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Publication 53BP1 Enforces Distinct Pre- and Post-resection Blocks on Homologous Recombination.(Cell Press, 2020-01-02) Callen, Elsa; Zong, Dali; Wu, Wei; Wong, Nancy; Stanlie, Andre; Ishikawa, Momoko; Pavani, Raphael; Dumitrache, Lavinia C; Byrum, Andrea K; Mendez-Dorantes, Carlos; Martinez, Paula; Canela, Andres; Maman, Yaakov; Day, Amanda; Kruhlak, Michael J; Blasco, MA; Stark, Jeremy M; Mosammaparast, Nima; McKinnon, Peter J; Nussenzweig, André; United States Department of Health and Human Services; Lawrence Ellison Foundation; United States Department of Defense; United States Department of Health and Human Services53BP1 activity drives genome instability and lethality in BRCA1-deficient mice by inhibiting homologous recombination (HR). The anti-recombinogenic functions of 53BP1 require phosphorylation-dependent interactions with PTIP and RIF1/shieldin effector complexes. While RIF1/shieldin blocks 5'-3' nucleolytic processing of DNA ends, it remains unclear how PTIP antagonizes HR. Here, we show that mutation of the PTIP interaction site in 53BP1 (S25A) allows sufficient DNA2-dependent end resection to rescue the lethality of BRCA1Δ11 mice, despite increasing RIF1 "end-blocking" at DNA damage sites. However, double-mutant cells fail to complete HR, as excessive shieldin activity also inhibits RNF168-mediated loading of PALB2/RAD51. As a result, BRCA1Δ1153BP1S25A mice exhibit hallmark features of HR insufficiency, including premature aging and hypersensitivity to PARPi. Disruption of shieldin or forced targeting of PALB2 to ssDNA in BRCA1D1153BP1S25A cells restores RNF168 recruitment, RAD51 nucleofilament formation, and PARPi resistance. Our study therefore reveals a critical function of shieldin post-resection that limits the loading of RAD51.Publication A Chemical Screen Identifies Compounds Capable of Selecting for Haploidy in Mammalian Cells(Cell Press, 2019-07-16) Olbrich, Teresa; Vega-Sendino, Maria; Murga, Matilde; de Carcer Diez, Guillermo; Malumbres Martinez, Marcos; Ortega Jimenez, Sagrario; Ruiz, Sergio; Fernandez-Capetillo, Oscar; Boehringer Ingelheim Fonds; Ministerio de Economía y Competitividad (España); Botín Foundation; Unión Europea. Comisión Europea. European Research Council (ERC)The recent availability of somatic haploid cell lines has provided a unique tool for genetic studies in mammals. However, the percentage of haploid cells rapidly decreases in these cell lines, which we recently showed is due to their overgrowth by diploid cells present in the cultures. Based on this property, we have now performed a phenotypic chemical screen in human haploid HAP1 cells aiming to identify compounds that facilitate the maintenance of haploid cells. Our top hit was 10-Deacetyl-baccatin-III (DAB), a chemical precursor in the synthesis of Taxol, which selects for haploid cells in HAP1 and mouse haploid embryonic stem cultures. Interestingly, DAB also enriches for diploid cells in mixed cultures of diploid and tetraploid cells, including in the colon cancer cell line DLD-1, revealing a general strategy for selecting cells with lower ploidy in mixed populations of mammalian cells.Publication A comprehensive analysis of prefoldins and their implication in cancer.(Cell Press, 2021-11-19) Herranz-Montoya, Irene; Park, Solip; Djouder, Nabil; Djouder, Nabil; Ministerio de Ciencia e Innovación (España); European Union (EU)Prefoldins (PFDNs) are evolutionary conserved co-chaperones, initially discovered in archaea but universally present in eukaryotes. PFDNs are prevalently organized into hetero-hexameric complexes. Although they have been overlooked since their discovery and their functions remain elusive, several reports indicate they act as co-chaperones escorting misfolded or non-native proteins to group II chaperonins. Unlike the eukaryotic PFDNs which interact with cytoskeletal components, the archaeal PFDNs can bind and stabilize a wide range of substrates, possibly due to their great structural diversity. The discovery of the unconventional RPB5 interactor (URI) PFDN-like complex (UPC) suggests that PFDNs have versatile functions and are required for different cellular processes, including an important role in cancer. Here, we summarize their functions across different species. Moreover, a comprehensive analysis of PFDNs genomic alterations across cancer types by using large-scale cancer genomic data indicates that PFDNs are a new class of non-mutated proteins significantly overexpressed in some cancer types.Publication A Genome-wide CRISPR Screen Identifies CDC25A as a Determinant of Sensitivity to ATR Inhibitors(Cell Press, 2016-04-21) Ruiz, Sergio; Mayor-Ruiz, Cristina; Lafarga, Vanesa; Murga, Matilde; Vega-Sendino, Maria; Ortega Jimenez, Sagrario; Fernandez-Capetillo, Oscar; Botín Foundation; Fundación La Marató TV3; Howard Hughes Medical Institute; Unión Europea. Comisión Europea. European Research Council (ERC); Fundación La Caixa; Ministerio de Economía y Competitividad (España)One recurring theme in drug development is to exploit synthetic lethal properties as means to preferentially damage the DNA of cancer cells. We and others have previously developed inhibitors of the ATR kinase, shown to be particularly genotoxic for cells expressing certain oncogenes. In contrast, the mechanisms of resistance to ATR inhibitors remain unexplored. We report here on a genome-wide CRISPR-Cas9 screen that identified CDC25A as a major determinant of sensitivity to ATR inhibition. CDC25A-deficient cells resist high doses of ATR inhibitors, which we show is due to their failure to prematurely enter mitosis in response to the drugs. Forcing mitotic entry with WEE1 inhibitors restores the toxicity of ATR inhibitors in CDC25A-deficient cells. With ATR inhibitors now entering the clinic, our work provides a better understanding of the mechanisms by which these compounds kill cells and reveals genetic interactions that could be used for their rational use.Publication A mechanistic view of the use of cold temperature in the treatment of cancer.(Cell Press, 2023-04-21) Grazioso, Tatiana P; Djouder, NabilIn their latest article, Seki and colleagues investigate the potential role of cold as a therapeutical option to treat various cancer types, including even clinically untreatable cancers such as pancreatic cancers. The authors suggest that cold exposure may have a tumor-suppressive effect mediated by the activation of brown adipose tissue (BAT), in charge of dissipating heat through non-shivering thermogenesis. In this regard, circulating blood glucose is decreased, restricting the tumor glucose uptake, which is redistributed, favoring BAT uptake to fuel thermogenesis.1.Publication A proteomic characterization of factors enriched at nascent DNA molecules.(Cell Press, 2013-04-25) Lopez-Contreras, Andres J; Ruppen, Isabel; Nieto-Soler, Maria; Murga, Matilde; Rodriguez-Acebes, Sara; Remeseiro, Silvia; Rodrigo-Perez, Sara; Rojas, Ana M; Mendez, Juan; Muñoz, Javier; Fernandez-Capetillo, Oscar; Asociación Española Contra el Cáncer; Fundación La Caixa; Ministerio de Ciencia (España)DNA replication is facilitated by multiple factors that concentrate in the vicinity of replication forks. Here, we developed an approach that combines the isolation of proteins on nascent DNA chains with mass spectrometry (iPOND-MS), allowing a comprehensive proteomic characterization of the human replisome and replisome-associated factors. In addition to known replisome components, we provide a broad list of proteins that reside in the vicinity of the replisome, some of which were not previously associated with replication. For instance, our data support a link between DNA replication and the Williams-Beuren syndrome and identify ZNF24 as a replication factor. In addition, we reveal that SUMOylation is widespread for factors that concentrate near replisomes, which contrasts with lower UQylation levels at these sites. This resource provides a panoramic view of the proteins that concentrate in the surroundings of the replisome, which should facilitate future investigations on DNA replication and genome maintenance.Publication A synthetic lethal interaction between APC/C and topoisomerase poisons uncovered by proteomic screens.(Cell Press, 2014-02-27) Eguren, Manuel; Alvarez Fernandez, Monica; García, Fernando; López-Contreras, Andrés J; Fujimitsu, Kazuyuki; Yaguchi, Hiroko; Luque-García, José Luis; Yamano, Hiroyuki; Fernandez-Capetillo, Oscar; Malumbres Martinez, Marcos; Munoz, Javier; Ministerio de Ciencia e Innovación (España); Asociación Española Contra el Cáncer; Howard Hughes Medical Institute; Unión Europea. Comisión Europea. European Research Council (ERC); Fundación Ramón Areces; Comunidad de Madrid (España); Unión Europea; Worldwide Cancer Research; Cancer Research UK (Reino Unido)The Anaphase-promoting complex/cyclosome (APC/C) cofactor Cdh1 modulates cell proliferation by targeting multiple cell-cycle regulators for ubiquitin-dependent degradation. Lack of Cdh1 results in structural and numerical chromosome aberrations, a hallmark of genomic instability. By using a proteomic approach in Cdh1-null cells and mouse tissues, we have identified kinesin Eg5 and topoisomerase 2α as Cdh1 targets involved in the maintenance of genomic stability. These proteins are ubiquitinated and degraded through specific KEN and D boxes in a Cdh1-dependent manner. Whereas Cdh1-null cells display partial resistance to Eg5 inhibitors such as monastrol, lack of Cdh1 results in a dramatic sensitivity to Top2α poisons as a consequence of increased levels of trapped Top2α-DNA complexes. Chemical inhibition of the APC/C in cancer cells results in increased sensitivity to Top2α poisons. This work identifies in vivo targets of the mammalian APC/C-Cdh1 complex and reveals synthetic lethal interactions of relevance in anticancer treatments.Publication APLF and long non-coding RNA NIHCOLE promote stable DNA synapsis in non-homologous end joining.(Cell Press, 2023-01-31) De Bragança, Sara; Aicart-Ramos, Clara; Arribas-Bosacoma, Raquel; Rivera-Calzada, Angel; Unfried, Juan Pablo; Prats-Mari, Laura; Marin-Baquero, Mikel; Fortes, Puri; Llorca Blanco, Oscar Antonio; Moreno-Herrero, Fernando; Ministerio de Ciencia, Innovación y Universidades (España); Unión Europea; Consejo Superior de Investigaciones Científicas (España)The synapsis of DNA ends is a critical step for the repair of double-strand breaks by non-homologous end joining (NHEJ). This is performed by a multicomponent protein complex assembled around Ku70-Ku80 heterodimers and regulated by accessory factors, including long non-coding RNAs, through poorly understood mechanisms. Here, we use magnetic tweezers to investigate the contributions of core NHEJ proteins and APLF and lncRNA NIHCOLE to DNA synapsis. APLF stabilizes DNA end bridging and, together with Ku70-Ku80, establishes a minimal complex that supports DNA synapsis for several minutes under piconewton forces. We find the C-terminal acidic region of APLF to be critical for bridging. NIHCOLE increases the dwell time of the synapses by Ku70-Ku80 and APLF. This effect is further enhanced by a small and structured RNA domain within NIHCOLE. We propose a model where Ku70-Ku80 can simultaneously bind DNA, APLF, and structured RNAs to promote the stable joining of DNA ends.Publication BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation.(Cell Press, 2019-03-21) Zong, Dali; Adam, Salomé; Wang, Yifan; Sasanuma, Hiroyuki; Callén, Elsa; Murga, Matilde; Day, Amanda; Kruhlak, Michael J; Wong, Nancy; Munro, Meagan; Ray Chaudhuri, Arnab; Karim, Baktiar; Xia, Bing; Takeda, Shunichi; Johnson, Neil; Durocher, Daniel; Nussenzweig, André; Ministerio de Educación, Cultura y Deporte (España); United States Department of Health and Human Services; Lawrence Ellison Foundation; United States Department of Defense; Alex's Lemonade Stand Foundation; NIH - National Cancer Institute (NCI) (Estados Unidos); Rutgers Cancer InstituteBRCA1 functions at two distinct steps during homologous recombination (HR). Initially, it promotes DNA end resection, and subsequently it recruits the PALB2 and BRCA2 mediator complex, which stabilizes RAD51-DNA nucleoprotein filaments. Loss of 53BP1 rescues the HR defect in BRCA1-deficient cells by increasing resection, suggesting that BRCA1's downstream role in RAD51 loading is dispensable when 53BP1 is absent. Here we show that the E3 ubiquitin ligase RNF168, in addition to its canonical role in inhibiting end resection, acts in a redundant manner with BRCA1 to load PALB2 onto damaged DNA. Loss of RNF168 negates the synthetic rescue of BRCA1 deficiency by 53BP1 deletion, and it predisposes BRCA1 heterozygous mice to cancer. BRCA1+/-RNF168-/- cells lack RAD51 foci and are hypersensitive to PARP inhibitor, whereas forced targeting of PALB2 to DNA breaks in mutant cells circumvents BRCA1 haploinsufficiency. Inhibiting the chromatin ubiquitin pathway may, therefore, be a synthetic lethality strategy for BRCA1-deficient cancers.Publication c-RAF Ablation Induces Regression of Advanced Kras/Trp53 Mutant Lung Adenocarcinomas by a Mechanism Independent of MAPK Signaling(Cell Press, 2018-05-01) Sanclemente, Manuel; Francoz, Sarah; Esteban-Burgos, Laura; Bousquet-Mur, Emilie; Djurec, Magdolna; Lopez-Casas, Pedro P; Hidalgo, Manuel; Guerra, Carmen; Drosten, Matthias; Musteanu, Mónica; Barbacid, Mariano; Unión Europea. Comisión Europea. European Research Council (ERC); Ministerio de Economía e Innovación (España); Comunidad de Madrid (España); Fundación AXAA quarter of all solid tumors harbor KRAS oncogenes. Yet, no selective drugs have been approved to treat these malignancies. Genetic interrogation of the MAPK pathway revealed that systemic ablation of MEK or ERK kinases in adult mice prevent tumor development but are unacceptably toxic. Here, we demonstrate that ablation of c-RAF expression in advanced tumors driven by KrasG12V/Trp53 mutations leads to significant tumor regression with no detectable appearance of resistance mechanisms. Tumor regression results from massive apoptosis. Importantly, systemic abrogation of c-RAF expression does not inhibit canonical MAPK signaling, hence, resulting in limited toxicities. These results are of significant relevance for the design of therapeutic strategies to treat K-RAS mutant cancers.Publication c-RAF Ablation Induces Regression of Advanced Kras/Trp53 Mutant Lung Adenocarcinomas by a Mechanism Independent of MAPK Signaling.(Cell Press, 2018-02-12) Sanclemente, Manuel; Francoz, Sarah; Esteban-Burgos, Laura; Bousquet-Mur, Emilie; Djurec, Magdolna; Lopez-Casas, Pedro P; Hidalgo, Manuel; Guerra, Carmen; Barbacid, Mariano; Musteanu, Mónica; Drosten, Matthias; Unión Europea. Comisión Europea. European Research Council (ERC); Unión Europea. Comisión Europea; Comunidad de Madrid (España); Fundación AXA; Instituto de Salud Carlos IIIA quarter of all solid tumors harbor KRAS oncogenes. Yet, no selective drugs have been approved to treat these malignancies. Genetic interrogation of the MAPK pathway revealed that systemic ablation of MEK or ERK kinases in adult mice prevent tumor development but are unacceptably toxic. Here, we demonstrate that ablation of c-RAF expression in advanced tumors driven by KrasG12V/Trp53 mutations leads to significant tumor regression with no detectable appearance of resistance mechanisms. Tumor regression results from massive apoptosis. Importantly, systemic abrogation of c-RAF expression does not inhibit canonical MAPK signaling, hence, resulting in limited toxicities. These results are of significant relevance for the design of therapeutic strategies to treat K-RAS mutant cancers.Publication Casein kinase 1δ is an APC/C(Cdh1) substrate that regulates cerebellar granule cell neurogenesis.(Cell Press, 2015-04-14) Penas, Clara; Govek, Eve-Ellen; Fang, Yin; Ramachandran, Vimal; Daniel, Mark; Wang, Weiping; Maloof, Marie E; Rahaim, Ronald J; Bibian, Mathieu; Kawauchi, Daisuke; Finkelstein, David; Han, Jeng-Liang; Long, Jun; Li, Bin; Robbins, David J; Roussel, Martine F; Roush, William R; Hatten, Mary E; Ayad, Nagi G; United States Department of Health and Human Services; NIH - Molecular Library Screening Center Network; American Lebanese Syrian Associated Charities; Ministerio de Economía y Competitividad (España); Unión EuropeaAlthough casein kinase 1δ (CK1δ) is at the center of multiple signaling pathways, its role in the expansion of CNS progenitor cells is unknown. Using mouse cerebellar granule cell progenitors (GCPs) as a model for brain neurogenesis, we demonstrate that the loss of CK1δ or treatment of GCPs with a highly selective small molecule inhibits GCP expansion. In contrast, CK1δ overexpression increases GCP proliferation. Thus, CK1δ appears to regulate GCP neurogenesis. CK1δ is targeted for proteolysis via the anaphase-promoting complex/cyclosome (APC/C(Cdh1)) ubiquitin ligase, and conditional deletion of the APC/C(Cdh1) activator Cdh1 in cerebellar GCPs results in higher levels of CK1δ. APC/C(Cdh1) also downregulates CK1δ during cell-cycle exit. Therefore, we conclude that APC/C(Cdh1) controls CK1δ levels to balance proliferation and cell-cycle exit in the developing CNS. Similar studies in medulloblastoma cells showed that CK1δ holds promise as a therapeutic target.Publication Cirrhosis: A Questioned Risk Factor for Hepatocellular Carcinoma.(Cell Press, 2021-01) Garrido, Amanda; Djouder, Nabil; Comunidad de Madrid (España); Ministerio de Economía e Innovación (España); European Foundation for the Study of DiabetesThe liver is one of the major metabolic organs in the body, susceptible to injury caused by various factors. In response to injury, sophisticated mechanisms are engaged to repair and regenerate the damaged liver, preventing its failure. When the damage is chronic, regeneration goes awry, impairing liver function and causing cirrhosis. Hence, cirrhosis may rather be a protective response to injury, where wound-healing processes are set to primarily repair the damaged liver. Although cirrhosis is clinically considered a risk factor for hepatocellular carcinoma (HCC), comprehensive population-based studies demonstrate a very modest incidence, refuting the idea that cirrhosis progresses to HCC. Here, we discuss and shed light on the provocative question of whether cirrhosis predisposes to HCC.Publication Cirrhosis: A Questioned Risk Factor for Hepatocellular Carcinoma.(Cell Press, 2021-01) Garrido, Amanda; Djouder, Nabil; Ministerio de Ciencia e Innovación (España); Comunidad de Madrid (España)The liver is one of the major metabolic organs in the body, susceptible to injury caused by various factors. In response to injury, sophisticated mechanisms are engaged to repair and regenerate the damaged liver, preventing its failure. When the damage is chronic, regeneration goes awry, impairing liver function and causing cirrhosis. Hence, cirrhosis may rather be a protective response to injury, where wound-healing processes are set to primarily repair the damaged liver. Although cirrhosis is clinically considered a risk factor for hepatocellular carcinoma (HCC), comprehensive population-based studies demonstrate a very modest incidence, refuting the idea that cirrhosis progresses to HCC. Here, we discuss and shed light on the provocative question of whether cirrhosis predisposes to HCC.Publication cKit Lineage Hemogenic Endothelium-Derived Cells Contribute to Mesenteric Lymphatic Vessels.(Cell Press, 2015-03-17) Stanczuk, Lukas; Martinez-Corral, Ines; Ulvmar, Maria H; Zhang, Yang; Laviña, Bàrbara; Fruttiger, Marcus; Adams, Ralf H; Saur, Dieter; Betsholtz, Christer; Alitalo, Kari; Graupera, Mariona; Mäkinen, Taija; European Molecular Biology Organization; Kjell och Märta Beijers Stiftelse; Swedish Research Council; Fundación Alfonso Martín Escudero; Ministerio de Economía y Competitividad (España); Medical Research Council (Reino Unido); Deutsche Forschungsgemeinschaft (Alemania); Unión Europea. Comisión Europea. European Research Council (ERC); Knut and Alice Wallenberg Foundation; Fondation Leducq; Swedish Cancer FoundationPathological lymphatic diseases mostly affect vessels in specific tissues, yet little is known about organ-specific regulation of the lymphatic vasculature. Here, we show that the vascular endothelial growth factor receptor 3 (VEGFR-3)/p110α PI3-kinase signaling pathway is selectively required for the formation of mesenteric lymphatic vasculature. Using genetic lineage tracing, we demonstrate that part of the mesenteric lymphatic vasculature develops from cKit lineage cells of hemogenic endothelial origin through a process we define as lymphvasculogenesis. This is contrary to the current dogma that all mammalian lymphatic vessels form by sprouting from veins. Our results reveal vascular-bed-specific differences in the origin and mechanisms of vessel formation, which may critically underlie organ-specific manifestation of lymphatic dysfunction in disease. The progenitor cells identified in this study may be exploited to restore lymphatic function following cancer surgery, lymphedema, or tissue trauma.Publication Complete Regression of Advanced Pancreatic Ductal Adenocarcinomas upon Combined Inhibition of EGFR and C-RAF(Cell Press, 2019-04-15) Blasco, María Teresa; Navas, Carolina; Martín-Serrano, Guillermo; Graña Castro, Osvaldo; Lechuga, Carmen G; Martín-Díaz, Laura; Djurec, Magdolna; Li, Jing; Morales-Cacho, Lucia; Esteban-Burgos, Laura; Perales-Patón, Javier; Bousquet-Mur, Emilie; Castellano, Eva; Jacob, Harrys K C; Cabras, Lavinia; Musteanu, Mónica; Drosten, Matthias; Ortega, Sagrario; Mulero, Francisca; Sainz, Bruno; Dusetti, Nelson; Iovanna, Juan; Sanchez-Bueno, Francisco; Hidalgo, Manuel; Khiabanian, Hossein; Rabadan, Raul; Al-Shahrour, Fatima; Guerra, Carmen; Barbacid, Mariano; Unión Europea. Comisión Europea. European Research Council (ERC); Ministerio de Economía y Competitividad (España); Asociación Española Contra el Cáncer; Ligue Nationale Contre le Cancer (Francia); NIH - National Cancer Institute (NCI) (Estados Unidos); Fundación La Caixa; Fundación AXAFive-year survival for pancreatic ductal adenocarcinoma (PDAC) patients remains below 7% due to the lack of effective treatments. Here, we report that combined ablation of EGFR and c-RAF expression results in complete regression of a significant percentage of PDAC tumors driven by Kras/Trp53 mutations in genetically engineered mice. Moreover, systemic elimination of these targets induces toxicities that are well tolerated. Response to this targeted therapy correlates with transcriptional profiles that resemble those observed in human PDACs. Finally, inhibition of EGFR and c-RAF expression effectively blocked tumor progression in nine independent patient-derived xenografts carrying KRAS and TP53 mutations. These results open the door to the development of targeted therapies for PDAC patients.Publication Complete Regression of Advanced Pancreatic Ductal Adenocarcinomas upon Combined Inhibition of EGFR and C-RAF.(Cell Press, 2019-04-15) Blasco, María Teresa; Navas, Carolina; Martín-Serrano, Guillermo; Martín-Díaz, Laura; Li, Jing; Morales-Cacho, Lucia; Esteban-Burgos, Laura; Perales-Patón, Javier; Bousquet-Mur, Emilie; Castellano, Eva; Jacob, Harrys K C; Cabras, Lavinia; Sainz, Bruno; Dusetti, Nelson; Iovanna, Juan; Sánchez-Bueno, Francisco; Hidalgo, Manuel; Khiabanian, Hossein; Rabadán, Raul; Graña Castro, Osvaldo; Lechuga C, Lechuga CG; Djurec M, Djurec M; Musteanu, Mónica; Drosten, Matthias; Ortega Jimenez, Sagrario; Mulero, Francisca; Guerra, Carmen; Barbacid, Mariano; Al-Shahrour, Fatima; Unión Europea. Comisión Europea. European Research Council (ERC); Unión Europea. Comisión Europea; Asociación Española Contra el Cáncer; Ligue Nationale Contre le Cancer (Francia); United States Department of Health and Human Services; Deutsche Forschungsgemeinschaft (Alemania); Ministerio de Ciencia e Innovación (España); Fundación La Caixa; Ministerio de Economía, Industria y Competitividad (España); Fundación AXAFive-year survival for pancreatic ductal adenocarcinoma (PDAC) patients remains below 7% due to the lack of effective treatments. Here, we report that combined ablation of EGFR and c-RAF expression results in complete regression of a significant percentage of PDAC tumors driven by Kras/Trp53 mutations in genetically engineered mice. Moreover, systemic elimination of these targets induces toxicities that are well tolerated. Response to this targeted therapy correlates with transcriptional profiles that resemble those observed in human PDACs. Finally, inhibition of EGFR and c-RAF expression effectively blocked tumor progression in nine independent patient-derived xenografts carrying KRAS and TP53 mutations. These results open the door to the development of targeted therapies for PDAC patients.Publication Cutaneous Immune Cell-Microbiota Interactions Are Controlled by Epidermal JunB/AP-1(Cell Press, 2019-10-22) Uluçkan, Azge; Jimenez Maria, M; Roediger, Ben; Schnabl, Jakob; Díez-Córdova, Lucía T; Troulé, Kevin; Weninger, Wolfgang; Wagner, Erwin Friedrich; Ministerio de Economía y Competitividad (España); Unión Europea. Comisión Europea. European Research Council (ERC)Atopic dermatitis (AD) is a multi-factorial skin disease with a complex inflammatory signature including type 2 and type 17 activation. Although colonization by S. aureus is common in AD, the mechanisms rendering an organism prone to dysbiosis, and the role of IL-17A in the control of S. aureus-induced skin inflammation, are not well understood. Here, we show several pathological aspects of AD, including type 2/type 17 immune responses, elevated IgE, barrier dysfunction, pruritus, and importantly, spontaneous S. aureus colonization in JunBΔep mice, with a large transcriptomic overlap with AD. Additionally, using Rag1-/- mice, we demonstrate that adaptive immune cells are necessary for protection against S. aureus colonization. Prophylactic antibiotics, but not antibiotics after established dysbiosis, reduce IL-17A expression and skin inflammation, examined using Il17a-eGFP reporter mice. Mechanistically, keratinocytes lacking JunB exhibit higher MyD88 levels in vitro and in vivo, previously shown to regulate S. aureus colonization. In conclusion, our data identify JunB as an upstream regulator of microbiota-immune cell interactions and characterize the IL-17A response upon spontaneous dysbiosis.Publication Development Refractoriness of MLL-Rearranged Human B Cell Acute Leukemias to Reprogramming into Pluripotency(Cell Press, 2016-10-11) Muñoz-López, Alvaro; Romero-Moya, Damià; Prieto, Cristina; Ramos-Mejía, Verónica; Agraz-Doblas, Antonio; Varela, Ignacio; Buschbeck, Marcus; Palau, Anna; Carvajal-Vergara, Xonia; Giorgetti, Alessandra; Ford, Anthony; Lako, Majlinda; Granada, Isabel; Ruiz-Xivillé, Neus; Rodriguez Perales, Sandra; Torres-Ruiz Raul, Raul; Stam, Ronald W; Fuster, Jose Luis; Fraga, Mario F; Nakanishi, Mahito; Cazzaniga, Gianni; Bardini, Michela; Cobo, Isabel; Bayon, Gustavo F; Fernandez, Agustín F; Bueno, Clara; Menendez, Pablo; Unión Europea. Comisión Europea. European Research Council (ERC); Instituto de Salud Carlos III; Ministerio de Economía y Competitividad (España); Asociación Española Contra el Cáncer; Ministerio de Ciencia e Innovación (España); Fundación La Caixa; Fundación Josep Carreras Contra la Leucemia; Government of Catalonia (España); Institució Catalana de Recerca i Estudis Avançats; Biotechnology and Biological Sciences Research Council (Reino Unido); Medical Research Council (Reino Unido)Induced pluripotent stem cells (iPSCs) are a powerful tool for disease modeling. They are routinely generated from healthy donors and patients from multiple cell types at different developmental stages. However, reprogramming leukemias is an extremely inefficient process. Few studies generated iPSCs from primary chronic myeloid leukemias, but iPSC generation from acute myeloid or lymphoid leukemias (ALL) has not been achieved. We attempted to generate iPSCs from different subtypes of B-ALL to address the developmental impact of leukemic fusion genes. OKSM(L)-expressing mono/polycistronic-, retroviral/lentiviral/episomal-, and Sendai virus vector-based reprogramming strategies failed to render iPSCs in vitro and in vivo. Addition of transcriptomic-epigenetic reprogramming "boosters" also failed to generate iPSCs from B cell blasts and B-ALL lines, and when iPSCs emerged they lacked leukemic fusion genes, demonstrating non-leukemic myeloid origin. Conversely, MLL-AF4-overexpressing hematopoietic stem cells/B progenitors were successfully reprogrammed, indicating that B cell origin and leukemic fusion gene were not reprogramming barriers. Global transcriptome/DNA methylome profiling suggested a developmental/differentiation refractoriness of MLL-rearranged B-ALL to reprogramming into pluripotency.Publication Dietary interventions and precision nutrition in cancer therapy.(Cell Press, 2023-07) Martínez-Garay, Carlos; Djouder, Nabil; Instituto de Salud Carlos III; Fundación BBVA; Asociación Española Contra el Cáncer; Ministerio de Ciencia (España)In recent years dietary interventions have become a promising tool in cancer treatment and have demonstrated a powerful ability to alter metabolism and tumor growth, development, and therapeutic response. However, because the mechanisms underlying dietary therapeutics are poorly understood, they are frequently ignored as a potential line of treatment for cancer. We discuss the proposed mechanisms behind the anticancer effects of various diets and their development for clinical use. This review aims to provide researchers and clinicians in the field of oncology with a complete overview of the contemporary landscape of nutritional interventions and precision nutrition as cancer therapeutics, and offers a perspective on the steps necessary to establish nutritional interventions as a standard line of treatment.
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