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Menegollo, Michela (2017) Specific mitochondrial biogenesis patterns drive nutrient choice in breast cancer subtypes. [Ph.D. thesis]

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Abstract (english)

Transformed cells undergo profound reprogramming of cellular metabolism to ensure high rate of proliferation (Hanahan D, 2011). Mitochondria are important for both bioenergetics and biosynthetic pathways, which have to be coordinated. Different cancer types heterogeneously express mitochondrial genes likely reflecting the existence of different mitochondrial pathways providing adaptation to altered needs of cancer cell metabolism. In this work we explored this hypothesis in breast cancer.
Breast cancer is heterogeneous disease classified according to diverse clinical and pathological features, histochemical markers and oncogenic transcriptional programs, that identify five breast cancer subtypes (basal-like, Her2-enriched, Luminal A, Luminal B and normal-like) (Sørlie T et al., 2001; Perou CM et al., 2000). So far, the mitochondrial transcriptional patterns were not considered as a basis of classification.
In this work we define for the first time breast cancer Mitochondrial Tumour Subtypes (MTSs), upper fork (UF) and lower fork (LF), according to their nuclear-encoded mitochondrial transcription profile. UF and LF are characterised by two groups of mitochondrial genes co-regulated in opposite way. The classification was performed applying the MCbiclust algorithm (Bentham et al., 2016, preprint) to a mitochondrial gene set (MitoCarta, Pagliarini et al., 2008).
The experimental characterisation of UF and LF revealed distinct bioenergetics and metabolic features. Interestingly, in basal condition UF has higher mitochondrial content, characterised by higher expression of CI and CIV resulting in higher respiration rate. At cellular level metabolism, UF and LF revealed different arrangement of metabolic enzymes belonging to particular pathways of the intermediate metabolism, UF cells express enzymes of which substrates are glucose-derived, whereas LF cells preferentially use enzymes exploiting glutamine-derived substrates. Moreover, metabolic flux analysis confirmed the substrate preference driven by the MTSs to feed into the TCA cycle, in particular UF cells mitochondria prefer glucose derived pyruvate while LF mitochondria catabolise glutamine.
In addition, experiments in restricted nutrient conditions were carried out. These further confirmed which is the substrate preferentially used by MTSs to sustain cell functionality. Moreover, the same experiments also revealed the activation of different mitochondrial biogenesis programs during deprivation treatments, both looking at mitochondrial protein expression and mtDNA content.
Overall, the mitochondrial biogenesis pattern associated with the MTSs drives nutrient choice and metabolic program, leading to a definition of the concept of substrate preference, new insight in the field of reprogramming of bioenergetics and cancer metabolism.

Abstract (italian)

Le cellule tumorali vanno incontro a profonde modifiche del proprio metabolismo cellulare per assicurarsi un alto tasso di proliferazione (Hanahan D, 2011). I mitocondri sono una sede importante sia per la produzione di energia che per i processi biosintetici, pertanto queste vie devono essere opportunamente coordinate. Molti tipi di cancro esprimono geni mitocondriali in modo eterogeneo, questo probabilmente riflette l’esistenza di diverse vie mitocondriali in grado di fornire diverse capacità di adattamento ad un metabolismo alterato, come lo è il profilo metabolico associato ai tumori. In questo lavoro abbiamo esplorato questa ipotesi nel modello tumorale del cancro alla mammella.
Il cancro alla mammella rappresenta una malattia comunemente classificata sulla base di caratteristiche cliniche e patologiche, marcatori istochimici e programmi di trascrizione genica che identificano cinque sottotipi di tumore alla mammella (basal-like, Her2-enriched, Luminal A, Luminal B e normal-like) (Sørlie T et al., 2001; Perou CM et al., 2000). Tuttavia, l’espressione di geni mitocondriali non è stata finora considerata nella classificazione di questi tumori.
In questo lavoro definiamo per la prima volta sottotipi tumorali mitocondriali di cancro alla mammella (MTSs), upper fork (UF) e lower fork (LF), definiti sulla base del loro profilo di trascrizione di geni mitocondriali di codificazione nucleare regolati in modo opposto. La classificazione è stata fatta utilizzando l’algoritmo MCbiclust (Bentham et al., 2016, preprint) su un set di geni mitocondriali (MitoCarta, Pagliarini et al., 2008).
Dalla caratterizzazione sperimentale di UF e LF sono emerse caratteristiche bioenergetiche e metaboliche distintive. In particolare, in condizioni basali UF ha un maggiore contenuto mitocondriale, caratterizzato da una maggiore espressione dei complessi I e IV della catena respiratoria, che culmina in un tasso di respirazione maggiore. A livello di metabolismo cellulare, UF e LF mostrano un diverso assetto di enzimi metabolici appartenenti a particolari vie del metabolismo intermedio. In particolare le cellule dell’UF esprimono enzimi i cui substrati sono derivati dal glucosio, mentre le cellule di LF preferiscono utilizzare enzimi i cui substrati sono derivati dalla glutammina. Inoltre l’analisi dei flussi metabolici ha confermato la preferenza di substrato determinata dai MTSs
per alimentare il ciclo di Krebs. In particolare i mitocondri delle cellule dell’UF preferiscono il piruvato derivato dal glucosio, mentre i mitocondri di LF catabolizzano la glutammina.
In aggiunta, sono stati eseguiti esperimenti con concentrazioni di nutrienti ridotte, i quali, in accordo con i risultati precedenti, hanno ulteriormente confermato i substrati preferenzialmente utilizzati dai MTSs per sostenere la funzionalità cellulare. Inoltre gli stessi esperimenti hanno rivelato l’attivazione di diversi programmi di biogenesi mitocondriale indotti dai trattamenti, sia a livello di espressine di proteine mitocondriali che in termini di contenuto di DNA mitocondriale.
Complessivamente, il pattern di biogenesi mitocondriale associato ai sottotipi tumorali mitocondriali determina la scelta di nutrienti e programmi metabolici, portando così alla definizione del concetto di preferenza di substrato, il quale fornisce una nuova visione nel campo della riprogrammazione bioenergetica e metabolica del cancro e la possibilità di classificare sottotipi tumorali sulla base dell’espressione dei geni mitocondriali.

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EPrint type:Ph.D. thesis
Tutor:Szabadkai, Gyorgy
Ph.D. course:Ciclo 28 > Scuole 28 > BIOSCIENZE E BIOTECNOLOGIE > BIOLOGIA CELLULARE
Data di deposito della tesi:31 January 2017
Anno di Pubblicazione:January 2017
Key Words:Mitocondri, biogenesi, nutrienti, cancro alla mammella/mitochondria, biogenesis, nutrients, breast cancer
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/13 Biologia applicata
Area 06 - Scienze mediche > MED/04 Patologia generale
Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Area 05 - Scienze biologiche > BIO/12 Biochimica clinica e biologia molecolare clinica
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Dipartimenti > Dipartimento di Scienze Biomediche
Codice ID:10177
Depositato il:14 Nov 2017 15:30
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