<jats:title>Abstract</jats:title><jats:p>Although p53 protein aggregates have been observed in cancer cell lines and tumour tissue, their impact in cancer remains largely unknown. Here, we extensively screened for p53 aggregation phenotypes in tumour biopsies, and identified nuclear inclusion bodies (<jats:styled-content style="fixed-case">nIBs</jats:styled-content>) of transcriptionally inactive mutant or wild‐type p53 as the most frequent aggregation‐like phenotype across six different cancer types. p53‐positive <jats:styled-content style="fixed-case">nIBs</jats:styled-content> co‐stained with nuclear aggregation markers, and shared molecular hallmarks of <jats:styled-content style="fixed-case">nIBs</jats:styled-content> commonly found in neurodegenerative disorders. In cell culture, tumour‐associated stress was a strong inducer of p53 aggregation and <jats:styled-content style="fixed-case">nIB</jats:styled-content> formation. This was most prominent for mutant p53, but could also be observed in wild‐type p53 cell lines, for which <jats:styled-content style="fixed-case">nIB</jats:styled-content> formation correlated with the loss of p53's transcriptional activity. Importantly, protein aggregation also fuelled the dysregulation of the proteostasis network in the tumour cell by inducing a hyperactivated, oncogenic heat‐shock response, to which tumours are commonly addicted, and by overloading the proteasomal degradation system, an observation that was most pronounced for structurally destabilized mutant p53. Patients showing tumours with p53‐positive <jats:styled-content style="fixed-case">nIBs</jats:styled-content> suffered from a poor clinical outcome, similar to those with loss of p53 expression, and tumour biopsies showed a differential proteostatic expression profile associated with p53‐positive <jats:styled-content style="fixed-case">nIBs</jats:styled-content>. p53‐positive <jats:styled-content style="fixed-case">nIBs</jats:styled-content> therefore highlight a malignant state of the tumour that results from the interplay between (1) the functional inactivation of p53 through mutation and/or aggregation, and (2) microenvironmental stress, a combination that catalyses proteostatic dysregulation. This study highlights several unexpected clinical, biological and therapeutically unexplored parallels between cancer and neurodegeneration. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</jats:p>