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Untitled ItemThe biology of mutant p53 associated cell-in-cell formation in cancer.

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posted on 2019-11-13, 11:09 authored by Hannah Mackay
A cell-in-cell (CIC) structure is formed when one viable cell becomes internalised within
a neighbouring cell. CIC structures have been observed in many human tumours, in
which their occurrence has been associated with high-grade disease or metastasis. On
the contrary, CIC structures have also been suggested to be anti-tumourigenic,
triggering death of matrix-detached cells. The findings presented here show how, in
adherent cancer cell lines, CIC structures form, and that this involves a mechanism of
live cell ‘phagocytic’ engulfment. Interestingly, mutant p53 status affects both the
frequency and subsequent outcomes of these structures. Internalised cells ultimately
either escaped, died, or divided and often appeared to physically interfere in the
cellular divisions of host cells. Host cells were observed to undergo failed and aberrant
division events upon disruption of cytokinesis due to the internalised cell. For cells
without p53, this lead to host cell death. In contrast, mutant p53 host cells survived
aberrant divisions, often becoming multinucleated and undergoing tripolar mitoses. In
tumour xenograft models, mutant p53/null p53 cell co-cultures which had increased
occurrence of CIC structures and also higher final tumour volume on average.
Furthermore, CIC structures were present in 50% of archival human lung cancers in a
cohort of 273 patients. CIC occurrence was an independent predictor of poor outcome,
and was also associated with mutant p53 expression, intra-tumour genomic
heterogeneity and genomic instability. These findings suggest that tumour cell
engulfment activity, in combination with mutant p53 status is pro-tumourigenic in lung
cancers.

History

Supervisor(s)

Patricia Muller; John Le Quesne

Date of award

2018-05-04

Author affiliation

Department of Cancer Studies

Awarding institution

University of Leicester

Qualification level

  • Doctoral

Qualification name

  • PhD

Language

en

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