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. 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.|
|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.
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.
Eric A. 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...|
Hi! My name is Katharina Huber and I joined the Fajas lab as a postdoctoral researcher in April 2019. I received my Ph.D. in Molecular Biosciences and Biotechnology from Graz University of Technology, Austria. As a PhD student at Graz University of Technology and as a research scholar in the department of cancer biology at University of Pennsylvania, I studied metabolic pathways in the context of cancer and lipid metabolism. I gained expertise in disciplines including molecular biology, cellular and mouse genetics, metabolomics, epigenetics, and imaging methods.
During my postdoctoral research at the CIG, I will investigate the role of cell cycle regulators, such as E2F1 transcription factor or the upstream activator cyclin-dependent kinase 4 in cancer metabolism.
Dorian studied cellular biology at the Ecole Normale Supérieure de Lyon, France. Early interested in investigating cellular senescence, a cell program involved in the age-related decline of tissues, he performed internship in Pr. Judith Campisi’s lab at the Buck Institute for Research on Aging, California. For his PhD, he joined the lab of Dr. David Bernard, at the Cancer Research Center of Lyon (CRCL) to study the role of metabolic homeostasis in the regulation of cellular senescence. In 2021, he moved to Lausanne in the group of Pr. Luis Fajas, in order to dig deeper into the interplay between metabolism, senescence, cancer and aging.
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