Metabolic reprogramming is a hallmark of normal physiological homeostasis, but also of pathological conditions such as cancer. Metabolic pathways are temporary orchestrated to satisfy the shifting demands of growth, proliferation, and differentiation. Growing evidences exist about the regulatory crosstalk between metabolic pathways, cell cycle progression and cell division: our laboratory, among others, has shown that cancer-cell metabolism is reprogrammed through the regulation of metabolic enzymes by various cell cycle regulators. Moreover, we have demonstrated that some of these cell cycle regulators, like the pRB-cdk4-E2F1 pathway, control metabolism of adult non-proliferative cells, and that their activity is altered especially under pathological conditions contributing to obesity and diabetes.
Our projects aim to contribute understanding the crosstalk between metabolism and proliferation.
Participation of the pRB-cdk4-E2F1 pathway in metabolism during normal and pathological conditions.
We have previously shown that the cyclin-dependent kinase 4 (CDK4) plays a role in adipogenesis and in the function of mature adipocytes. We have also proven that the pRB-CDK4-E2F1 pathway represses oxidative metabolism in muscle and in brown adipose tissue, while promoting lipid synthesis and glycolysis in the liver.
Taking advantage of tissue-specific conditional knockout mice for E2f1 and for Cdk4, we are currently exploring the role of E2f1 and Cdk4 in regulating other major metabolic pathways. In particular, we study the role of E2f1 in gluconeogenesis and cholesterol metabolism in the liver, two processes deregulated in diabetes and in cardiovascular diseases, respectively. In parallel, we are trying to elucidate the function of Cdk4 in thermogenesis in brown adipose tissue, an emerging player in regulating energy expenditure, body weight and global metabolic homeostasis.
We are also further characterizing the role of E2F1 in cancer biology. We have identified several novel E2F1 target genes playing a role in glutamine uptake and metabolism, which is key for sustaining proliferation in transformed cells. Our working hypothesis is that E2F1 plays a key role in cancer progression by coupling cell cycle proliferation and DNA synthesis with the regulation of metabolic pathways that provide the necessary metabolic intermediates to sustain cell growth.
Molecular interplay between CDK4 and other signaling pathways that control proliferation and metabolism.
We have recently shown that IRS2 is a novel target of CDK4, highlighting the importance of this cell cycle regulator in modulating insulin-AKT signaling. Interestingly, IRS proteins are involved in the activation of growth factor receptor pathways and transduce mitogenic, anti-apoptotic, and anti-differentiation signals to the cell. Recent data from our laboratory show that CDK4 modulates AMPK and mTOR pathways, two master regulators that sense and integrate nutritional and environmental cues and regulate cell proliferation and metabolism. Significantly, aberrant AKT, AMPK or mTOR signaling is involved in cancer, cardiovascular disease, and diabetes. We are currently exploring the central role of CDK4 integrating several signaling pathways, linking cell proliferation and metabolism in normal and pathological conditions.
Implication of other CDKs in the control of metabolism.
Our laboratory has already shown that members of the CDK family, such as CDK4 and CDK9, respond to nutritional status and are key factors in the regulation of metabolism independently from cell proliferation. Interestingly, other CDKs are expressed in highly metabolic tissues in adult mice and humans, suggesting that they could also play a role in the regulation of metabolism and energy homeostasis. We have generated tissue-specific knockout mice for CDK7 and CDK10 that are being extensively characterized in order to elucidate the role of these novel potential metabolic regulators.
Targeting tumor metabolism.
The metabolism of cancer cells is reprogrammed in order to support their uncontrolled proliferation rates. This process is orchestrated by several oncogenes such as MYC and RAS, emphasizing the importance of shuffling metabolic pathways to sustain cancer progression. Among many others, increased de novo fatty acid (FA) synthesis is a hallmark of tumor cells. De novo synthesized FA are not only used for the generation of new cell membranes, but also for the production of lipid signaling molecules required for carcinogenesis and cancer cell survival. Thus, targeting lipid synthesis is a new promising therapeutic strategy against some types of cancer. We have previously shown that pharmacologic inhibition of the lipogenic enzyme stearoyl-CoA desaturase 1 (SCD1) activity impairs lipid synthesis and results in decreased progression in prostate cancer models. We are now interested in identifying new actors playing a role in cancer lipid metabolism and in finding new drugs that inhibit de novo FA synthesis to target cancer progression.
Prof. Lluis Fajas Coll
|Prof. Lluis Fajas Coll was born in Barcelona, Spain. He studied Biology at the University of Barcelona were he got his Master’s degree. He next moved to the Ernst Boehringer Institute in Vienna, Austria were he did his PhD studies. After two post-doctoral stages in France in the laboratory of Prof. Auwerx at Pasteur Institute in Lille and at the IGMM in Dr. Sardet lab in Montpellier he was recruited as Inserm associated scientist at the IGBMC in Strasbourg. He next was appointed as junior group leader with an Inserm Avenir grant in Montpellier. He is now Professor and director of the department of physiology at the University of Lausanne. The main focus of his research has been the link between cell cycle regulation, proliferation and metabolism in the context of metabolic pathologies, such as obesity and diabetes and in the context of cancer.|
Judit Castillo Armengol
|Judit Castillo Armengol obtained her Bachelor in Biology from the University of Barcelona in 2013 and her Master’s degree in Biomedical Research from the University Pompeu Fabra (Barcelona) in 2014. Currently, she is a PhD student and she is focusing on the participation of CDK4 in adipose tissue biology.|
|Lab technician, Dep. Physiology, Unil, Fajas lab CH (2013-)
Lab technician, Dep. Physiology, Unil, CH (2001-)
Technical degree in Biology
General Tasks: apart from being responsible of the Department Common Stock (with Gilles Dubuis), and of the logistics of the Fajas lab (maintenance, ordering, budgets), I actively participate in a number of projects of the team, with a large expertise in metabolic profiling by Seahorse.
|Honglei obtained his Bachelor in Biological engineering in 2011 and his Master’s degree in Zoology in 2014 at Northwest A&F University in China. Currently, he is a PhD student and he is working on the role of CDK7 in adipose tissue metabolism and energy homeostasis.|
Isabel C. Lopez-Mejia
I moved from Colombia to France in 2002 to pursue my studies in biology. I completed her PhD in Biochemistry and Molecular Biology in the University of Montpellier in 2011. I focused on the alternative splicing of LMNA gene in the context of premature aging and on the alternative splicing of the FN gene in the context of endometrial invasion.
In 2012, I moved to the Fajas lab and started investigating how CDK4 regulates energy homeostasis and mitochondrial function. In parallel, I work on the identification of the signaling pathways involved in the onset of obesity and insulin resistance in adipose tissue.
|Anita Nasrallah completed her Bachelor degree in Biology (2010) and her Masters degree in Molecular Biology (2013) from the Lebanese American University. After working as a laboratory instructor and a research assistant for a year at the Lebanese American University, she started her PhD in the Fajas group in 2014. Currently, she is working on the role of CDK10 in highly metabolic tissues, especially brown adipose tissue.|
Laia Martinez Carreres
|Laia Martínez Carreres completed her Bachelor in Biomedical Sciences and Masters in Traslational Medicine at University of Barcelona. She is currently a PhD student since September 2014. Her project is directed towards understanding the role of CDK4 in cancer metabolism. In addition, she also participates actively in another project that studies the effect of E2F1 in muscle regeneration.|
|Yizhe completed her Bachelor degree in Biological Technology in 2015 at Northwest A&F University in China. After that, she continued her successive Master-PhD program in China. She joined the lab in November 2017 as a visiting scholar.|
Eric Aria Fernandez
|Eric Aria Fernandez received his Bachelor’s degree in Clinical Pharmacy from Bandung Institute of Technology in 2015. He followed that with a Master’s degree in Translational Medicine in 2016 and is expected to officially graduate in the winter of 2017. For his Master’s degree, which is the Master of Research, he worked in Prof. Karen McCloskey’s lab which focuses on Ion channels and genitourinary oncology. He now joins Prof. Fajas’ lab as a Ph D candidate under the supervision of Dr. Isabel Lopez-Mejia.|
|I am Valentin Barquissau, a southern French scientist. I obtained a PhD in human nutrition at the Université d'Auvergne (Clermont-Ferrand, France) focusing on skeletal muscle metabolism during obesity-induced insulin resistance. In 2012, I moved to Toulouse (France) in Dominique Langin's lab to study white-to-brown adipocyte conversion. Since february 2018, I have joined Lluis Fajas' group to investigate the role of CDK4 in metabolic control, especially in skeletal muscle. Additionally, I plan to improve my knowledge of the Alps in both winter and summer conditions, then do not hesitate to get in touch to share your experience and/or for mountain trips...|
|Matteo Cornaglia obtained his M.S. degree in Nanotechnologies as a joint study agreement between Polytechnic University of Turin, Grenoble Institute of Technology and EPFL, with his Master’s thesis pursued as part of The Molecular Foundry at the Lawrence Berkeley National Lab. He received his Ph.D. in Microsystems and Microelectronics from EPFL in 2015 and worked as a post-doc in Prof. Gijs’s lab, where he created innovative technological solutions for the automated culture and analysis of the model organism Caenorhabditis elegans. Matteo will now join Prof. Fajas’s group, with the goal of employing C. elegans-based screening technologies as novel powerful tool for research on developmental biology and metabolic diseases.|
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