Role of PI3K/Akt/Pten in tumorigenesis: a link between inflammation and reprogramming of the host metabolism

Although cancer begins locally, symptoms associated with disease progression can be manifested systemically and be extremely debilitating for the patient. Identifying the genes that drive and mediate both local and systemic effects of tumorigenesis is important not only for developing treatments aim...

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Detalles Bibliográficos
Autor: García López, Lucía
Tipo de recurso: tesis doctoral
Fecha de publicación:2021
País:España
Institución:Universidad Miguel Hernández de Elche
Repositorio:REDIUMH. Depósito Digital de la UMH
OAI Identifier:oai:dspace.umh.es:11000/28207
Acceso en línea:https://hdl.handle.net/11000/28207
Access Level:acceso abierto
Palabra clave:Oncología
Biología molecular
CDU::6 - Ciencias aplicadas::61 - Medicina::616 - Patología. Medicina clínica. Oncología::616.8 - Neurología. Neuropatología. Sistema nervioso
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spelling Role of PI3K/Akt/Pten in tumorigenesis: a link between inflammation and reprogramming of the host metabolismGarcía López, LucíaOncologíaBiología molecularCDU::6 - Ciencias aplicadas::61 - Medicina::616 - Patología. Medicina clínica. Oncología::616.8 - Neurología. Neuropatología. Sistema nerviosoAlthough cancer begins locally, symptoms associated with disease progression can be manifested systemically and be extremely debilitating for the patient. Identifying the genes that drive and mediate both local and systemic effects of tumorigenesis is important not only for developing treatments aimed at targeting cancer, but also for maintaining and improving patient quality of life. Here we use a multidisciplinary approach to uncover new mechanisms underlying Notch-PI3K/Akt-driven tumorigenesis in a well-established cancer paradigm in Drosophila melanogaster with highly predictive value (Palomero et al., 2007; Villegas et al., 2018). First, we designed an unbiased in vivo chemical screen to identify drugs that can selectively dampen this oncogenic cooperation without side effects. We identified a novel nitric oxide- dependent inflammatory pathway that is associated with Notch/Pten-dependent oncogenesis and perhaps amenable to pharmacological intervention. On the other hand, phospho-proteomic analysis of these tumors revealed that aberrant PI3K/Akt signaling fuels Notch tumorigenesis in part by triggering mitochondrial dysfunction and generating oxidative stress. Our results also indicate that stress-activated Jnk signal might be restricting tumor progression by inducing apoptosis, and therefore acting as a tumor suppressor in this context. Surprisingly, we found that Notch-PI3K/Akt tumors not only consume high amounts of glucose, but also remotely alter whole-body metabolism. High throughput large-scale and tissue-specific metabolomics revealed an unexpected interplay between the tumor and the host tryptophan-kynurenine metabolism, especially in the fat body, which ultimately leads to a systemic inflammation. Moreover, we detected changes related to tryptophan metabolism in the hemolymph, gut microbiota and brain of tumor- bearing hosts, further confirming for the first time that tumors can induce a multi-organ metabolic reprogramming. Consequently, diet supplementation with tryptophan was sufficient to prevent tumor formation through different multi-layered mechanisms. These findings could have important implications, since dietary interventions may hold the promise for the development of better treatments against cancer.Universidad Miguel HernándezDomínguez Castellano, MaríaVillegas Nieto, Santiago NahuelInstituto de Neurociencias202220222021info:eu-repo/semantics/doctoralThesisapplication/pdf248application/pdfhttps://hdl.handle.net/11000/28207reponame:REDIUMH. Depósito Digital de la UMHinstname:Universidad Miguel Hernández de ElcheInglésinfo:eu-repo/semantics/openAccessAttribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/oai:dspace.umh.es:11000/282072026-05-27T13:36:21Z
dc.title.none.fl_str_mv Role of PI3K/Akt/Pten in tumorigenesis: a link between inflammation and reprogramming of the host metabolism
title Role of PI3K/Akt/Pten in tumorigenesis: a link between inflammation and reprogramming of the host metabolism
spellingShingle Role of PI3K/Akt/Pten in tumorigenesis: a link between inflammation and reprogramming of the host metabolism
García López, Lucía
Oncología
Biología molecular
CDU::6 - Ciencias aplicadas::61 - Medicina::616 - Patología. Medicina clínica. Oncología::616.8 - Neurología. Neuropatología. Sistema nervioso
title_short Role of PI3K/Akt/Pten in tumorigenesis: a link between inflammation and reprogramming of the host metabolism
title_full Role of PI3K/Akt/Pten in tumorigenesis: a link between inflammation and reprogramming of the host metabolism
title_fullStr Role of PI3K/Akt/Pten in tumorigenesis: a link between inflammation and reprogramming of the host metabolism
title_full_unstemmed Role of PI3K/Akt/Pten in tumorigenesis: a link between inflammation and reprogramming of the host metabolism
title_sort Role of PI3K/Akt/Pten in tumorigenesis: a link between inflammation and reprogramming of the host metabolism
dc.creator.none.fl_str_mv García López, Lucía
author García López, Lucía
author_facet García López, Lucía
author_role author
dc.contributor.none.fl_str_mv Domínguez Castellano, María
Villegas Nieto, Santiago Nahuel
Instituto de Neurociencias
dc.subject.none.fl_str_mv Oncología
Biología molecular
CDU::6 - Ciencias aplicadas::61 - Medicina::616 - Patología. Medicina clínica. Oncología::616.8 - Neurología. Neuropatología. Sistema nervioso
topic Oncología
Biología molecular
CDU::6 - Ciencias aplicadas::61 - Medicina::616 - Patología. Medicina clínica. Oncología::616.8 - Neurología. Neuropatología. Sistema nervioso
description Although cancer begins locally, symptoms associated with disease progression can be manifested systemically and be extremely debilitating for the patient. Identifying the genes that drive and mediate both local and systemic effects of tumorigenesis is important not only for developing treatments aimed at targeting cancer, but also for maintaining and improving patient quality of life. Here we use a multidisciplinary approach to uncover new mechanisms underlying Notch-PI3K/Akt-driven tumorigenesis in a well-established cancer paradigm in Drosophila melanogaster with highly predictive value (Palomero et al., 2007; Villegas et al., 2018). First, we designed an unbiased in vivo chemical screen to identify drugs that can selectively dampen this oncogenic cooperation without side effects. We identified a novel nitric oxide- dependent inflammatory pathway that is associated with Notch/Pten-dependent oncogenesis and perhaps amenable to pharmacological intervention. On the other hand, phospho-proteomic analysis of these tumors revealed that aberrant PI3K/Akt signaling fuels Notch tumorigenesis in part by triggering mitochondrial dysfunction and generating oxidative stress. Our results also indicate that stress-activated Jnk signal might be restricting tumor progression by inducing apoptosis, and therefore acting as a tumor suppressor in this context. Surprisingly, we found that Notch-PI3K/Akt tumors not only consume high amounts of glucose, but also remotely alter whole-body metabolism. High throughput large-scale and tissue-specific metabolomics revealed an unexpected interplay between the tumor and the host tryptophan-kynurenine metabolism, especially in the fat body, which ultimately leads to a systemic inflammation. Moreover, we detected changes related to tryptophan metabolism in the hemolymph, gut microbiota and brain of tumor- bearing hosts, further confirming for the first time that tumors can induce a multi-organ metabolic reprogramming. Consequently, diet supplementation with tryptophan was sufficient to prevent tumor formation through different multi-layered mechanisms. These findings could have important implications, since dietary interventions may hold the promise for the development of better treatments against cancer.
publishDate 2021
dc.date.none.fl_str_mv 2021
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
format doctoralThesis
dc.identifier.none.fl_str_mv https://hdl.handle.net/11000/28207
url https://hdl.handle.net/11000/28207
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
rights_invalid_str_mv Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.format.none.fl_str_mv application/pdf
248
application/pdf
dc.publisher.none.fl_str_mv Universidad Miguel Hernández
publisher.none.fl_str_mv Universidad Miguel Hernández
dc.source.none.fl_str_mv reponame:REDIUMH. Depósito Digital de la UMH
instname:Universidad Miguel Hernández de Elche
instname_str Universidad Miguel Hernández de Elche
reponame_str REDIUMH. Depósito Digital de la UMH
collection REDIUMH. Depósito Digital de la UMH
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301603

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