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La idea de la creación de un banco de recursos didácticos para mejorar la Competencia en Comunicación Lingüística (CCL) de una lengua extranjera en Educación Primaria, surge a raíz de observar la metodología utilizada para impartirla en colegios, tanto de España como de Francia, y observar una clara necesidad de cambio que precisan realizar los maestros de y en Lenguas Extranjeras con el fin de motivar al alumnado para alcanzar mejoras significativas en su aprendizaje. Para ello, ha sido necesaria una investigación en torno a las competencias clave y la competencia lingüística, y en torno a las metodologías y los recursos didácticos empleados en las aulas de Educación Primaria. Como respuesta a este proceso indagador, he observado una necesidad crucial en la creación o actualización de distintos recursos específicos didácticos, que sitúen al alumnado en el centro del proceso de enseñanza-aprendizaje. Estos han de ser manipulativos –para conseguir una mayor implicación en su puesta en práctica–, motivacionales –para conseguir una buena acogida–, y eficaces –para cumplir con los objetivos didácticos y, en especial, para mejorar la Competencia Lingüística en la lengua francesa–. Confío en que el uso y la aplicación de este banco de recursos sea de provecho, y proporcione los beneficios esperados en los alumnos, incentivándoles al aprendizaje de otras lenguas y velando por una correcta adquisición de la CCL en las mismas., L'idée de créer une banque de ressources pédagogiques pour améliorer la Compétence Communicative Langagière (CCL) d'une langue étrangère dans l'enseignement primaire est née de l'observation de la méthodologie utilisée pour l'enseigner dans les écoles, tant en Espagne qu'en France, et de la constatation d’un besoin clair de changement que les enseignants de et en Langues Étrangères doivent réaliser afin de motiver leurs élèves à obtenir des améliorations significatives dans leur apprentissage. Pour ce faire, il était nécessaire de mener des recherches sur les compétences clés et la compétence linguistique, ainsi que sur les méthodologies et les ressources pédagogiques utilisées dans les classes de l’enseignement primaire. En réponse à ce processus de recherche, j’ai observé un besoin crucial de création ou de mise à jour de différentes ressources pédagogiques spécifiques, qui placent aux élèves au centre du processus d'enseignement-apprentissage. Celles-ci doivent être manipulables –pour obtenir une plus grande implication dans leur mise en oeuvre–, motivantes –pour obtenir un bon accueil–, et efficaces –pour atteindre les objectifs didactiques et, en particulier, améliorer la Compétence Linguistique en langue française–. Je suis persuadé que l’utilisation et l’application de cette banque de ressources seront bénéfiques et apporteront les avantages escomptés aux élèves, en les encourageant à apprendre d'autres langues et en assurant l'acquisition correcte du CCL dans ces langues., The idea of creating a bank of teaching resources to improve Language Competence (LCC) of a foreign language in Primary Education arose from observing the methodology used to teach it in schools, both in Spain and France, and observing a clear need for change those teachers of and in Foreign Languages need to make in order to motivate students to achieve significant improvements in their learning. To achieve this, it was necessary to carry out more research into key and linguistic competences, and into the methodologies and teaching resources used in Primary Education classrooms. In response to this research process, I have observed a crucial need for the creation or the update of different specific teaching resources, which place pupils at the centre of the teaching-learning process. These must be easily manipulated - to achieve greater involvement in their implementation -, motivational - to achieve a good reception -, and effective - to meet the didactic objectives and, in particular, to improve Linguistic Competence in the French language. I trust that the use and application of this resource bank will be of benefit, and will provide the expected benefits for students, encouraging them to learn other languages and ensuring the correct acquisition of LCC in these languages., Departamento de Didáctica de la Lengua y Literatura, Grado en Educación Primaria

© 2020 American Association for Cancer Research. A hallmark of metastasis is the adaptation of tumor cells to new environments. Metabolic constraints imposed by the serine and glycine–limited brain environment restrict metastatic tumor growth. How brain metastases overcome these growth-prohibitive conditions is poorly understood. Here, we demonstrate that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is a major determinant of brain metastasis in multiple human cancer types and preclinical models. Enhanced serine synthesis proved important for nucleotide production and cell proliferation in highly aggressive brain metastatic cells. In vivo, genetic suppression and pharmacologic inhibition of PHGDH attenuated brain metastasis, but not extracranial tumor growth, and improved overall survival in mice. These results reveal that extracellular amino acid availability determines serine synthesis pathway dependence, and suggest that PHGDH inhibitors may be useful in the treatment of brain metastasis. SIGNIFICANCE: Using proteomics, metabolomics, and multiple brain metastasis models, we demonstrate that the nutrient-limited environment of the brain potentiates brain metastasis susceptibility to serine synthesis inhibition. These findings underscore the importance of studying cancer metabolism in physiologically relevant contexts, and provide a rationale for using PHGDH inhibitors to treat brain metastasis.

Aerobic glycolysis, or preferential fermentation of glucose-derived pyruvate to lactate despite available oxygen, is associated with proliferation across many organisms and conditions. To better understand that association, we examined the metabolic consequence of activating the pyruvate dehydrogenase complex (PDH) to increase pyruvate oxidation at the expense of fermentation. We find that increasing PDH activity impairs cell proliferation by reducing the NAD /NADH ratio. This change in NAD /NADH is caused by increased mitochondrial membrane potential that impairs mitochondrial electron transport and NAD regeneration. Uncoupling respiration from ATP synthesis or increasing ATP hydrolysis restores NAD /NADH homeostasis and proliferation even when glucose oxidation is increased. These data suggest that when demand for NAD to support oxidation reactions exceeds the rate of ATP turnover in cells, NAD regeneration by mitochondrial respiration becomes constrained, promoting fermentation, despite available oxygen. This argues that cells engage in aerobic glycolysis when the demand for NAD is in excess of the demand for ATP. + + + + + + +

A hallmark of metastasis is the adaptation of tumor cells to new environments. Metabolic constraints imposed by the serine and glycine-limited brain environment restrict metastatic tumor growth. How brain metastases overcome these growth-prohibitive conditions is poorly understood. Here, we demonstrate that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is a major determinant of brain metastasis in multiple human cancer types and preclinical models. Enhanced serine synthesis proved important for nucleotide production and cell proliferation in highly aggressive brain metastatic cells. In vivo, genetic suppression and pharmacological inhibition of PHGDH attenuated brain metastasis, but not extracranial tumor growth, and improved overall survival in mice. These results reveal that extracellular amino acid availability determines serine synthesis pathway dependence, and suggests that PHGDH inhibitors may be useful in the treatment of brain metastasis.

Defining the metabolic limitations of tumour growth will help to develop cancer therapies 1 . Cancer cells proliferate slower in tumours than in standard culture conditions, indicating that a metabolic limitation may restrict cell proliferation in vivo. Aspartate synthesis can limit cancer cell proliferation when respiration is impaired 2-4 ; however, whether acquiring aspartate is endogenously limiting for tumour growth is unknown. We confirm that aspartate has poor cell permeability, which prevents environmental acquisition, whereas the related amino acid asparagine is available to cells in tumours, but cancer cells lack asparaginase activity to convert asparagine to aspartate. Heterologous expression of guinea pig asparaginase 1 (gpASNase1), an enzyme that produces aspartate from asparagine 5 , confers the ability to use asparagine to supply intracellular aspartate to cancer cells in vivo. Tumours expressing gpASNase1 grow at a faster rate, indicating that aspartate acquisition is an endogenous metabolic limitation for the growth of some tumours. Tumours expressing gpASNase1 are also refractory to the growth suppressive effects of metformin, suggesting that metformin inhibits tumour growth by depleting aspartate. These findings suggest that therapeutic aspartate suppression could be effective to treat cancer., American Cancer Society. Post-Doctoral Fellowship (PF-15-096-01-TBE), National Institutes of Health (U.S.). Pathway to Independence Award (K99CA218679), Nation al Science Foundation (U.S.) (Grant GRFP DGE-1122374), National Institutes of Health (U.S.). Ruth Kirschstein Fellowship (F32CA210421), Damon Runyon Cancer Research Foundation. Robert Black Fellow ( DRG-2241-15), National Institutes of Health (U.S.) (Grant R01CA201276), National Institutes of Health (U.S.) (Grant R01CA168653), National Institutes of Health (U.S.) (Grant P30CA14051)

Increased glucose uptake and metabolism is a prominent phenotype of most cancers, but efforts to clinically target this metabolic alteration have been challenging. Here, we present evidence that lactoylglutathione (LGSH), a byproduct of methylglyoxal detoxification, is elevated in both human and murine non-small cell lung cancers (NSCLC). Methylglyoxal is a reactive metabolite byproduct of glycolysis that reacts non-enzymatically with nucleophiles in cells, including basic amino acids, and reduces cellular fitness. Detoxification of methylglyoxal requires reduced glutathione (GSH), which accumulates to high levels in NSCLC relative to normal lung. Ablation of the methylglyoxal detoxification enzyme glyoxalase I (Glo1) potentiates methylglyoxal sensitivity and reduces tumor growth in mice, arguing that targeting pathways involved in detoxification of reactive metabolites is an approach to exploit the consequences of increased glucose metabolism in cancer., National Science Foundation (U.S.). Graduate Research Fellowship Program (Grant DGE-1122374)), National Science Foundation (U.S.). Graduate Research Fellowship Program (Grant T32GM007287), United States. Department of Defense. Peer-Reviewed Medical Research Program (Grant W81XWH-15-1), National Institutes of Health (U.S.) (Grant 01CA201276), National Institutes of Health (U.S.) (Grant 01CA168653), National Institutes of Health (U.S.) (Grant 30CA14051)

Mitochondrial function is important for aspartate biosynthesis in proliferating cells. Here, we show that mitochondrial aspartate export via the aspartate-glutamate carrier 1 (AGC1) supports cell proliferation and cellular redox homeostasis. Insufficient cytosolic aspartate delivery leads to cell death when TCA cycle carbon is reduced following glutamine withdrawal and/or glutaminase inhibition. Moreover, loss of AGC1 reduces allograft tumor growth that is further compromised by treatment with the glutaminase inhibitor CB-839. Together, these findings argue that mitochondrial aspartate export sustains cell survival in low-glutamine environments and AGC1 inhibition can synergize with glutaminase inhibition to limit tumor growth. Alkan et al. show that, under conditions in which cytosolic glutamine is limiting, mitochondrial aspartate export, via the aspartate-glutamate carrier 1 (AGC1), supports cell proliferation and cellular redox homeostasis and that AGC1 inhibition can synergize with glutaminase inhibition to limit tumor growth., Austrian Science Fund (Grant FWF SFB LIPTOX F3018), Austrian Science Fund (Grant P27108, P28854), Austrian Science Fund (Grant W1226 DK), National Cancer Institute (U.S.) (Grant P30 CA1405141), National Cancer Institute (U.S.) (Grant R01 CA168653), National Science Foundation (U.S.) (Grant GRFP DGE-1122374), National Science Foundation (U.S.) (Grant T32GM007287), Damon Runyon Cancer Research Foundation (Grant DRG-2241-15)

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2018., This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections., Cataloged student-submitted from PDF version of thesis. Vita., Includes bibliographical references., Metabolic reprogramming is essential for cancer cells to balance energetics, maintain redox homeostasis, and synthesize biosynthetic precursors. Many chemotherapeutics that target metabolism are essential components of standard cancer treatment regimens, arguing that there is a therapeutic window to target the metabolic dependencies of cancer cells. However, the use of these drugs as cancer therapies was determined empirically, and rational approaches to directly target the metabolism of cancer cells, especially reprogrammed glucose metabolism, have proved challenging, in part because it is not well understood which metabolic processes are most important for cancer cell proliferation and survival. The goal of this dissertation is to explore metabolic pathways preferentially used by cancer cells in order to identify potential tumor dependencies that could be exploited for clinical benefit. We first determined that production of reactive byproducts is an indirect consequence of the altered glucose metabolism of cancer cells, which suggests that clinically targeting secondary effects of reprogrammed tumor metabolism could be an approach for designing novel cancer treatments. Next, we found that a molecular driver for the altered glucose metabolism of cancer cells is limited electron acceptor availability, suggesting that interventions that further restrict the oxidative capacity of tumors could also have anticancer efficacy. Finally, we interrogated the metabolic fluxes of breast cancers proliferating in different microenvironments and determined that tumors in the brain parenchyma display enhanced lipid biosynthesis, which could guide therapeutic strategies to treat cancer based on tumor site. Collectively, these studies contribute to an understanding of how the reprogrammed metabolism of cancer cells introduces targetable dependencies, with the aim of optimizing cancer therapies., by Alba Luengo., Ph. D.

Cultured cells convert glucose to lactate, and glutamine is the major source of tricarboxylic acid (TCA)-cycle carbon, but whether the same metabolic phenotype is found in tumors is less studied. We infused mice with lung cancers with isotope-labeled glucose or glutamine and compared the fate of these nutrients in tumor and normal tissue. As expected, lung tumors exhibit increased lactate production from glucose. However, glutamine utilization by both lung tumors and normal lung was minimal, with lung tumors showing increased glucose contribution to the TCA cycle relative to normal lung tissue. Deletion of enzymes involved in glucose oxidation demonstrates that glucose carbon contribution to the TCA cycle is required for tumor formation. These data suggest that understanding nutrient utilization by tumors can predict metabolic dependencies of cancers in vivo. Furthermore, these data argue that the in vivo environment is an important determinant of the metabolic phenotype of cancer cells., National Science Foundation (U.S.) (Grant T32GM007287)

Mammalian tissues rely on a variety of nutrients to support their physiological functions. It is known that altered metabolism is involved in the pathogenesis of cancer, but which nutrients support the inappropriate growth of intact malignant tumors is incompletely understood. Amino acids are essential nutrients for many cancer cells that can be obtained through the scavenging and catabolism of extracellular protein via macropinocytosis. In particular, macropinocytosis can be a nutrient source for pancreatic cancer cells, but it is not fully understood how the tumor environment influences metabolic phenotypes and whether macropinocytosis supports the maintenance of amino acid levels within pancreatic tumors. Here we utilize miniaturized plasma exchange to deliver labeled albumin to tissues in live mice, and we demonstrate that breakdown of albumin contributes to the supply of free amino acids in pancreatic tumors. We also deliver albumin directly into tumors using an implantable microdevice, which was adapted and modified from ref. 9. Following implantation, we directly observe protein catabolism and macropinocytosis in situ by pancreatic cancer cells, but not by adjacent, non-cancerous pancreatic tissue. In addition, we find that intratumoral inhibition of macropinocytosis decreases amino acid levels. Taken together, these data suggest that pancreatic cancer cells consume extracellular protein, including albumin, and that this consumption serves as an important source of amino acids for pancreatic cancer cells in vivo., National Science Foundation (U.S.) (Grant T32GM007287), National Cancer Institute (U.S.) (Grant F30CA183474), National Institute of General Medical Sciences (U.S.) (Award T32GM007753), National Institutes of Health (U.S.) (Grant P30CA1405141), National Institutes of Health (U.S.) (Grant R01CA168653)

Metformin use is associated with reduced cancer mortality, but how metformin impacts cancer outcomes is controversial. Although metformin can act on cells autonomously to inhibit tumor growth, the doses of metformin that inhibit proliferation in tissue culture are much higher than what has been described in vivo. Here, we show that the environment drastically alters sensitivity to metformin and other complex I inhibitors. We find that complex I supports proliferation by regenerating nicotinamide adenine dinucleotide (NAD)+, and metformin's anti-proliferative effect is due to loss of NAD+/NADH homeostasis and inhibition of aspartate biosynthesis. However, complex I is only one of many inputs that determines the cellular NAD+/NADH ratio, and dependency on complex I is dictated by the activity of other pathways that affect NAD+ regeneration and aspartate levels. This suggests that cancer drug sensitivity and resistance are not intrinsic properties of cancer cells, and demonstrates that the environment can dictate sensitivity to therapies that impact cell metabolism. Keywords: cancer metabolism; metformin; biguanide; NAD+/NADH ratio; drug sensitivity; complex I; mitochondria; aspartate, National Institutes of Health (U.S.) (Grant P30CA1405141), National Institutes of Health (U.S.) (Grant GG006413), National Institutes of Health (U.S.) (Grant R01 CA168653), National Institutes of Health (U.S.) (Grant R01 CA201276)

Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of pyruvate kinase (PK), and PKM2 expression is closely linked to embryogenesis, tissue regeneration, and cancer. To interrogate the functional requirement for PKM2 during development and tissue homeostasis, we generated germline PKM2-null mice (Pkm2[superscript −/−]). Unexpectedly, despite being the primary isoform expressed in most wild-type adult tissues, we found that Pkm2[superscript −/−] mice are viable and fertile. Thus, PKM2 is not required for embryonic or postnatal development. Loss of PKM2 leads to compensatory expression of PKM1 in the tissues that normally express PKM2. Strikingly, PKM2 loss leads to spontaneous development of hepatocellular carcinoma (HCC) with high penetrance that is accompanied by progressive changes in systemic metabolism characterized by altered systemic glucose homeostasis, inflammation, and hepatic steatosis. Therefore, in addition to its role in cancer metabolism, PKM2 plays a role in controlling systemic metabolic homeostasis and inflammation, thereby preventing HCC by a non-cell-autonomous mechanism., National Cancer Institute (U.S.) (Cancer Center Support Grant P30CA14051), Howard Hughes Medical Institute, Burroughs Wellcome Fund, Smith Family Foundation, United States. Dept. of Health and Human Services (P01CA117969), United States. Dept. of Health and Human Services (R01CA168653), American Society for Engineering Education. National Defense Science and Engineering Graduate Fellowship, Jane Coffin Childs Memorial Fund for Medical Research (Postdoctoral Fellowship)

Serine is a both a proteinogenic amino acid and the source of one-carbon units essential for de novo purine and deoxythymidine synthesis. In the canonical glucose-derived serine synthesis pathway, Homo sapiens phosphoglycerate dehydrogenase (PHGDH) catalyzes the first, ratelimiting step. Genetic loss of PHGDH is toxic towards PHGDH-overexpressing breast cancer cell lines even in the presence of exogenous serine. Here, we use a quantitative high-throughput screen to identify small molecule PHGDH inhibitors. These compounds reduce the production of glucose-derived serine in cells and suppress the growth of PHGDH-dependent cancer cells in culture and in orthotopic xenograft tumors. Surprisingly, PHGDH inhibition reduced the incorporation into nucleotides of one-carbon units from glucose-derived and exogenous serine. We conclude that glycolytic serine synthesis coordinates the use of one-carbon units from endogenous and exogenous serine in nucleotide synthesis, and suggest that one-carbon unit wasting may contribute to the efficacy of PHGDH inhibitors in vitro and in vivo., Damon Runyon Cancer Research Foundation (Sally Gordon Fellowship DRG-112-12), United States. Dept. of Defense. Breast Cancer Research Program (Postdoctoral Fellowship BC120208), American Society for Radiation Oncology (Resident Seed Grant RA-2011-1), European Molecular Biology Organization (Long-Term Fellowship), National Institutes of Health (U.S.) (R03 DA034602-01A1, R01 CA129105, R01 CA103866, and R37 AI047389), United States. Department of Defense (W81XWH-14-PRCRP-IA), Alexander and Margaret Stewart Trust

Metformin has been a first-line treatment for type II diabetes mellitus for decades and is the most widely prescribed antidiabetic drug. Retrospective studies have found that metformin treatment is associated with both reduced cancer diagnoses and cancer-related deaths. Despite the prevalence of metformin use in the clinic, its molecular mechanism of action remains controversial. In a recent issue of Cancer & Metabolism, Andrzejewski et al. present evidence that metformin acts directly on mitochondria to inhibit complex I and limits the ability of cancer cells to cope with energetic stress. Here, we discuss evidence that supports the role of metformin as a cancer therapeutic.

We are presenting an action and research experience with students of Early Chilhood Education Degree. Taking advantage of the practicum period in schools— when language of children aged 3, 4 and 5 years old are observed, we have proposed to the future teachers to collect all the words that do not conform the standard vocabulary of the Spanish language. Subsequently, we proposed them to carry out an analysis and categorization of the constructed words and then a reflection that will allow them in the future to understand their students and put into practice what they have learnt in this experience. Finally, as it is indicated in the aims, along with the performance of this study of the linguistic produccions, it is manifested the correlation between theory and practice, acquiring the abilities expressed in the title, related to skills and know-how (savoir faire) and ability to learn (savoir apprendre)., Presentamos una experiencia de investigación–acción realizada con el alumnado que cursa el título de Grado en Educación Infantil a los que, aprovechando el periodo de practicum en los centros escolares donde se realiza una observación del lenguaje del alumnado de tres, cuatro y cinco años, les hemos propuesto la recogida de todas aquellas palabras que no se ajustan a la norma del léxico de la lengua castellana. Posteriormente realizaron un análisis y categorización de las palabras construidas y una reflexión que les permitirá en el futuro entender a su alumnado y aplicar lo aprendido en esta experiencia cuando se conviertan en responsables de una clase. Finalmente y tal como se expresa en los objetivos con la realización del estudio de las producciones lingüísticas se pone de manifiesto la relación de la teoría y la práctica y con ello adquieren las competencias expresadas en el título relacionadas con saber y saber hacer.