurodegeneration.

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