In the recent decade, one of the important keynote message derived through the summation of our global efforts against cancer is the need to better understand cancer cell metabolism for the development of better and efficacious personalized therapy. Cancer cells undertake a multifaceted rewiring of metabolic pathways in order to support their proliferative and invasive nature, which requires a systems level investigation to fully comprehend the scale of metabolic deregulation. In this study, we systematically investigated the metabolic differences using untargeted metabolomics and 13C flux omics approach in oncogenic K-Ras driven tumours. We tested the effects of drug inhibitors targeting glucose and glutamine metabolism to unravel the alternative metabolic pathways required for cancer cell survival. We further expanded our research towards understanding the role of cellular metabolism in driving resistance to endocrine therapeutic drugs in ERα positive breast cancer. We identified specific metabolic mechanisms of utilization of glutamine in resistant cells while also providing further basis for the use of metformin as an adjuvant in the treatment of endocrine therapyresistant cancers. Finally, we contributed to current understanding about cancer cell metabolism by exploring the role of glutamine beyond its role as a carbon and nitrogen source in driving growth and proliferation of cancer cells. Upon substitution of glutamine with appropriateiv nitrogen and carbon sources, cancer cells exhibited reverse Warburg phenotype. The findings from this thesis open up new avenues of research through the identification of new putative targets and bring us one step closer towards designing much better and efficacious therapeutic strategy for the treatment of cancer patients.
Nell'ultimo decennio, uno dei messaggi chiave derivante dalle ricerche scientifiche sul cancro è la necessità di comprendere meglio il metabolismo delle cellule tumorali per lo sviluppo di una terapia personalizzata migliore e più efficace. Le cellule tumorali attuano un riarrangiamento metabolico che coinvolge diversi processi per supportare la loro natura proliferativa ed invasiva. Per meglio comprendere l’entità del cambiamento metabolico, in questo studio abbiamo utilizzato un approccio systems level impiegando la metabolomica untargeted e la flussomica mediante isotopi stabili del carbonio (13C) in cellule tumorali esprimenti un K-Ras oncogenico. Abbiamo testato gli effetti di farmaci inibitori del metabolismo di glucosio e glutammina per indagare eventuali vie metaboliche alternative attivate per la sopravvivenza delle cellule tumorali. Inoltre abbiamo investigato il ruolo del metabolismo cellulare nello sviluppo della resistenza alla terapia endocrina nel carcinoma mammario ERα positivo. I dati ottenuti hanno permesso di identificare specifici meccanismi metabolici di utilizzo della glutammina in cellule resistenti alla terapia, suggerendo l’utilizzo del farmaco metformina come adiuvante nel trattamento dei tumori resistenti alla terapia ormonale. Infine, abbiamo contribuito alla comprensione del metabolismo delle cellule tumorali nel guidare la crescita e la proliferazione, esplorando il ruolo della glutammina oltre la nota funzione di fonte di carbonio e azoto; infatti sostituendo la glutammina con fonti alternative di carbonio e azoto, si osserva un fenotipo reverse Warburg. I risultati di questa tesi aprono strade di ricerca per l'identificazione di nuovi potenziali obiettivi terapeutici e ci portano verso la progettazione di una strategia terapeutica migliore e più efficace per il trattamento dei pazienti oncologici.
(2019). Targeting cancer cell metabolism: Gateway towards personalized medicine. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2019).
Targeting cancer cell metabolism: Gateway towards personalized medicine
BHARAT, ROHIT
2019
Abstract
In the recent decade, one of the important keynote message derived through the summation of our global efforts against cancer is the need to better understand cancer cell metabolism for the development of better and efficacious personalized therapy. Cancer cells undertake a multifaceted rewiring of metabolic pathways in order to support their proliferative and invasive nature, which requires a systems level investigation to fully comprehend the scale of metabolic deregulation. In this study, we systematically investigated the metabolic differences using untargeted metabolomics and 13C flux omics approach in oncogenic K-Ras driven tumours. We tested the effects of drug inhibitors targeting glucose and glutamine metabolism to unravel the alternative metabolic pathways required for cancer cell survival. We further expanded our research towards understanding the role of cellular metabolism in driving resistance to endocrine therapeutic drugs in ERα positive breast cancer. We identified specific metabolic mechanisms of utilization of glutamine in resistant cells while also providing further basis for the use of metformin as an adjuvant in the treatment of endocrine therapyresistant cancers. Finally, we contributed to current understanding about cancer cell metabolism by exploring the role of glutamine beyond its role as a carbon and nitrogen source in driving growth and proliferation of cancer cells. Upon substitution of glutamine with appropriateiv nitrogen and carbon sources, cancer cells exhibited reverse Warburg phenotype. The findings from this thesis open up new avenues of research through the identification of new putative targets and bring us one step closer towards designing much better and efficacious therapeutic strategy for the treatment of cancer patients.File | Dimensione | Formato | |
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