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Montagner, Marco (2009) Role of TGFbeta and mutant-p53 in metastasis control. [Tesi di dottorato]

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Abstract (inglese)

TGFbeta ligands act as tumor suppressors in early stage tumors but are paradoxically diverted into potent prometastatic factors in advanced cancers. The molecular nature of this switch remains enigmatic. Here we show the workings of a previously undescribed pathway by which TGFbeta fosters cell migration, invasion and metastasis. We found that TGFbeta, together with oncogenic Ras and mutant-p53, but notably neither of these factors alone, is required for the assembly of a mutant- p53/Smad biochemical complex that binds p63, antagonizing its antimetastatic properties. In vitro, mutant-p53 is required to empower TGFbeta-dependent invasion and migration and p63 is epistatic for these effects. Mechanically, Smad proteins bridge mutant-p53 to p63, allowing the former to inhibit the DNA binding of the latter, blocking the transcriptional activation of its downstream targets. In vivo, loss-of-mutant-p53, or gain-of p63, disables TGFbeta-driven metastatic spread. Conversely, inhibition of p63 transforms noninvasive cells into motile-invasive cells. By transcriptomic analyses, functional validation and clinical verification we found two novel candidate metastasis suppressor genes downstream of this pathway associated with metastasis risk in a large cohort of breast cancer patients. Together, these results support a model in which the combination of two common oncogenic lesions, mutant-p53 and Ras, selected in early neoplasms to promote growth and survival, also prefigure a cellular set-up with particular metastasis proclivity. This trait can be exploited later during progression to drive a metastatic switch, once cells gain access to high levels of TGFbeta, either autonomously produced or extracted from the microenvironment.

Abstract (italiano)

I ligandi della famiglia TGFbeta agiscono come oncosoppressori nei primi stadi della tumorigenesi, ma paradossalmente sono mutati in fattori prometastatici nei tumori avanzati. La natura molecolare di questo cambiamento rimane enigmatica. In questo lavoro presentiamo il funzionamento di una via di segnale mai caratterizzata attraverso cui TGFbeta stimola la migrazione cellulare, l’invasione tumorale e la metastasi. Abbiamo scoperto che TGFbeta, assieme a p53 mutante e ad un’attivazione aberrante di Ras, è richiesto per l’assemblamento di un complesso biochimico p53-mutante/Smad, che lega p63, antagonizzando la sua attività anti-metastatica. Questo fenomeno non si osserva con nessuno dei tre fattori singolarmente. In vitro, p53 mutante è richiesta per permettere una migrazione cellulare indotta da TGFbeta e p63 è epistatica a questo effetto. Meccanicisticamente, le proteine Smad fanno da ponte tra p53 mutante e p63, consentendo alla prima di bloccare il dominio di interazione al DNA della seconda, inibendo in questo modo l’attivazione trascrizionale dei geni bersaglio. In vivo, la perdita di p53 mutante, o l’acquisto di p63, disattivano la diffusione metastatica promossa da TGFbeta. Dall’altra parte, l’inibizione di p63 trasforma cellule non invasive in invasive. Per mezzo di analisi del trascrittoma, validazione funzionale e clinica abbiamo scoperto due nuovi geni soppressori delle metastasi che agiscono a valle di questa cascata di eventi e che sono associati a rischio di metastasi in una significativa coorte di pazienti con cancro alla mammella. Sommati, questi risultati supportano un modello in cui la combinazione di due lesioni oncogeniche frequenti, p53 mutante e Ras, selezionate negli stadi precoci dei tumori per promuovere la sopravvivenza e la crescita, favoriscano uno scenario con una particolare tendenza alla metastasi. Questo tratto può essere sfruttato successivamente durante la progressione tumorale per indurre un comportamento metastatico, una volta che le cellule entrano in contatto con alti livelli di TGFbeta prodotto autonomamente o dall’ambiente circostante.

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Tipo di EPrint:Tesi di dottorato
Relatore:Piccolo, Stefano
Dottorato (corsi e scuole):Ciclo 21 > Scuole per il 21simo ciclo > BIOCHIMICA E BIOTECNOLOGIE > BIOTECNOLOGIE
Data di deposito della tesi:27 Gennaio 2009
Anno di Pubblicazione:2009
Parole chiave (italiano / inglese):TGF?, mutant p53, p63, metastasis, breast cancer
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Struttura di riferimento:Dipartimenti > Dipartimento di Istologia, Microbiologia e Biotecnologie Mediche
Codice ID:1498
Depositato il:27 Gen 2009
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