Campus ICO-Germans Trias i Pujol
Josep Carreras Leukaemia Research Institute
Can Ruti Campus
Ctra de Can Ruti, Camí de les Escoles s/n
08916 Badalona, Barcelona, Spain
Our laboratory is dedicated to understanding and exploiting the unique characteristics of cancer that could be targeted to halt the disease. One of the key areas of focus for us is the metabolic reprogramming of tumor cells, which has been recognized as a defining feature of cancer. Tumor cells often alter their metabolism to support their rapid growth and proliferation. However, these same metabolic reactions can also produce harmful toxins, such as formaldehyde and reactive oxygen species, that can damage the cancer cells. Our research focuses on identifying the mechanisms that cancer cells use to protect themselves from these toxins, and on exploiting these mechanisms to develop new cancer therapies.
Cellular defenses against toxic metabolites in acute leukemia.
Glutathione (GSH) is likely the most abundant antioxidant protecting cells from oxidative damage caused by reactive oxygen species (ROS). It is also an important molecule required to initiate the metabolization of the cellular toxin formaldehyde, an environmental and ubiquous mutagen. GSH is also particularly important in preventing ferroptosis, a non-apoptotic type of cell death. This project focused on studying the basic biology of GSH, building on our discovery that acute lymphoblastic leukemia (ALL) cells are vulnerable to inhibition of GSH synthesis and to ferroptosis-inducing agents. To this end, we combine genetic engineering with genome-wide transcriptomics, proteomics, epigenomic and metabolic studies. By understanding the role of GSH in cancer cells, we hope to uncover new potential therapeutic targets for the treatment of leukemia.
Metabolic vulnerabilities in DNA repair deficient tumors.
Mutations in genes coding for DNA repair factors are recognized drivers of breast and ovarian tumors, and are found in 3 % of pediatric B-ALL tumors (Target II Cohort). We have recently discovered that cancer cells with mutations in the Fanconi Anemia DNA repair pathway require GSH synthesis for growth. In this project, we aim to further study this selective vulnerability in cancer cells with mutations in the Fanconi Anemia DNA repair or in the breast cancer susceptibility genes (BRCA1/2). By characterizing the role of GSH metabolism in these cancer cells, we anticipate gaining a better understanding of the underlying mechanisms and identifying potential therapeutic targets.
Exploiting tumor-specific vulnerabilities for personalized treatment of refractory myeloid and lymphoblastic leukemias.
The current pipeline to treat a cancer patient usually consists of a conventional chemotherapy that might lead to remission. In most of the cases, cancer returns, and a second chemotherapy is given. Immunotherapy is likely to be used if available for the tumor under treatment. After a new relapse, very few therapeutic options are still available, and the cancer cells have become resilient to them. For example, in acute myeloid leukemia (AML), relapse is usually observed within the first 18 months after initial chemotherapy in 60-70% of patients. After a first relapse, 29% of the patients survive more than 12 months and only 11% survive 5 years. In ALL, between 10-20% of patient relapse with a medium survival after relapse of only 4.5 months.
This project focuses on uncovering druggable vulnerabilities in relapsed patients with AML and ALL, who have exhausted all current therapeutic options. We are developing a novel technology to identify druggable dependencies in patient-derived tumor biopsies, thus advicing a personalized off-the-shelf drug for the treatment of these refractory cancers.
2023- 2028 Ramón and Cajal: Title: “The role of metabolism in disease ethiology”. Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación Spain.
1. Prof. Chris Chang (University of California at Berkeley, USA).
2. Prof. Manel Esteller (Josep Carreras Leukemia Research Institute, Barcelona, Spain).
3. Prof. Vanesa Gottifredi (Leloir Institute, Argentina).
4. Dr. Maria Eugenia Monge (CIBION, Buenos Aires, Argentina).
5. Prof. Angel Nebreda (IRB, Barcelona, Spain).
6. Dr. Gaël Roué (Josep Carreras Leukemia Research Institute, Barcelona, Spain).
7. Prof. Björn Schumacher (CECAD, Cologne, Germany).
8. Prof. Natascha Sommer (University of Giessen, Giessen, Germany).
9. Prof. Jordi Surrallés (Sant Pau Research Institute, Barcelona, Spain).
10. Prof. Iván Rosado (CABIMER, Sevilla, Spain).
Show all publications
Umansky C, Morellato AE, Rieckher M, Scheidegger MA, Martinefski MR, Fernández GA, Pak O, Kolesnikova K, Reingruber H, Bollini M, Crossan GP, Sommer N, Monge ME, Schumacher B, Pontel LB
Endogenous formaldehyde scavenges cellular glutathione resulting in redox disruption and cytotoxicity.Nat Commun 8 Feb 2022, 13 (1) 745. Epub 8 Feb 2022
Formaldehyde (FA) is a ubiquitous endogenous and environmental metabolite that is thought to exert cytotoxicity through DNA and DNA-protein crosslinking, likely contributing to the onset of the human DNA repair condition Fanconi Anaemia. Mutations in the genes coding for FA detoxifying enzymes underlie a human inherited bone marrow failure syndrome (IBMFS), even in the presence of functional DNA repair, raising the question of whether FA causes relevant cellular damage beyond genotoxicity. Here, we report that FA triggers cellular redox imbalance in human cells and in Caenorhabditis elegans. Mechanistically, FA reacts with the redox-active thiol group of glutathione (GSH), altering the GSH:GSSG ratio and causing oxidative stress. FA cytotoxicity is prevented by the enzyme alcohol dehydrogenase 5 (ADH5/GSNOR), which metabolizes FA-GSH products, lastly yielding reduced GSH. Furthermore, we show that GSH synthesis protects human cells from FA, indicating an active role of GSH in preventing FA toxicity. These findings might be relevant for patients carrying mutations in FA-detoxification systems and could suggest therapeutic benefits from thiol-rich antioxidants like N-acetyl-L-cysteine.More information
Pontel LB, Bueno-Costa A, Morellato AE, Carvalho Santos J, Roué G, Esteller M
Acute lymphoblastic leukemia necessitates GSH-dependent ferroptosis defenses to overcome FSP1-epigenetic silencing.Redox Biol 31 Jul 2022, 55 102408. Epub 31 Jul 2022
Ferroptosis is a form of cell death triggered by phospholipid hydroperoxides (PLOOH) generated from the iron-dependent oxidation of polyunsaturated fatty acids (PUFAs). To prevent ferroptosis, cells rely on the antioxidant glutathione (GSH), which serves as cofactor of the glutathione peroxidase 4 (GPX4) for the neutralization of PLOOHs. Some cancer cells can also limit ferroptosis through a GSH-independent axis, centered mainly on the ferroptosis suppressor protein 1 (FSP1). The significance of these two anti-ferroptosis pathways is still poorly understood in cancers from hematopoietic origin. Here, we report that blood-derived cancer cells are selectively sensitive to compounds that block the GSH-dependent anti-ferroptosis axis. In T- and B- acute lymphoblastic leukemia (ALL) cell lines and patient biopsies, the promoter of the gene coding for FSP1 is hypermethylated, silencing the expression of FSP1 and creating a selective dependency on GSH-centered anti-ferroptosis defenses. In-trans expression of FSP1 increases the resistance of leukemic cells to compounds targeting the GSH-dependent anti-ferroptosis pathway. FSP1 over-expression also favors ALL-tumor growth in an in vivo chick chorioallantoic membrane (CAM) model. Hence, our results reveal a metabolic vulnerability of ALL that might be of therapeutic interest.More information
Morellato AE, Umansky C, Pontel LB
The toxic side of one-carbon metabolism and epigenetics.Redox Biol Apr 2021, 40 101850. Epub 28 Dec 2020
One-carbon metabolism is a central metabolic hub that provides one-carbon units for essential biosynthetic reactions and for writing epigenetics marks. The leading role in this hub is performed by the one-carbon carrier tetrahydrofolate (THF), which accepts formaldehyde usually from serine generating one-carbon THF intermediates in a set of reactions known as the folate or one-carbon cycle. THF derivatives can feed one-carbon units into purine and thymidine synthesis, and into the methionine cycle that produces the universal methyl-donor S-adenosylmethionine (AdoMet). AdoMet delivers methyl groups for epigenetic methylations and it is metabolized to homocysteine (Hcy), which can enter the transsulfuration pathway for the production of cysteine and lastly glutathione (GSH), the main cellular antioxidant. This vital role of THF comes to an expense. THF and other folate derivatives are susceptible to oxidative breakdown releasing formaldehyde, which can damage DNA -a consequence prevented by the Fanconi Anaemia DNA repair pathway. Epigenetic demethylations catalysed by lysine-specific demethylases (LSD) and Jumonji histone demethylases can also release formaldehyde, constituting a potential threat for genome integrity. In mammals, the toxicity of formaldehyde is limited by a metabolic route centred on the enzyme alcohol dehydrogenase 5 (ADH5/GSNOR), which oxidizes formaldehyde conjugated to GSH, lastly generating formate. Remarkably, this formate can be a significant source of one-carbon units, thus defining a formaldehyde cycle that likely restricts the toxicity of one-carbon metabolism and epigenetic demethylations. This work describes recent advances in one-carbon metabolism and epigenetics, focusing on the steps that involve formaldehyde flux and that might lead to cytotoxicity affecting human health.More information
Umansky C, Morellato AE, Pontel LB
Illuminating cellular formaldehyde.Nat Commun 25 Jan 2021, 12 (1) 580. Epub 25 Jan 2021
Writing in Nature communications, Zhu and collaborators reported the development of a genetically encoded sensor for the detection of formaldehyde in cells and tissues. This tool has great potential to transform formaldehyde research; illuminating a cellular metabolite that has remained elusive in live structures.More information
Burgos-Barragan G, Wit N, Meiser J, Dingler FA, Pietzke M, Mulderrig L, Pontel LB, Rosado IV, Brewer TF, Cordell RL, Monks PS, Chang CJ, Vazquez A, Patel KJ
Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism.Nature 31 Aug 2017, 548 (7669) 549-554. Epub 16 Aug 2017
The folate-driven one-carbon (1C) cycle is a fundamental metabolic hub in cells that enables the synthesis of nucleotides and amino acids and epigenetic modifications. This cycle might also release formaldehyde, a potent protein and DNA crosslinking agent that organisms produce in substantial quantities. Here we show that supplementation with tetrahydrofolate, the essential cofactor of this cycle, and other oxidation-prone folate derivatives kills human, mouse and chicken cells that cannot detoxify formaldehyde or that lack DNA crosslink repair. Notably, formaldehyde is generated from oxidative decomposition of the folate backbone. Furthermore, we find that formaldehyde detoxification in human cells generates formate, and thereby promotes nucleotide synthesis. This supply of 1C units is sufficient to sustain the growth of cells that are unable to use serine, which is the predominant source of 1C units. These findings identify an unexpected source of formaldehyde and, more generally, indicate that the detoxification of this ubiquitous endogenous genotoxin creates a benign 1C unit that can sustain essential metabolism.More information
Pontel LB, Rosado IV, Burgos-Barragan G, Garaycoechea JI, Yu R, Arends MJ, Chandrasekaran G, Broecker V, Wei W, Liu L, Swenberg JA, Crossan GP, Patel KJ
Endogenous Formaldehyde Is a Hematopoietic Stem Cell Genotoxin and Metabolic Carcinogen.Mol Cell 1 Oct 2015, 60 (1) 177-88. Epub 24 Sep 2015
Endogenous formaldehyde is produced by numerous biochemical pathways fundamental to life, and it can crosslink both DNA and proteins. However, the consequences of its accumulation are unclear. Here we show that endogenous formaldehyde is removed by the enzyme alcohol dehydrogenase 5 (ADH5/GSNOR), and Adh5(-/-) mice therefore accumulate formaldehyde adducts in DNA. The repair of this damage is mediated by FANCD2, a DNA crosslink repair protein. Adh5(-/-)Fancd2(-/-) mice reveal an essential requirement for these protection mechanisms in hematopoietic stem cells (HSCs), leading to their depletion and precipitating bone marrow failure. More widespread formaldehyde-induced DNA damage also causes karyomegaly and dysfunction of hepatocytes and nephrons. Bone marrow transplantation not only rescued hematopoiesis but, surprisingly, also preserved nephron function. Nevertheless, all of these animals eventually developed fatal malignancies. Formaldehyde is therefore an important source of endogenous DNA damage that is counteracted in mammals by a conserved protection mechanism.More information