Endocytic Control of Cell-Autonomous and Non-Cell-Autonomous Functions of p53

Roberta Cacciatore; Andrea Basile; Stefano Freddi; Irene Schiano Lomoriello; Carlo Ribelle Zucca; Giuseppe Ciossani; Luigi Scietti; Alessandro Cuomo; Simona Ronzoni; Simone Pelicci; Mario Faretta; Elena Zaccheroni; Giuliana Pelicci; Vittoria Matafora; Angela Bachi; Rosalind Helen Gunby; Salvatore Pece; Sara Sigismund; Letizia Lanzetti; Ivan Nicola Colaluca; Pier Paolo Di Fiore

doi:10.1002/advs.202513765

Endocytic Control of Cell-Autonomous and Non-Cell-Autonomous Functions of p53

Roberta Cacciatore
, Andrea Basile
, Stefano Freddi
, Irene Schiano Lomoriello
, Carlo Ribelle Zucca
, Giuseppe Ciossani
, Luigi Scietti
, Alessandro Cuomo
, Simona Ronzoni
, Simone Pelicci
, Mario Faretta
, Elena Zaccheroni
, Giuliana Pelicci
, Vittoria Matafora
, Angela Bachi
, Rosalind Helen Gunby
, Salvatore Pece
, Sara Sigismund
, Letizia Lanzetti
, Ivan Nicola Colaluca

Pier Paolo Di Fiore

Department of Translational Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

NUMB is an endocytic protein with tumor suppressor activity, largely mediated by its ability to inhibit p53 degradation. This function depends on the inclusion of a short alternatively spliced exon (Ex3) in NUMB, although the mechanistic link between endocytosis and p53 regulation remains unclear. Here, we show that the Ex3-encoded sequence directs NUMB to the plasma membrane, where it forms a complex with the endocytic adaptor SNX9. This complex recruits p53 in an SNX9-dependent manner and is internalized and trafficked to multivesicular bodies, culminating in exosomal secretion, in a process requiring both SNX9 and NUMB. Exosomal p53 is taken up by recipient cells and translocated to the nucleus, where it activates p53-dependent transcriptional and phenotypic programs. These findings suggest that exosome-mediated p53 transfer may contribute to the establishment of a tumor-suppressive microenvironment.

Original language	English
Article number	e13765
Journal	Advanced Science
Volume	13
Issue number	30
DOIs	https://doi.org/10.1002/advs.202513765
Publication status	Published - 28 May 2026

Keywords

NUMB
SNX9
exosomes
non-cell-autonomous
p53

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10.1002/advs.202513765

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Cacciatore, R., Basile, A., Freddi, S., Schiano Lomoriello, I., Zucca, C. R., Ciossani, G., Scietti, L., Cuomo, A., Ronzoni, S., Pelicci, S., Faretta, M., Zaccheroni, E., Pelicci, G., Matafora, V., Bachi, A., Gunby, R. H., Pece, S., Sigismund, S., Lanzetti, L., ... Di Fiore, P. P. (2026). Endocytic Control of Cell-Autonomous and Non-Cell-Autonomous Functions of p53. Advanced Science, 13(30), Article e13765. https://doi.org/10.1002/advs.202513765

@article{65525255f7c54a6f84ba89aea40334c6,

title = "Endocytic Control of Cell-Autonomous and Non-Cell-Autonomous Functions of p53",

abstract = "NUMB is an endocytic protein with tumor suppressor activity, largely mediated by its ability to inhibit p53 degradation. This function depends on the inclusion of a short alternatively spliced exon (Ex3) in NUMB, although the mechanistic link between endocytosis and p53 regulation remains unclear. Here, we show that the Ex3-encoded sequence directs NUMB to the plasma membrane, where it forms a complex with the endocytic adaptor SNX9. This complex recruits p53 in an SNX9-dependent manner and is internalized and trafficked to multivesicular bodies, culminating in exosomal secretion, in a process requiring both SNX9 and NUMB. Exosomal p53 is taken up by recipient cells and translocated to the nucleus, where it activates p53-dependent transcriptional and phenotypic programs. These findings suggest that exosome-mediated p53 transfer may contribute to the establishment of a tumor-suppressive microenvironment.",

keywords = "NUMB, SNX9, exosomes, non-cell-autonomous, p53",

author = "Roberta Cacciatore and Andrea Basile and Stefano Freddi and \{Schiano Lomoriello\}, Irene and Zucca, \{Carlo Ribelle\} and Giuseppe Ciossani and Luigi Scietti and Alessandro Cuomo and Simona Ronzoni and Simone Pelicci and Mario Faretta and Elena Zaccheroni and Giuliana Pelicci and Vittoria Matafora and Angela Bachi and Gunby, \{Rosalind Helen\} and Salvatore Pece and Sara Sigismund and Letizia Lanzetti and Colaluca, \{Ivan Nicola\} and \{Di Fiore\}, \{Pier Paolo\}",

note = "Publisher Copyright: {\textcopyright} 2026 The Author(s). Advanced Science published by Wiley-VCH GmbH.",

year = "2026",

month = may,

day = "28",

doi = "10.1002/advs.202513765",

language = "English",

volume = "13",

journal = "Advanced Science",

issn = "2198-3844",

publisher = "John Wiley and Sons Inc.",

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Cacciatore, R, Basile, A, Freddi, S, Schiano Lomoriello, I, Zucca, CR, Ciossani, G, Scietti, L, Cuomo, A, Ronzoni, S, Pelicci, S, Faretta, M, Zaccheroni, E, Pelicci, G, Matafora, V, Bachi, A, Gunby, RH, Pece, S, Sigismund, S, Lanzetti, L, Colaluca, IN & Di Fiore, PP 2026, 'Endocytic Control of Cell-Autonomous and Non-Cell-Autonomous Functions of p53', Advanced Science, vol. 13, no. 30, e13765. https://doi.org/10.1002/advs.202513765

TY - JOUR

T1 - Endocytic Control of Cell-Autonomous and Non-Cell-Autonomous Functions of p53

AU - Cacciatore, Roberta

AU - Basile, Andrea

AU - Freddi, Stefano

AU - Schiano Lomoriello, Irene

AU - Zucca, Carlo Ribelle

AU - Ciossani, Giuseppe

AU - Scietti, Luigi

AU - Cuomo, Alessandro

AU - Ronzoni, Simona

AU - Pelicci, Simone

AU - Faretta, Mario

AU - Zaccheroni, Elena

AU - Pelicci, Giuliana

AU - Matafora, Vittoria

AU - Bachi, Angela

AU - Gunby, Rosalind Helen

AU - Pece, Salvatore

AU - Sigismund, Sara

AU - Lanzetti, Letizia

AU - Colaluca, Ivan Nicola

AU - Di Fiore, Pier Paolo

PY - 2026/5/28

Y1 - 2026/5/28

N2 - NUMB is an endocytic protein with tumor suppressor activity, largely mediated by its ability to inhibit p53 degradation. This function depends on the inclusion of a short alternatively spliced exon (Ex3) in NUMB, although the mechanistic link between endocytosis and p53 regulation remains unclear. Here, we show that the Ex3-encoded sequence directs NUMB to the plasma membrane, where it forms a complex with the endocytic adaptor SNX9. This complex recruits p53 in an SNX9-dependent manner and is internalized and trafficked to multivesicular bodies, culminating in exosomal secretion, in a process requiring both SNX9 and NUMB. Exosomal p53 is taken up by recipient cells and translocated to the nucleus, where it activates p53-dependent transcriptional and phenotypic programs. These findings suggest that exosome-mediated p53 transfer may contribute to the establishment of a tumor-suppressive microenvironment.

AB - NUMB is an endocytic protein with tumor suppressor activity, largely mediated by its ability to inhibit p53 degradation. This function depends on the inclusion of a short alternatively spliced exon (Ex3) in NUMB, although the mechanistic link between endocytosis and p53 regulation remains unclear. Here, we show that the Ex3-encoded sequence directs NUMB to the plasma membrane, where it forms a complex with the endocytic adaptor SNX9. This complex recruits p53 in an SNX9-dependent manner and is internalized and trafficked to multivesicular bodies, culminating in exosomal secretion, in a process requiring both SNX9 and NUMB. Exosomal p53 is taken up by recipient cells and translocated to the nucleus, where it activates p53-dependent transcriptional and phenotypic programs. These findings suggest that exosome-mediated p53 transfer may contribute to the establishment of a tumor-suppressive microenvironment.

KW - NUMB

KW - SNX9

KW - exosomes

KW - non-cell-autonomous

KW - p53

UR - https://www.scopus.com/pages/publications/105028993239

U2 - 10.1002/advs.202513765

DO - 10.1002/advs.202513765

M3 - Article

SN - 2198-3844

VL - 13

JO - Advanced Science

JF - Advanced Science

IS - 30

M1 - e13765

ER -

Endocytic Control of Cell-Autonomous and Non-Cell-Autonomous Functions of p53

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Keywords

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