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Abbasi, Nooshin (2015) Searching for molecular mechanisms sustaining tumor formation and progression in Neurofibromatosis type 1. [Ph.D. thesis]

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Abstract (english)

Neurofibromatosis type 1 (NF1, OMIM # 162200), also known as von Recklinghausen, is an autosomal dominant disease caused by mutations of the NF1 gene coding a 2818 amino acid protein, neurofibromin (Nf1). More than 900 different mutations in the NF1 gene have been identified (HGMD, Human Genetic Mutation Database). Mutations of NF1 gene cause a variety of clinical manifestations such as the optic gliomas, neoplasms of the haematopoietic system and learning disabilities. However, the hallmark of NF1 is the development of multiple benign peripheral nerve sheath tumors called neurofibromas. Neurofibromas are complex tumors arising from peripheral nerve sheaths and mainly composed of Schwann Cells (SCs) homozygous for mutated NF1, mast cells (MCs) and fibroblasts (FBRs) both heterozygous for the same mutation. The plexiform variety can progress to highly malignant sarcomas termed Malignant Peripheral Nerve Sheath Tumors (MPNSTs), which are almost invariably lethal.
Up to now, any effective therapy able to either reduces neurofibroma size and its incidence or to counteract its formation, has not been developed yet. The main feature of neurofibroma is a rigid structure due to massive deposition of collagen of different types by activated FBRs. These cells, named myofibroblasts (mFBRs), are massively stimulated by mast cell-secreting Transcription Growth Factor-Beta (TGF-Beta) to produce growth factors such as Platelet Growth Factor (PDGF), Fibroblast Growth Factor (FGF) and collagen. This leads to both potent SCs proliferation and deposition of rigid extracellular matrix (ECM).
Cells’ haploinsufficient for Nf1 display hyper-activation of Rat Sarcoma (Ras), which further increases when Loss of Heterozigozyty (LOH) of NF1 occurs. Thus, the activation of Ras/ Rapidly Accelerated Fibrosarcoma (Raf) /Extracellular signal-regulated Kinase (ERK) signaling in SCs is sufficient to make them more susceptible to proliferative signals provided by a NF1+/- niche. However, the physiological response to Ras hyper-activation is cell-cycle arrest and/or senescence rather than transformation. Ras-mediated transformation of SCs probably relies on a step-wise process that integrates circuits of amplification signals from the local niche. A major component of the niche is the ECM, a complex network of macromolecules whose the elasticity (ranging from soft to stiff and rigid),contributes to development and cancer. ECM elasticity determines how a cell senses and perceives external forces and thus provides a major environmental cue that determines cell behavior. Indeed, the focal adhesion complex, which consists of integrins, multicomplex of adaptors and signaling proteins, can be viewed as a mechanosensor linking the actomyosin cytoskeleton with the ECM. How lack of Nf1 may impact on the complexity of ECM-cell dynamic and how the great rigidity of the ECM in neurofibromas influences SCs’ behavior, is still unknown. Among the three functional domains described in the Nf1 protein, a Focal Adhesion Kinas (FAK) binding domain has been identified and Nf1 has been shown to interact with FAK, paving the way for the enunciation of new hypothesis aimed to explain the route of SCs transformation toward cancer.
Rational: as in other tumors {Lu, 2012 #289}, {Yu, 2011 #292}), also in the plexiform neurofibromas, the tumorigenic phenotype of SCs is fostered by the amplification of integrated signaling pathways triggered by loss of Nf1, Ras hyper activation and deregulated ECM. Changes of the mechanical properties of ECM due to increased collagen secretion by mFBRs might actively contribute to tumor progression by influencing gene expression profile of the cells through the enhancement of Ras signaling pathway triggered by FAK. The deep investigation of these biological changes triggered in SCs by ECM formation is the goal of the present project.
Project Goals: To shed light into this issue, we intend 1) to generate a novel three-dimensional experimental model in vitro reproducing the multicellular complexity of neurofibromas with primary cells. Immortalized cells, indeed, are not suitable for our aims since the molecular oncologists consider the immortalization process as the first hit leading to tumorigenic phenotype, because of the changes which made for cell cycle control in gene expression 2) to assess the requirement ECM for SCs transformation in this new in vitro system identifying the proper ECM composition and stiffness in matrigel (structural and non structural components) required for neurofibroma’s formation.
Isolation of primary SCs and FBRs from Neurofibromas and their biological characterization:
1) We have already isolated and cultured in 2D our SCs and FBRs NF1+/- according to Serra methodology {Serra, 2000 #210}. These cells have been isolated from plexiform neurofibroma biopsies after informed consent of patients by our Milan and Rome University collaborators.
To get two populations of SCs and FBRs we have cultured cells in selective Medium (according to {Serra, 2000 #210}, and our new unpublished protocol) and characterized them biochemically by: S100B {Tucker, 2011 #321} and p75 markers specifically recognizing SCs and collagen I secretion, alpha smooth muscle actin (α-SMA) expression, Smad2/3 activation, Abl kinase activation characterizing mFBR activity {Kojima, 2010 #150}.
2) We have already obtained colonies of SCs growing in 3D in vitro system as described in step 1 and 2 (in transwell-like chambers to permit autocrine stimulation between mFBRs and SCs). Our preliminary data show that primary SCs generate colonies only when plated in an ECM/reconstituted basement membrane Collagen I-Matrigel of at list 3 mg/ml. However, we have still to set up the culture conditions to keep cells in highly proliferating state.
Preliminary indications in immortalized Mouse Embrionic Fibroblasts (MEFs)
In other cellular models as in mouse FBRs NF1-/-, we have found that the absence of Neurofibromin correlates with deregulation of FAK Y397 and Y925 phosphorylation both in absence of integrin clustering and after ligand stimulation. Further, the tumorigenesis assay showed that MEFNF1-/-ability to form colonies is affected by both MECK inhibitor and FAK inhibitor (Y15) indicating the cooperative role of FAK and PDGFBB growth factor in the tumorigenesis process mediated by Nf1. Consistently, immunoprecipitation experiments showed that in Nf1 null cells, Growth factor receptor-bound protein2 (Grb-2), the RAS pathway initiator, interacts with FAK also in absence of collagen in a PDGFBB ligand-dependent way, thus suggesting that FAK and growth factor receptors can cooperate to increase the Ras activity to a threshold required to induce tumorigenesis.

Abstract (italian)

Neurofibromatosi tipo 1 (NF1, OMIM # 162200), nota anche come di von Recklinghausen, è una malattia autosomica dominante causata da mutazioni del gene NF1 che codifica una proteina coi 2818 aminoacidi , detta neurofibromina (Nf). Più di 900 diverse mutazioni nel gene NF1 sono state identificate (HGMD, Database di mutazione genetica umana). Mutazioni del gene NF1 causano una varietà di manifestazioni cliniche quali il glioma ottico, neoplasie del sistema ematopoietico e disabilità dell'apprendimento. Tuttavia, il segno distintivo della NF1 è lo sviluppo dei tumori benigni nella guaina dei nervi periferici, chiamati neurofibromi. I neurofibromi sono tumori complessi originati da guaine nervose periferiche e costituiti prevalentemente da cellule di Schwann omozigote mutate per NF1, mastociti e fibroblasti entrambi eterozigoti per la stessa mutazione. I plessiformi possono progredire a sarcomi altamente maligni denominati MPNSTs (schwannomi maligni), che sono quasi sempre letali.
Ad oggi non e’ ancora stata sviluppata alcuna terapia efficace in grado di ridurre la dimensione e incidenza dei neurofibromi, o atta a contrastarne la formazione. La caratteristica principale dei neurofibromi è la loro struttura rigida conseguente alla massiccia deposizione di collagene prodotto dai fibroblasti attivati. Queste cellule, denominate miofibroblasti, sono fortemente stimolate da mastociti che producono fattore di crescita trascrizionale-Beta (TGF-Beta) per produrre poi fattori di crescita, come fattore di crescita piastrinico, fattore di crescita dei fibroblasti e collagene. Ciò comporta sia la potente proliferazione di cellule di Schwann che la deposizione di matrice extracellulare rigida.
Cellule aploinsufficienti per Nf1 comportano iperattivazione di Ras, che aumenta ulteriormente con LOH. L'attivazione di vie di segnale di Ras/Raf/ERK in cellule di Schwann rende le cellule più suscettibili ai segnali proliferativi forniti dalla nicchia NF1+/-. Tuttavia, la risposta fisiologica a Ras iperattivato è l’arresto del ciclo cellulare e/o senescenza piuttosto che trasformazione. La trasformazione Ras-mediata di cellule di Schwann probabilmente si basa su un procedimento che integra diversi segnali dipendenti da circuiti di amplificazione della nicchia stessa. Uno dei più importanti componenti della nicchia è la matrice extracellulare (ECM), una rete complessa di macromolecole con plasticità variabile che contribuisce alla progressione tumorale. L’elasticità di ECM determina la modalità con cui una cellula percepisce le forze esterne e quindi fornisce un importante spunto ambientale che determina il comportamento cellulare. In effetti le adesioni focali, che consistono di integrine, adattatori multicomplesi e proteine di segnale, possono essere visti come meccano-sensori che collegano il citoscheletro con la ECM. Come la mancanza di Nf1 possa avere un impatto significativo sulla complessità di dinamismo di ECM-cellula o come la grande rigidezza dell'ECM in neurofibroma influenzi il comportamento delle cellule di Schwann, è ancora sconosciuto. Tra i tre domini funzionali descritti nella proteina, un dominio di legame, FAK, sulla proteina è stato identificato e Nf1 ha mostrato di interagire con FAK, spianando la strada per l'enunciazione di una nuova ipotesi per spiegare il percorso trasformazionale delle cellule di Schwann verso il cancro.
Razionale: come in altri tumori {Lu, 2012 #289}, {Yu, 2011 #292}), anche nei neurofibromi plessiformi il fenotipo trasformato di SCs è favorito dall'amplificazione della segnalazione di percorsi integrati attivati sia da perdita di Nf1, Ras iperattivazione che deregolamentato di matrice extracellulare (ECM). Le modifiche delle proprietà meccaniche di ECM a causa dell'aumento di secrezione di collagene dai miofibroblasti potrebbe contribuire attivamente alla progressione del tumore, influenzando profili di espressione genica delle cellule attraverso la valorizzazione di segnale di Ras pathway generato dall'adesione focale (FAK). L'indagine in profondità di queste modificazioni biologiche attivate in SCs dalla formazione di ECM è l'obiettivo del presente progetto.
Al fine di far luce su questo argomento, abbiamo intenzione di 1) generare un nuovo modello sperimentale tridimensionale in vitro che riproduce la complessità di neurofibroma pluricellulari con le cellule primarie. Cellule immortalizzate, infatti, non sono adatte per i nostri scopi poiché gli oncologi molecolari consideranno il processo di immortalizzazione come il primo colpo che conduce al fenotipo oncogenico, a causa dei cambiamenti che sono stati fatti per il controllo del ciclo cellulare di espressione genica; 2) valutare l'esigenza di ECM nella trasformazione di cellule di Schwann cell (SCs) in questo nuovo sistema in vitro identificando la corretta composizione dell'ECM e rigidità in matrigel (strutturali e non strutturali) per formazione di neurofibroma.
Isolamento delle cellule di Schwann e Fibroblasti primarie da Neurofibromi e la loro caratterizzazione biologica:
1) Abbiamo già isolato e coltivato in 2D le nostre cellule di Schwann e Fibroblasti NF1+/- secondo la metodologia di Serra {Serra, 2000 #210}. Queste cellule sono state isolate da biopsie di neurofibromi plessiformi dopo aver consenso informato dei pazienti mediante i nostri collaboratori presso Università di Milano e di Roma.
Per ottenere due popolazioni delle cellule di Schwann e Fibroblasti abbiamo coltivato le cellule in terreno selettivo (secondo {Serra, 2000 #210}, e il nostro nuovo protocollo inedito) e caratterizzato dal punto di vista biochimico: S100B {Tucker, 2011 #321} e p75 marcatori che riconoscono specificamente le cellule di Schwann e secrezione del collagene di tipo I, espressione dell’actìna alfa del muscolo liscio (α-SMA), attivazione di Smad2/3, attivazione di abl chinasi e caratterizzare l'attività di myo-fibroblasti {Kojima, 2010 #150}.
2) abbiamo già ottenuto le colonie di cellule di Schwann cresciute nel sistema 3D in vitro come descritto nella fase 1 e 2 (in transwell-like chamber per permettere la stimolazione autocrina tra myofibroblasti e le cellule di Schwann). I nostri dati preliminari mostrano che le cellule primarie di Schwann generano delle colonie solo quando piastrate in una ECM/ membrana basale ricostituita del collagene di tipo I di Matrigel di almeno 3 mg/ml. Tuttavia, dobbiamo ancora impostare le condizioni migliori di cultura per mantenere le cellule altamente proliferanti.
Indicazioni preliminari in fibroblasti Embrionali immortalati Murini (MEFs)
In altri modelli cellulari come nel fibroblasti NF1-/- murini (MEFs), abbiamo trovato che l'assenza di neurofibromina scorrela con la deregolata di fosforilazione del FAK in Y397 e Y925 sia in assenza di raggruppamento di integrine che dopo la stimolazione con ligando. Inoltre, il saggio di tumorigenesi mostrava che la capacità di cellule di MEFNf1-/- di formare colonie è influenzata sia da inibitore di MECK che inibitore FAK Y15 indicante il ruolo di cooperatzione di FAK e PDGFBB, fattore di crescita, nel processo di tumorigenesi mediato da NF1. Coerentemente, gli esperimenti di immunoprecipitazione hanno mostrato che in cellule null NF1, il recettore del fattore di crescita di proteina legata2 (Grb-2), l’iniziatore di via di segnale di RAS, interagisce con FAK anche in assenza di collagene in un modo PDGFBB ligando-dipendente, suggerendo così che FAK e recettori di fattori di crescita possono cooperare per aumentare l'attività di Ras con un valore di soglia necessario per indurre la tumorigenesi.

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EPrint type:Ph.D. thesis
Tutor:Trevisan, Andrea and Chiara, Federica
Ph.D. course:Ciclo 28 > Scuole 28 > BIOMEDICINA > MEDICINA MOLECOLARE
Data di deposito della tesi:20 January 2016
Anno di Pubblicazione:20 January 2015
Key Words:Neurofibromatosis type 1 (NF1), Extra Cellular Matrix (ECM), Focal Adhesion Kinase (FAK), Schwann Cells (SCs), Fibroblasts (FBRs), myoFibroblasts (mFBRs), Collagne I
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina Molecolare
Codice ID:9048
Depositato il:21 Oct 2016 09:53
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