Cancer Metabolism and Microenvironment

Metabolism is undoubtedly a rediscovered research field and it is certainly a niche of scientific discoveries that will allow the evolution of the knowledge and treatment of diseases, namely cancer.

Metabolism does not consist solely of the intracellular network that shares and provides organic compounds among the various chemical reactions that make up the metabolic dynamics, but also encompasses the extracellular organic and signaling molecules that supplement and mediate stimuli, which regulate the entire metabolic functioning of a cell. In cancer, the tumor microenvironment (TME) impacts cancer cell biology and metabolism.

The research area of CMM group is cancer metabolism not only the metabolic adaptive features that allow the establishment of a tumor in a certain TME but also the way these metabolic adaptations limit the response to therapy. Our main goal is to take advantage of metabolic rewiring of cancer, in order to design new and more effective therapies.

Graphical Abstract

Resumo projetos_Jacinta Serpa

 

  • 2017/2019- iNOVA4HEALTH Project 35: 2015\CEDOC\IPOLFG\IBET

Targeting monocytes as angiogenesis promoters in cancer- New application for old drugs.

The role of monocytes as endothelial precursors is not a new subject in other diseases, but in cancer this issue was not extensively studied. Studies showed that a subset of circulating monocytes are capable of in vitro EC differentiation, and in vivo incorporation in new blood vessels, in cancer. Reactive oxygen species (ROS) are reported as essential in endothelium homeostasis, acting as regulators of intracellular signaling.
Moreover, it is known that some drugs (i.e. β-blockers), already approved for human use, have simultaneously a pro-apoptotic role in EC and a modulatory role in monocytes differentiation.
Our hypothesis is that monocytes are relevant endothelial precursors and the manipulation of oxidative stress with the use of some drugs can be a new weapon to control cancer angiogenesis.
Our main goals are to disclose monocytes as endothelial precursors, unravel the role of oxidative stress in angiogenesis and take advantage of redox state to control vessels growth.

Publications:

Lopes-Coelho F, Silva F, Hipólito A, Mendes C, Sequeira CO, Pires RF, Almeida AM, Bonifácio VDB, Pereira SA, Serpa J. The activation of endothelial cells relies on a ferroptosis-like mechanism: novel perspectives in management of angiogenesis and cancer therapy. Front. Oncol., 10 May 2021. doi:10.3389/fonc.2021.656229.

Lopes-Coelho F, Silva F, Gouveia-Fernandes S, Martins C, Lopes N, Domingues G, Brito C, Almeida AM, Pereira SA, Serpa J. Monocytes as Endothelial Progenitor Cells (EPCs), Another Brick in the Wall to Disentangle Tumor Angiogenesis. Cells. 2020 Jan 1;9(1):107. doi: 10.3390/cells9010107.

 

  • 2015/2017- iNOVA4HEALTH Project 4: 2015\CEDOC\IPOLFG\IBET

Ovarian cancer a suitable model to define metabolic profile as a tool to predict chemoresistance

EOC is a natural model to study therapy resistance. Approximately 70% of patients have extraovarian disease and besides the initial response to therapy, over 60% have recurrence of disease and the mortality rate is 70-90%, mainly due to chemoresistance. We published a study that shows, in ovarian clear cell carcinoma, that amino acids metabolism and glutathione production underlie the intrinsic resistance of this histological cancer type to carboplatin.
Thus, alterations in metabolic profile induced by exposure to chemotherapy can be an useful tool to predict, anticipate and abrogate chemoresistance in ovarian cancer patients.

The main objective is to use the ovarian cancer model to evaluate the impact of metabolic fitness in chemoresistance.

Publications:

Nunes SC, Ramos C, Santos I, et al. Cysteine Boosts Fitness Under Hypoxia-Mimicked Conditions in Ovarian Cancer by Metabolic Reprogramming. Front Cell Dev Biol. 2021 Aug 11;9:722412. doi: 10.3389/fcell.2021.722412.

Santos I, Ramos C, Mendes C, et al.. Targeting Glutathione and Cystathionine β-Synthase in Ovarian Cancer Treatment by Selenium-Chrysin Polyurea Dendrimer Nanoformulation. Nutrients. 2019 Oct 19;11(10):2523. doi: 10.3390/nu11102523.

Nunes SC, Ramos C, Lopes-Coelho F, et al.. Cysteine allows ovarian cancer cells to adapt to hypoxia and to escape from carboplatin cytotoxicity. Scientific Reports. 2018 Jun 22;8(1):9513. doi: 10.1038/s41598-018-27753-y.

Nunes SC, Lopes-Coelho F, Gouveia-Fernandes S, et al.. Cysteine boosters the evolutionary adaptation to CoCl2 mimicked hypoxia conditions, favouring carboplatin resistance in ovarian cancer. BMC Evololutionary Biology 2018 Jun 19;18(1):97. doi: 10.1186/s12862-018-1214-1.

 

Projects - principal researcher (since 2015)

  • 2021/2022- Speed Grant Merck; June 2021
  • 2017/2019- iNOVA4HEALTH Project 35: 2015\CEDOC\IPOLFG\IBET
  • 2015/2017- iNOVA4HEALTH Project 4: 2015\CEDOC\IPOLFG\IBET


Projects - participant researcher (since 2015)

  • 2020/2023- PTDE/MED-QUI/3542/2020. PI: Nuno Martinho- iBB-IST
  • 2018/2021- PTDC/MEC-ONC/29327/2017. PI: Vasco Bonifácio- iBB-IST
  • 2017/2019- iNOVA4HEALTH Project 21: 2015\CEDOC\IPOLFG\ITQB
  • 2015/2017- iNOVA4HEALTH Project 6: 2015\CEDOC\IPOLFG
  • 2015/2017: PTDC\BIMMEC\4905\2014. PI: Duarte Barral CEDOC

Cysteine Boosts Fitness Under Hypoxia-Mimicked Conditions in Ovarian Cancer by Metabolic Reprogramming. Front Cell Dev Biol. 2021. doi: 10.3389/fcell.2021.722412.

Molecular and Metabolic Reprogramming: Pulling the Strings Toward Tumor Metastasis. Front Oncol. 2021. doi: 10.3389/fonc.2021.656851.

The activation of endothelial cells relies on a ferroptosis-like mechanism: novel perspectives in management of angiogenesis and cancer therapy. Front. Oncol., 2021. doi:10.3389/fonc.2021.656229.

Anti-Angiogenic Therapy: Current Challenges and Future Perspectives. Int. J. Mol. Sci. 2021; doi: 10.3390/ijms22073765

Cysteine metabolic circuitries: druggable targets in cancer. Br J Cancer. 2021. doi: 10.1038/s41416-020-01156-1.

Cysteine as a Carbon Source, a Hot Spot in Cancer Cells Survival. Front Oncol. 2020. doi: 10.3389/fonc.2020.00947.

Take Advantage of Glutamine Anaplerosis, the Kernel of the Metabolic Rewiring in Malignant Gliomas. Biomolecules. 2020. doi: 10.3390/biom10101370.

Cysteine Aminotransferase (CAT): A Pivotal Sponsor in Metabolic Remodeling and an Ally of 3-Mercaptopyruvate Sulfurtransferase (MST) in Cancer. Molecules. 2020. doi: 10.3390/molecules25173984.

Revisiting lactate dynamics in cancer-a metabolic expertise or an alternative attempt to survive? J Mol Med (Berl). 2020. doi: 10.1007/s00109-020-01965-0.

Polyurea Dendrimer Folate-Targeted Nanodelivery of l-Buthionine sulfoximine as a Tool to Tackle Ovarian Cancer Chemoresistance. Antioxidants (Basel). 2020. doi: 10.3390/antiox9020133.

Monocytes as Endothelial Progenitor Cells (EPCs), Another Brick in the Wall to Disentangle Tumor Angiogenesis. Cells. 2020. doi: 10.3390/cells9010107.

Unraveling FATP1, regulated by ER-b as a targeted breast cancer innovative therapy, Scientific reports. 2019. doi: 10.1038/s41598-019-50531-3.

Targeting Glutathione and Cystathionine β-Synthase in Ovarian Cancer Treatment by Selenium-Chrysin Polyurea Dendrimer Nanoformulation. Nutrients. 2019. doi: 10.3390/nu11102523.

Glutathione in Ovarian Cancer: A Double-Edged Sword. International Journal of Molecular Science 2018. doi: 10.3390/ijms19071882.

Acetylation drives hepatocyte nuclear factor 1ß stability by blocking proteasome-mediated degradation. Journal of Cellular Biochemistry. 2018. doi: 10.1002/jcb.28209

Cysteine allows ovarian cancer cells to adapt to hypoxia and to escape from carboplatin cytotoxicity. Scientific Reports. 2018. doi: 10.1038/s41598-018-27753-y.

Cysteine boosters the evolutionary adaptation to CoCl2 mimicked hypoxia conditions, favouring carboplatin resistance in ovarian cancer. BMC Evololutionary Biology 2018. doi: 10.1186/s12862-018-1214-1.

Cysteine oxidative dynamics underlies hypertension and kidney dysfunction induced by chronic intermittent hypoxia. Adv Exp Med Biol. 2018. doi: 10.1007/978-3-319-91137-3_10

Cooperation of cancer and normal cells is pivotal in cancer metabolic fitness. Tumor Biology, 2018. doi: 10.1177/1010428318756203.

Monocarboxylate transporter 1 (MCT1), a tool to stratify acute myeloid leukemia (AML) patients and a vehicle to kill cancer cells. Oncotarget, 2017, doi: 10.18632/oncotarget.20294

Breast cancer metabolic cross-talk: Fibroblasts are hubs and breast cancer cells are gatherers of lipids. Molecular and Cellular Endocrinology. 2017. doi:10.1016/j.mce.2017.01.031. 3.

STAT3:FOXM1 and MCT1 drive uterine cervix carcinoma fitness to a lactate-rich microenvironment. Tumor Biology 2016; DOI 10.1007/s13277-015-4385-z

HNF1ß drives glutathione (GSH) synthesis underlying intrinsic carboplatin resistance of ovarian clear cell carcinoma (OCCC). Tumor Biology 2016; DOI 10.1007/s13277-015-4290-5

  • “Bolsa da Liga Portuguesa Contra o Cancro” em Novembro 2008.
  • Stefano Mazzoleni - Lab Applied Ecology and System Dynamics, Dip. Agraria , Università di Napoli "Federico II"
  • Stefaan van Gool- University of Leuven
  • Shinozuka Tsuyoshi - Daiichi Sankyo Co., Ltd
  • Valdemar Máximo- IPATIMUP e Faculdade de Medicina da Universidade do Porto
  • José Cabeçadas - Instituto Português de Oncologia de Lisboa, Francisco Gentil
  • Maria Gomes da Silva - Instituto Português de Oncologia de Lisboa, Francisco Gentil
  • António Almeida - Instituto Português de Oncologia de Lisboa, Francisco Gentil e Hospital da Luz
  • Saudade André - Instituto Português de Oncologia de Lisboa, Francisco Gentil
  • António Guimarães - Instituto Português de Oncologia de Lisboa, Francisco Gentil
  • Duarte Salgado - Instituto Português de Oncologia de Lisboa, Francisco Gentil
  • Vasco Bonifácio - Instituto Superior Técnico da Universidade de Lisboa
  • Alexandra Antunes - Instituto Superior Técnico da Universidade de Lisboa
  • João B Vicente - Instituto de Tecnologia Química e Biológica
  • Luís G Gonçalves - Instituto de Tecnologia Química e Biológica
  • Sofia A Pereira – CEDOC, NOVA Medical School
  • Duarte Barral – CEDOC, NOVA Medical School
  • Cristina Casalou – UCD School of Medicine, Charles Institute of Dermatology, University College Dublin

Principal Investigator

Jacinta Serpa

Team

Ana Rita Hipólito
MSc, PhD student
Cindy Mendes
MSc, PhD student
Filipa Martins
MSc, PhD student
Filipe Gonçalves
MD, PhD student