Dr Manuela Santos, Ph.D.

Full Professor, Departement of Medicine;
Accredited Professor, Departement of Nutrition;
Departement of Microbiology, Infectiology and Immunology;
Université de Montréal, CRCHUM and Institut du cancer de Montréal.

 

Key words: Microbiota, cancer, inflammation, inflammatory bowel disease (IBD), iron, hereditary hemochromatosis gene (HFE), hepcidin, hemojuvelin, toll-like receptors, major histocompatibility complex I (MHC class I); lipocalin 2 (Lcn2)

Contact :

manuela.santos@umontreal.ca

Office: 514-890-8000 x.28928

1987-91  B.Sc. / M.Sc., Sofia University “St. Kliment Ohridski”- Microbiology and Virology, Supervisor - Dr. Tatiana Varadinova. (Bulgaria)

1992-94  M.Sc., University of Porto - Immunology, Supervisor - Dr. Maria De Sousa. (Portugal)

1994-98  Ph.D., Utrech University - Immunology and iron metabolism Supervisors - Dr. Hans Clevers et Dr.  J.J.M. Marx. (The Netherlands)

1999-2001  PDF, Université de Montréal - Iron metabolism in Friedreich ataxia, Supervisor - Dr. Massimo Pandolfo.

2010-2014  FRSQ Research Scholars: Senior

2007-2010  FRSQ Research Scholars: Junior 2

2002-2007  CIHR New Investigator Salary Award

  • 2014-17  (PI), Innovation grant, Canadian Cancer Society Research Institute (CCSRI).
    “Colon cancer and inflammation: the interplay of iron, microbiota and host at the mucosal interface”

  • 2014-19  (co-PI), Operating grant, Canadian Institutes of Health Research (CIHR).

    “TMPRSS6 in iron overload disorders”

  • 2012-17 (PI), Operating grant, Canadian Institutes of Health Research (CIHR).

    “Iron metabolism and immune system interactions”

  • 2011-19  (PI), Discovery grant, Natural Sciences and Engineering Research Council of Canada (NSERC).

    “Iron uptake, utilization and storage in mice”

 

Awards and prizes

1998-2001  Post-doctoral Fellowship, Portuguese Foundation of Science and Technology (FCT).

1994-1998  PhD Studenships, Portuguese Foundation of Science and Technology (FCT).

1992-1994  Master’s Award,  Portuguese Foundation of Science and Technology (FCT).

Gut microbiome, colorectal cancer, iron metabolism, hereditary hemochromatosis

Iron, a transition metal, is required for survival by practically all living organisms. Its most useful characteristic is the ability to exist in two different redox states and thus to catalyze many fundamental biochemical reactions. Paradoxically, these same properties become hazardous when ionic iron accelerates the formation of free radicals. Consequently, iron homeostasis is tightly regulated. This regulation aims to provide sufficient iron for the body’s needs (to virtually every cell and, in particular, erythrocytes – for oxygen fixation) while at the same time, avoiding its toxicity through safe storage in specialized molecules.

 

Our research aims to understand how cells and organisms regulate their iron content, and how distinct tissues coordinate iron distribution, in both health and disease. Because iron is a growth-limiting factor, we are particularly interested in unraveling the mechanisms developed by the host, microorganisms and tumor cells to compete for iron.

 

Current projects (techniques used):

Colon cancer and inflammation: the interplay of iron, microbiota and the host at the mucosal interface.

The human body contains a large bacterial community in the intestinal tract – the microbiota. Many studies have shown that the gut microbiota is an essential factor in driving inflammation in inflammatory bowel disease (IBD) and ultimately contributes to the development of colitis-associated colon cancer. Iron represents an important micronutrient at the interface between the microbiota and the host, as it is used as a cofactor in many metabolic pathways essential to both, and may thus influence the composition of gut microbiota. Bacterial constituents of the gut microbiota have evolved many different ways of acquiring iron from diverse sources within the host, for which they compete in order to successfully colonize the intestinal tract.

 

Our lab’s aim is to strengthen the understanding of this association by finding underlying mechanisms, identifying related biomarkers, and by testing new ways to avoid dysbiosis and/or restore intestinal metabolic homeostasis.

 

Lines of investigation include:

  1. understanding how competition for the uptake of dietary microelements affects the composition of the gut microbiota and may promote inflammation and carcinogenesis;

  2. identification of microbiota biomarkers and regulators in order to manipulate and restore a healthy microbiota after cancer treatments;

  3. identification of the underlying mechanisms by which the host controls gut microbial ecology;

  4. investigation of how pathogens and pathobionts alter the microbiota in a manner leading to carcinogenesis;

  5. and evaluation of the protective role of probiotics.

 

Iron metabolism and the immune system

Cross-regulation between iron metabolism and the immune system is evidenced by: 1) the high degree of homology shared between many genes related to iron metabolism and genes associated with pathogen resistance and immune recognition; 2) the regulation of iron-related genes by immune mediators; and 3) the antimicrobial activity of iron-binding proteins and iron regulators.

 

We are investigating the cross-regulation between iron metabolism and the immune system, the mechanisms by which one regulates the other, and the biological implications of such interactions. These research projects aim to identify linking elements and pathways between iron metabolism and the two branches of the immune system: innate and adaptive immunity.

 

Lines of investigation include:

  1. Contribution of Toll-like receptor (TLR) signaling to the maintenance of iron homeostasis;

  2. Identification of participating elements and elucidation of the molecular mechanisms involved in TLR signaling leading to iron metabolism regulation;

  3. Hierarchy among the signaling pathways;

  4. Mechanisms by which wild-type and mutated HFE interfere with the function of antigen-presenting cells (classical and cross-presentation pathways for MHC-I antigen presentation. 

 

Associated websites:

  1. CRCHUM webpage 

  2. UdeM webpage

  3. McGill webpage

 

Platforms:

  1. DNA

  2. RNA technologies and microbiome ressources

 

Pharma Collaborators: 

  • GlaxoSmithKline (GSK)

 

 

 

1. Annie Calvé (MSc, research assistant, anniecalve@gmail.com)

2. Marco Constante (PhD, PDF, marco.constante@gmail.com)

3. Gabriela Fragoso (PhD, research assistant, fragosogabriela@yahoo.com)

4. Macha Samba (MSc, PhD, macha.samba.mondonga@umontreal.ca)

5. Joseph Lupien-Meilleur (MSc, PhD, josephlupienmeilleur@gmail.com)

 

Former students

Edward T Bagu (PDF)

Carlos J Miranda (PDF)

Antonio Layoun (PhD & MSc)

Alexandre Reuben (PhD)

Hua Huang (PhD)

Sanae Medelci  (MSc)

Marco Pereira (MSc)

Wenlei Jiang (MSc)

Ricardo J Soares (MSc equivalent)

Cristina IC Escrevente (MSc equivalent)

  1. Fillebeen, C., et al., Mice are poor heme absorbers and do not require intestinal Hmox1 for dietary heme iron assimilation. Haematologica, 2015. 100(9): p. e334-e337.

  2. Reuben, A., et al., The WT hemochromatosis protein HFE inhibits CD8+ T-lymphocyte activation. European Journal of Immunology, 2014. 44(6): p. 1604-1614.

  3. Bagu, E.T., et al., Friend of GATA and GATA-6 modulate the transcriptional up-regulation of hepcidin in hepatocytes during inflammation. BioMetals, 2013. 26(6): p. 1051-1065.

  4. Layoun, A., et al., Toll-Like Receptor Signal Adaptor Protein MyD88 Is Required for Sustained Endotoxin-Induced Acute Hypoferremic Response in Mice. The American Journal of Pathology, 2012. 180(6): p. 2340-2350.

  5. Gannon, P.O., et al., Impact of hemochromatosis gene (HFE) mutations on epithelial ovarian cancer risk and prognosis. International Journal of Cancer, 2011. 128(10): p. 2326-2334.

  6. Huang, H., et al., Contribution of STAT3 and SMAD4 pathways to the regulation of hepcidin by opposing stimuli. Blood, 2009. 113(15): p. 3593-9.

  7. Jiang, W., M. Constante, and M.M. Santos, Anemia upregulates lipocalin 2 in the liver and serum. Blood Cells, Molecules, and Diseases 2008. 41(2): p. 169-174.

  8. Constante, M., et al., Repression of repulsive guidance molecule C during inflammation is independent of Hfe and involves tumor necrosis factor-alpha. The American Journal of Pathology, 2007. 170(2): p. 497-504.

  9. Miranda, C.J., et al., Hfe deficiency increases susceptibility to cardiotoxicity and exacerbates changes in iron metabolism induced by doxorubicin. Blood, 2003. 102(7): p. 2574-80.

  10. Santos, M., et al., Defective iron homeostasis in beta 2-microglobulin knockout mice recapitulates hereditary hemochromatosis in man. Journal of Experimental Medicine, 1996. 184(5): p. 1975-85.