Targeting cancer cell metabolism as a therapeutic strategy

In the past 15 years the field of cancer metabolism has burst providing vast quantities of information regarding the metabolic adaptations found in cancer cells and offering promising hints for the development of therapies that target metabolic features of cancer cells. By making use of the powerful combination of metabolomics and 13C-labelled metabolite tracing we have contributed to the field by identifying a mitochondrial enzymatic cascade crucial for oncogene-induced senescence (OIS), which is a tumour suppressive mechanism important in melanoma, linking in this way OIS to the regulation of metabolism. Furthermore, we have identified the dependency on glutamine metabolism as an important adaptation occurring concomitantly with the acquisition of resistance to vemurafenib (BRAF inhibitor) in melanoma, which opens the possibility to combine therapies targeting glutamine metabolism with BRAF inhibitors, in order to overcome or avoid the onset of resistance in melanoma. Using the same strategy we have discovered an important mechanism of interregulation between glycolysis and amino acid metabolism, identifying the glucose-derived amino acid serine as an activator of the main isoform of pyruvate kinase present in cancer cells, PKM2. In addition, we provide new insights into the mechanism of allosteric regulation of this complex protein and a better understanding of the way it regulates central carbon metabolism. In summary, our results open new possibilities for the development of cancer therapies that manipulate metabolic adaptations found in cancer cells in order to kill them specifically or halt their growth

Modeling cancer metabolism on a genome scale

Cancer cells have fundamentally altered cellular metabolism that is associated with their tumorigenicity and malignancy. In addition to the widely studied Warburg effect, several new key metabolic alterations in cancer have been established over the last decade, leading to the recognition that altered tumor metabolism is one of the hallmarks of cancer. Deciphering the full scope and functional implications of the dysregulated metabolism in cancer requires both the advancement of a variety of omics measurements and the advancement of computational approaches for the analysis and contextualization of the accumulated data. Encouragingly, while the metabolic network is highly interconnected and complex, it is at the same time probably the best characterized cellular network. Following, this review discusses the challenges that genome‐scale modeling of cancer metabolism has been facing. We survey several recent studies demonstrating the first strides that have been done, testifying to the value of this approach in portraying a network‐level view of the cancer metabolism and in identifying novel drug targets and biomarkers. Finally, we outline a few new steps that may further advance this field

Resistance to BRAF inhibitors induces glutamine dependency in melanoma cells

BRAF inhibitors can extend progression-free and overall survival in melanoma patients whose tumors harbor mutations in BRAF. However, the majority of patients eventually develop resistance to these drugs. Here we show that BRAF mutant melanoma cells that have developed acquired resistance to BRAF inhibitors display increased oxidative metabolism and increased dependency on mitochondria for survival. Intriguingly, the increased oxidative metabolism is associated with a switch from glucose to glutamine metabolism and an increased dependence on glutamine over glucose for proliferation. We show that the resistant cells are more sensitive to mitochondrial poisons and to inhibitors of glutaminolysis, suggesting that targeting specific metabolic pathways may offer exciting therapeutic opportunities to treat resistant tumors, or to delay emergence of resistance in the first-line setting

Progress in creating a joint research agenda that allows networked long-term socio-ecological research in southern South America : addressing crucial technological and human capacity gaps limiting its application in Chile and Argentina

Since 1980, more than 40 countries have implemented long-term ecological research (LTER) programs, which have shown their power to affect advances in basic science to understand the natural world at meaningful temporal and spatial scales and also help link research with socially relevant outcomes. Recently, a disciplinary paradigmatic shift has integrated the human dimensions of ecosystems, leading to a long-term socio-ecological research (LTSER) framework to address the world's current environmental challenges. A global gap in LTER/LTSER only exists in the latitudinal range of 40–60°S, corresponding to Argentina and Chile's temperate/sub-Antarctic biome. A team of Chilean, Argentine and US researchers has participated in an ongoing dialogue to define not only conceptual, but also practical barriers limiting LTER/LTSER in southern South America. We have found a number of existing long-term research sites and platforms throughout the region, but at the same time it has been concluded an agenda is needed to create and implement further training courses for students, postdoctoral fellows and young scientists, particularly in the areas of data and information management systems. Since LTER/LTSER efforts in Chile and Argentina are incipient, instituting such courses now will enhance human and technical capacity of the natural science and resource community to improve the collection, storage, analysis and dissemination of information in emerging LTER/LTSER platforms. In turn, having this capacity, as well as the ongoing formalization of LTER/LTSER programs at national levels, will allow the enhancement of crucial collaborations and comparisons between long-term research programs within the region and between hemispheres and continents. For Spanish version of the entire article, see Online Supporting Information (Appendix S1).Desde 1980, más de cuarenta países han implementado programas de Investigación Ecológica a Largo Plazo (LTER por sus siglas en inglés), los cuales han mostrado su capacidad para influir sobre los avances en las ciencias básicas que permiten entender el mundo natural en escalas temporales y espaciales significativas, y también ayudar a enfocar la investigación hacia estudios socialmente relevantes. Recientemente, gracias a un cambio de paradigma en la disciplina, se integró también la dimensión humana de los ecosistemas, llevándola a un marco conceptual de Investigación Socio-Ecológica a Largo Plazo (LTSER por sus siglas en inglés) para enfrentar los desafíos medio-ambientales del mundo actual. Existe un vacío global en LTER/LTSER en el rango latitudinal de 40–60°S, correspondiente a los biomas templados/subantárticos de Argentina y Chile. Un equipo de investigadores chilenos, argentinos y estadounidenses ha trabajado por varios años para definir cuáles son la barreras que actualmente limitan la creación de una Red de LTER/LTSER en el sur de Sudamérica, no solamente en términos conceptuales, sino también a nivel práctico. Existe un buen número de sitios de investigación a largo plazo en la región, pero también concluimos que es necesario crear e implementar más cursos de capacitación para estudiantes, investigadores post-doctorales y jóvenes científicos, particularmente en las áreas de sistemas de manejo de datos e información. Considerando que los esfuerzos LTER/LTSER en Chile y Argentina son incipientes, este tipo de cursos podría mejorar la capacidad humana y técnica en la comunidad de las ciencias y los recursos naturales, así como mejorar los procesos de recolección, almacenamiento, análisis y difusión de la información. A su vez, la formalización de cursos de programas LTER/LTSER a nivel nacional para adquirir dicha capacidad de manejo de la información, permitirá un fortalecimiento crucial de las colaboraciones y comparaciones entre programas de investigación a largo plazo dentro de la región, y entre hemisferios y continentes. La versión en castellano del artículo se encuentra disponible en forma digital como Online Supporting Information S1.Fil: Anderson, Chistopher B. University of North Texas. Department of Biological Sciences; Estados UnidosFil: Celis-Diez, Juan Luis. Pontificia Universidad Católica de Valparaíso, Escuela de Agronomía; ChileFil: Bond, Barbara J.H.G. Oregon State University. Andrews Forest Long-Term Ecological Research Site. Department of Forest Ecosystems and Society; Estados UnidosFil: Martínez Pastur, Guillermo José. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Cientificas; ArgentinaFil: Little, Christian. Universidad Austral de Chile. Facultad de Ciencias. Instituto de Ciencias de la Tierra y Evolución; Chile. Fundación Centro de los Bosques Nativos FORECOS; ChileFil: Armesto, Juan J. Pontificia Universidad Católica de Valparaíso, Escuela de Agronomía; ChileFil: Ghersa, Claudio Marco. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Austin, Amy Theresa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Schlichter, Tomas Miguel. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Bariloche. Grupo de Ecología Forestal; ArgentinaFil: Lara, Antonio. Fundación Centro de los Bosques Nativos FORECOS; Chile. Universidad Austral de Chile. Facultad de Ciencias Forestales y Recursos Naturales. Instituto de Silvicultura; ChileFil: Carmona, Martin. Universidad de Chile. Instituto de Ecologıa y Biodiversidad; ChileFil: Chaneton, Enrique Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; Argentina. Universidad de Buenos Aires. Facultad de Agronomia. Departamento de Recursos Naturales y Ambiente; ArgentinaFil: Gutierrez, Julio R. Universidad de La Serena. Departamento de Biología. Instituto de Ecología y Biodiversidad. Centro de Estudios Avanzados en Zonas Aridas; ChileFil: Rozzi, Ricardo. Universidad de La Serena. Departamento de Biología. Instituto de Ecología y Biodiversidad; ChileFil: Vanderbilt, Kristin University of New Mexico. Department of Biology. Sevilleta Long-Term Ecological Research Site; Estados UnidosFil: Oyarce, Guillermo University of North Texas. Library and Information Sciences; Estados UnidosFil: Fernandez, Roberto J. University of North Texas, Department of Biological Sciences; Estados Unido

Mowing does not redress the negative effect of nutrient addition on alpha and beta diversity in a temperate grassland

Species loss due to an increasing the number of added nutrients has been explained by both light competition through biomass increase and by niche dimension reduction as a result of species-specific limiting soil resources trade-offs. Disturbances, by reducing community biomass, species dominance and increasing light availability, may counteract above-ground nutrient effects. However, it is unknown if diversity loss at local or spatial scales generated by increasing the number of added nutrients can be redressed with canopy disturbance. We evaluated if local (alpha) and spatial scale (beta) diversity loss generated by the number of added nutrients can be reverted by disturbances in Flooding Pampa grasslands, Argentina. In a 4-year replicated field experiment, we added soil resources combining nitrogen, phosphorus and potassium to obtain 0, 1, 2 or 3 nutrients and manipulated the regime of canopy disturbance by seasonal mowing and biomass removal. We found that the increasing the number of added nutrients strongly reduced local and spatial plant diversity, despite biomass and light changes generated by mowing. In mown plots, nutrient-driven local diversity loss intensified along time, thus increasing species dominance. While mowing did not affect dominant species loss, increasing the number of added nutrients promoted rare species loss and reduced spatial dissimilarity. Furthermore, mowing increased local and spatial diversity regardless of light or biomass effects, suggesting alternative pathway effects for disturbance. Synthesis. Our results demonstrate that even when disturbance generated a positive effect on local and spatial diversity, it did not completely counteract the negative effect of number of added nutrients. Thus, the relative importance of above- and below-ground resource competition may change when chronic disturbances alter community dominance. Under low light availability, above-ground competition may drive species richness loss but when disturbance reduces light limitation, the increasing the number of added nutrients may reduce niche dimensionality and thus species coexistence. In sum, faced with the need to manage eutrophized grasslands, our study showed that disturbance may not completely mitigate the negative effect of multiple nutrient inputs on local and spatial grassland diversity.Fil: Molina, Cecilia Denisse. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; Argentina. Universidad de Buenos Aires. Facultad de Agronomía; ArgentinaFil: Tognetti, Pedro Maximiliano. Universidad de Buenos Aires. Facultad de Agronomía. Departamento de Métodos Cuantitativos y Sistemas de Información; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Graff, Barbara Pamela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; Argentina. Universidad de Buenos Aires. Facultad de Agronomía. Departamento de Recursos Naturales y Ambiente; ArgentinaFil: Chaneton, Enrique Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; Argentin

A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence

In response to tenacious stress signals, such as the unscheduled activation of oncogenes, cells can mobilize tumour suppressor networks to avert the hazard of malignant transformation. A large body of evidence indicates that oncogene-induced senescence (OIS) acts as such a break, withdrawing cells from the proliferative pool almost irreversibly, thus crafting a vital pathophysiological mechanism that protects against cancer. Despite the widespread contribution of OIS to the cessation of tumorigenic expansion in animal models and humans, we have only just begun to define the underlying mechanism and identify key players. Although deregulation of metabolism is intimately linked to the proliferative capacity of cells and senescent cells are thought to remain metabolically active, little has been investigated in detail about the role of cellular metabolism in OIS. Here we show, by metabolic profiling and functional perturbations, that the mitochondrial gatekeeper pyruvate dehydrogenase (PDH) is a crucial mediator of senescence induced by BRAFV600E, an oncogene commonly mutated in melanoma and other cancers. BRAFV600E-induced senescence was accompanied by simultaneous suppression of the PDH-inhibitory enzyme pyruvate dehydrogenase kinase 1 (PDK1) and induction of the PDH-activating enzyme pyruvate dehydrogenase phosphatase 2 (PDP2). The resulting combined activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress. Abrogation of OIS, a rate-limiting step towards oncogenic transformation, coincided with reversion of these processes. Further supporting a crucial role of PDH in OIS, enforced normalization of either PDK1 or PDP2 expression levels inhibited PDH and abrogated OIS, thereby licensing BRAFV600E-driven melanoma development. Finally, depletion of PDK1 eradicated melanoma subpopulations resistant to targeted BRAF inhibition, and caused regression of established melanomas. These results reveal a mechanistic relationship between OIS and a key metabolic signalling axis, which may be exploited therapeutically

Serine is a natural ligand and allosteric activator of pyruvate kinase M2

Cancer cells exhibit several unique metabolic phenotypes that are critical for cell growth and proliferation(1). Specifically, they overexpress the M2 isoform of the tightly regulated enzyme pyruvate kinase (PKM2), which controls glycolytic flux, and are highly dependent on de novo biosynthesis of serine and glycine(2). Here we describe a new rheostat-like mechanistic relationship between PKM2 activity and serine biosynthesis. We show that serine can bind to and activate human PKM2, and that PKM2 activity in cells is reduced in response to serine deprivation. This reduction in PKM2 activity shifts cells to a fuel-efficient mode in which more pyruvate is diverted to the mitochondria and more glucose-derived carbon is channelled into serine biosynthesis to support cell proliferation

Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase

Fumarate hydratase (FH) is an enzyme of the tricarboxylic acid cycle (TCA cycle) that catalyses the hydration of fumarate into malate. Germline mutations of FH are responsible for hereditary leiomyomatosis and renal-cell cancer (HLRCC)1. It has previously been demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions2, 3, 4. However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables Fh1-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render Fh1-deficient cells non-viable, while sparing wild-type Fh1-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a new potential target for treating HLRCC patients.demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions. However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables Fh1-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render Fh1-deficient cells non-viable, while sparing wild-type Fh1-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a new potential target for treating HLRCC patients