Mutant p53 induces Golgi tubulo-vesiculation driving a prometastatic secretome

被引：60

作者：

Capaci, Valeria ^{[1
]}

Bascetta, Lorenzo ^{[1
,2
]}

Fantuz, Marco ^{[1
,2
]}

Beznoussenko, Galina, V ^{[3
]}

Sommaggio, Roberta ^{[4
]}

Cancila, Valeria ^{[5
]}

Bisso, Andrea ^{[1
,12
]}

Campaner, Elena ^{[1
,6
]}

Mironov, Alexander A. ^{[3
]}

Wisniewski, Jacek R. ^{[7
]}

Severino, Luisa Ulloa ^{[6
]}

Scaini, Denis ^{[2
]}

Bossi, Fleur ^{[6
]}

Lees, Jodi ^{[8
]}

Alon, Noa ^{[8
]}

Brunga, Ledia ^{[8
]}

Malkin, David ^{[8
,9
]}

Piazza, Silvano ^{[1
]}

Collavin, Licio ^{[1
,6
]}

Rosato, Antonio ^{[4
,10
]}

Bicciato, Silvio ^{[11
]}

Tripodo, Claudio ^{[5
]}

Mantovani, Fiamma ^{[1
,6
]}

Del Sal, Giannino ^{[1
,3
,6
]}

机构：

[1] Lab Nazl CIB LNCIB, I-34149 Trieste, Italy

[2] Int Sch Adv Studies SISSA, I-34146 Trieste, Italy

[3] Fdn Ist FIRC Oncol Mol IFOM, I-20139 Milan, Italy

[4] IRCCS, Veneto Inst Oncol IOV, I-35128 Padua, Italy

[5] Univ Palermo, Sch Med, Dept Hlth Sci, Tumor Immunol Unit,Human Pathol Sect, I-90133 Palermo, Italy

[6] Univ Trieste, Dipartimento Sci Vita, I-34127 Trieste, Italy

[7] Max Planck Inst Biochem, Dept Prote & Signal Transduct, D-85152 Martinsried, Germany

[8] Hosp Sick Children, Genet & Genome Biol Program, Toronto, ON, Canada

[9] Univ Toronto, Dept Pediat, Toronto, ON, Canada

[10] Univ Padua, Dept Surg Oncol & Gastroenterol, I-35128 Padua, Italy

[11] Univ Modena Arid Reggio Emilia, Ctr Genome Res, I-41125 Modena, Italy

[12] IRCCS, European Inst Oncol, IEO, Dept Expt Oncol, I-20141 Milan, Italy

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

关键词：

TOTAL PROTEIN; CANCER; CELLS; TUMOR; SIGNATURE; TRAFFICKING; METASTASIS; EXPRESSION; MICRORNAS; CHAPERONE;

D O I：

10.1038/s41467-020-17596-5

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

TP53 missense mutations leading to the expression of mutant p53 oncoproteins are frequent driver events during tumorigenesis. p53 mutants promote tumor growth, metastasis and chemoresistance by affecting fundamental cellular pathways and functions. Here, we demonstrate that p53 mutants modify structure and function of the Golgi apparatus, culminating in the increased release of a pro-malignant secretome by tumor cells and primary fibroblasts from patients with Li-Fraumeni cancer predisposition syndrome. Mechanistically, interacting with the hypoxia responsive factor HIF1 alpha, mutant p53 induces the expression of miR-30d, which in turn causes tubulo-vesiculation of the Golgi apparatus, leading to enhanced vesicular trafficking and secretion. The mut-p53/HIF1 alpha/miR-30d axis potentiates the release of soluble factors and the deposition and remodeling of the ECM, affecting mechano-signaling and stromal cells activation within the tumor microenvironment, thereby enhancing tumor growth and metastatic colonization. p53 mutants can promote tumorigenesis by affecting fundamental cellular pathways and functions. In this study, the authors demonstrate a novel mutant-p53/HIF1 alpha/miR-30d axis that impacts Golgi structure, trafficking, and secretion of proteins essential for tumor growth and metastasis.

引用

页数：19

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