Investigating the Mechanisms of Mutant-p53-Dependent Cell Engulfment in Cancer

Cell-in-cell (CIC) structures form when one cell becomes internalised within another. While this can occur in homeostasis, it is most prevalent in cancer, and is commonly associated with aggressive tumour types and poor patient prognoses. Two contrasting models explain the mechanisms of cancer CIC formation: cannibalism, a phagocytic-like process driven by the outer cell, and entosis, in which the internal cell actively invades into its host. However, distinction between these two models is often unclear in the literature, and the underlying molecular mechanisms are poorly defined. Our lab previously demonstrated that gain-of-function (GOF) mutations in the tumour suppressor, p53, promote CIC formation in cancer, with mutant p53 (mutp53) cells frequently assuming host cell fate. Based on live imaging, RhoA expression patterns, and FLIM analysis of membrane tension, we propose that mutp53-dependent engulfment is cannibalistic rather than entotic. We also demonstrate the role of SH3BGRL, a target gene of mutp53, in driving CIC formation and contributing to mutp53‘s GOF activity through anchorage-independent growth. Finally, immunofluorescence staining for SOX2 and ALDH1A1 indicates a possible association between CIC formation and cancer stemness. Together, these findings contribute to our understanding of the mechanisms of mutp53-dependent engulfment, and its potential impacts on worsening tumour progression.