Sarah-Maria Fendt Lab

Research focus

Our vision is to reach an understanding of cellular metabolism and its regulation that enables us to 
normalize aberrant disease metabolism by exploiting its naturally embedded control mechanisms. 
This level of understanding will allow us to design drugs that only target the diseased cells and will 
yield no side effects on healthy cells. To reach our long-term vision, we focus on a functional 
and mechanistic understanding of cellular metabolism by dissecting metabolic auto-regulation, 
the link between cellular metabolism and signaling, and the regulatory impact of the nutrient 
environment on cellular metabolism during tumor initiation, proliferation and progression 
towards metastasis formation. To gain crucial insights into these research areas we exploit our 
metabolism expertise, which includes the generation of intracellular metabolism data using steady 
state 13C tracer infusions to mice, 13C metabolic flux analysis and metabolomics.​  

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Do cancer cells have placticity in their lipid metabolism?

Fatty Acid_Sarah Maria Fendt.jpg
Most tumours have an aberrantly activated lipid metabolism
that enables them to synthesize, elongate and desaturate fatty
acids to support proliferation. However, only particular subsets 
of cancer cells are sensitive to approaches that target fatty acid 
metabolism and, in particular, fatty acid desaturation. 
This suggests that many cancer cells contain an unexplored 
plasticity in their fatty acid metabolism. Here we discovered 
that some cancer cells can exploit an alternative fatty acid 
desaturation pathway. We identify various cancer cell lines, 
mouse hepatocellular carcinomas, and primary human liver and
lung carcinomas that desaturate palmitate to the unusual 
fatty acid sapienate to support membrane biosynthesis during
proliferation. Accordingly, we found that sapienate biosynthesis enables cancer cells to bypass the
known fatty acid desaturation pathway that is dependent on stearoyl-CoA desaturase. Thus, only by 
targeting both desaturation pathways is the in vitro and in vivo proliferation of cancer cells that 
synthesize sapienate impaired.  Our discovery explains metabolic plasticity in fatty acid desaturation 
and constitutes an unexplored metabolic rewiring in cancers. (Vriens & Christen et al, 2019, Nature)

 

Metabolic hallmarks of metastasis formation
Metastasis to distant organs is a predictor of poor prognosis. Therefore, it is of paramount importance to understand the mechanisms that impinge on the different steps of the metastatic cascade. Recent work has revealed that particular metabolic pathways are rewired in cancer cells to support their transition through the metastatic cascade, resulting in the formation of sec- ondary tumors in distant organs. Indeed, metabolic rewiring induces signaling pathways during initial cancer invasion, circulating cancer cells depend on enhanced antioxidant defenses, and cancer cells colonizing a distant organ require increased ATP production. Moreover, the local environment of the metastatic niche dictates the metabolic pathways secondary tumors rely on. Here we describe mechanisms of metabolic rewiring associated with distinct steps of metastasis formation. (Elia et al., 2018 Trends in Cell Biology)
Invastion_Sarah Maria Fendt.jpg
 
 
How does pyruvate support metastasis formation?
Pyruvate_Sarah Maria Fendt.jpg

The extracellular matrix is a major component of the local environment—that is, the niche—that determines cell behavior. During metastatic growth, cancer cells shape the extracellular matrix of the metastatic niche by hydroxylating collagen to promote their own metastatic growth. However, only particular nutrients might support the ability of cancer cells to hydroxylate collagen, because nutrients dictate which enzymatic reactions are active in cancer cells. Here we discovered that breast cancer cells rely on the nutrient pyruvate to drive collagen-based remodeling of the extracellular matrix in the lung metastatic niche. Specifically, we discovered that pyruvate uptake induces the production of alpha-ketoglutarate. This metabolite in turn activates collagen hydroxylation by increasing the activity of the enzyme collagen prolyl-4-hydroxylase. Inhibition of pyruvate metabolism was sufficient to impair collagen hydroxylation and consequently the growth of breast-cancer-derived lung metastases in different mouse models. In summary, we provide a mechanistic understanding of the link between collagen remodeling and the nutrient environment in the metastatic niche. (Elia et al, 2019, Nature)

 
Can we inhibit metastasis formation by targeting cancer metabolism?
Prodh_Sarah Maria Fendt.png
We are investigating how the metabolism of cancer cells changes during metastasis formation. We discovered that proline catabolism via proline dehydrogenase (Prodh) supports growth of breast cancer cells in 3D culture by providing energy in form of ATP. Subsequently, we linked proline catabolism to in vivo metastasis formation. In particular, we found that PRODH expression and proline catabolism is increased in metastases compared to primary breast cancers of patients and mice. Moreover, inhibiting Prodh was sufficient to impair formation of lung metastases in the orthotopic breast cancer mouse models, without adverse effects on healthy tissue and organ function. In conclusion, we discovered that Prodh is a potential drug target for inhibiting metastasis formation. (Elia et al, 2017, Nature Communications)

 
Does the microenvironment shape the metabolism of cancer cells during metastasis formation?
Christen-et-al.jpg
W
e investigated the role of the microenvironment in shaping cancer metabolism during breast cancer metastasis to the lungs. We discovered that breast cancer-derived lung metastases activate PC-dependent anaplerosis as a function of the nutrient availability within the lung microenvironment. While primary breast cancers often rely on glutamine anaplerosis, the resulting and genetically similar lung metastases activate PC-dependent anaplerosis in response to the lung microenvironment. Thus, we discovered that pyruvate carboxylase-dependent anaplerosis distinguishes lung metastases from their corresponding primary breast cancers. This shows that primary cancer and their resulting metastases can have different metabolic vulnerabilities and consequently should be targeted with different drugs  (Christen et al., 2016, Cell Reports)​

 
The latest news can be found below. Interested in more news?
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Publications

Evidence for an alternative fatty acid desaturation pathway increasing cancer plasticityVriens K* Christen S* Parik S Broekaert D Yoshinaga K Talebi A Dehairs J Escalona C Schmieder R Cornfield T Charlton C Romero-Perez L Rossi M Rinaldi G Orth M Boon R Kerstens A Kwan S Faubert B Mendez-Lucas A Kopitz C Chen T Fernandez Garcia J Duarte J Schmitz A Steigemann P Najimi M Hägebarth A Van Ginderachter J Sokal E Gotoh N Wong K Verfaillie C Derua R Munck S Yuneva M Beretta L Deberardinis R Swinnen J Hodson L Cassiman D Verslype C Christian S Grunewald S Grunewald T Fendt SNATURE, 566, 403-406, 2019* These authors contributed equally
Breast cancer cells rely on environmental pyruvate to shape the metastatic nicheElia Ilaria Rossi Matteo* Stegen S* Broekaert Dorien* Doglioni Ginevra* Van Gorsel Marit* Boon R Escalona-Noguero Carmen Torrekens S Verfaillie C Verbeken E Carmeliet G Fendt Sarah-Maria@NATURE, 568, 117-121, 2019* These authors contributed equally@ These authors are corresponding.
Metabolic Hallmarks of Metastasis FormationElia Ilaria Doglioni Ginevra Fendt Sarah-MariaTRENDS IN CELL BIOLOGY, 28, 673-684, 2018
Proline metabolism supports metastasis formation and could be inhibited to selectively target metastasizing cancer cellsElia Ilaria Broekaert Dorien Christen Stefan Boon R Radaelli Enrico Orth M. F Verfaillie C. M. Grünewald T. G Fendt Sarah-MariaNature Communications, 8, 15267, 2017
Breast Cancer-Derived Lung Metastases Show Increased Pyruvate Carboxylase-Dependent AnaplerosisChristen Stefan Lorendeau Doriane Schmieder Roberta Broekaert Dorien Metzger Kristine Veys Koen Elia Ilaria Buescher Joerg Orth M. F Davidson S. M Grünewald T. G De Bock Katrien Fendt Sarah-MariaCell Reports, 17, 837-848, 2016

Job openings

News

Breast cancer cells rely on pyruvate to expand in new tissues

04/03/2019 - Cancer cells alter their metabolism to grow and expand across other organs. A study by Sarah-Maria Fendt & team (VIB-KU Leuven Center for Cancer Biology) shown that breast cancer cells require the nutrient pyruvate to do this.

VIB welcomes new Marie Curie fellows

04/03/2019 - Each year, the EU launches calls for postdoc research fellowships through the Marie Sklodowksa-Curie Actions. Fellowships provided through these actions support researchers regardless of age & nationality.

A hidden route for fatty acids can make cancers resistant to therapy

06/02/2019 - Researchers from the lab of Prof. Sarah-Maria Fendt at the VIB-KU Leuven Center for Cancer Biology now demonstrate that certain tumor cells use an alternative – previously unexplored - pathway to produce fatty acids.

ERC Consolidator Grants for three VIB scientists: boost for innovative research

28/11/2017 - The European Research Council (ERC) has awarded 3 VIB scientists a consolidator grant: Anna Sablina, Sarah-Maria Fendt and Massimiliano Mazzone, all from the VIB-KU Leuven Center for Cancer Biology.

Researchers identify nutrient metabolism that drives breast tumor metastasis

11/05/2017 - ​A group of scientists, led by Sarah-Maria Fendt (VIB-KU Leuven), discovered that breast cancer cells that have invaded other organs rely on different nutrient metabolism to produce energy than normal cells and non-metastasizing cancer cells.

Research from the group of Sarah Fendt reveals how succinate dehydrogenase is linked to both tumor and neurodegeneration

15/11/2016 - Sarah-Maria Fendt (VIB-KU Leuven): “In this project we have studied mutations in the enzyme succinate dehydrogenase, which are associated with tumors, but also neurodegeneration.

Scientists uncover how spreading cancer adapts to its environment

11/10/2016 - Spreading tumor cells are able to adapt their metabolism to the specific organs they are invading. This conclusion forms the gist of a VIB-KU Leuven paper published in the renowned scientific journal Cell Reports.

Sarah-Maria Fendt (VIB/KU Leuven) guest editor of Current Opinion in Biotechnology (vol34)

19/10/2015 - Systems biology provides a unifying framework for biological data collection, analysis and informed intervention. In both biotechnology and biomedicine the ultimate goal is to understand and redirect or repair biological processes.

New insights in function of fatty acids in metabolism of endothelial cells

10/07/2015 - Sandra Schoors, Ulrike Bruning, Sarah-Maria Fendt and Peter Carmeliet (VIB Vesalius Research Center, KU Leuven) have discovered, contrary to all expectations, that fatty acid breakdown is essential for the proliferation of endothelial cells.

VIB conference - Metabolism in Cancer and Stromal Cells

01/07/2015 - From September 8 – 10, 2015 VIB will host the interdisciplinary meeting on “Metabolism in Cancer and Stromal Cells” in Leuven.

Revolutionary new insights into blood vessel formation in cancer

01/04/2015 - Peter Carmeliet and Sarah-Maria Fendt (VIB/ KU Leuven) have discovered a new strategy to counteract blood vessel formation, based on their research which indicates that fatty acid breakdown is essential in the creation of new blood vessels.

Sarah-Maria Fendt

Sarah-Maria Fendt

Research area(s)

Model organism(s)

Bio

PhD: ETH Zurich, Institute of Molecular Systems Biology, 2009
Postdoctoral Fellow: Harvard Medical School, Boston, 2010
Postdoctoral Fellow: Massachusetts Institute of Technology , Cambridge, 2011-2012
VIB Group leader since 2013

Contact Info

VIB-KU Leuven Center for Cancer BiologyO&N 4, 9e verdCampus GasthuisbergHerestraat 49, bus 912 3000 LEUVENRoute description