Grupos de investigación

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/16991

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Claudin-3 Loss of Expression Is a Prognostic Marker in Castration-Resistant Prostate Cancer.
(MPDI, 2023-01-02) Orea, María J; Angulo, Javier C; González-Corpas, Ana; Echegaray, David; Marvá, Marcos; Lobo, María V T; Colás, Begoña; Ropero, Santiago
Castration-resistant prostate cancer (CRPC) development is the foremost concern after treatment of patients with high risk with locally advanced or metastatic prostate cancer. Androgen receptor (AR) is the main driver of CRPC development, through its interaction with epigenetic modifier genes, placing epigenetics modifications in the forefront of CRPC development. Comparing the DNA methylation and expression profile of androgen-sensitive and -refractory prostate cancer cells, we describe the epigenetic silencing of claudin-3 (CLDN3) in AR positive cells resistant to androgen deprivation (LNCaP-abl). CLDN3 silencing was associated with DNA methylation, loss of histone acetylation and H3K27 methylation, and was re-expressed by the combined treatment with the epigenetic modulators Aza and SAHA. From a functional point of view, CLDN3 loss was associated with increased cellular invasion. Immunohistochemical analysis showed decreased CLDN3 expression in samples from CRPC patients. Interestingly, CLDN3 expression was significantly decreased in samples from patients with high total Gleason score (≥8) and locally advanced tumors. Finally, CLDN3 loss of expression was associated with worse disease-free survival and time to clinical progression. In conclusion, our findings strongly indicate that epigenetic silencing of CLDN3 is a common event in CRPC that could be useful as a molecular marker for the prognosis of prostate cancer patients and to discriminate aggressive from indolent prostate tumors.
Targeting the nucleolus as a therapeutic strategy in human disease.
(Cell Press, 2023-03) Corman, Alba; Sirozh, Oleksandra; Lafarga, Vanesa; Fernandez-Capetillo, Oscar
The nucleolus is the site of ribosome biogenesis, one of the most resource-intensive processes in eukaryotic cells. Accordingly, nucleolar morphology and activity are highly responsive to growth signaling and nucleolar insults which are collectively included in the actively evolving concept of nucleolar stress. Importantly, nucleolar alterations are a prominent feature of multiple human pathologies, including cancer and neurodegeneration, as well as being associated with aging. The past decades have seen numerous attempts to isolate compounds targeting different facets of nucleolar activity. We provide an overview of therapeutic opportunities for targeting nucleoli in different pathologies and currently available therapies.
STAT3 expression in brain metastases from breast cancer is correlated with molecular subtype and impacts clinical outcome.
(Oxford, 2025-12-01) Pellerino, Alessia; Priego, Neibla; Bertero, Luca; Ricci, Alessia Andrea; Mangherini, Luca; Bruno, Francesco; Beano, Alessandra; Mittica, Gloria; Mistrangelo, Marinella; Garbossa, Diego; Bosch-Barrera, Joaquim; Cassoni, Paola; Valiente, Manuel; Soffietti, Riccardo; Rudà, Roberta
A high pSTAT3 expression in reactive astrocytes surrounding brain metastases (BrM) promotes tumor growth in preclinical models. The impact of STAT3 expression on outcome of patients with BrM from breast cancer is unknown.
Dietary Intake Regulates the Circulating Inflammatory Monocyte Pool.
(Cell Press, 2019-08-22) Jordan, Stefan; Tung, Navpreet; Casanova-Acebes, Maria; Chang, Christie; Cantoni, Claudia; Zhang, Dachuan; Wirtz, Theresa H; Naik, Shruti; Rose, Samuel A; Brocker, Chad N; Gainullina, Anastasiia; Hornburg, Daniel; Horng, Sam; Maier, Barbara B; Cravedi, Paolo; LeRoith, Derek; Gonzalez, Frank J; Meissner, Felix; Ochando, Jordi; Rahman, Adeeb; Chipuk, Jerry E; Artyomov, Maxim N; Frenette, Paul S; Piccio, Laura; Berres, Marie-Luise; Gallagher, Emily J; Merad, Miriam
Caloric restriction is known to improve inflammatory and autoimmune diseases. However, the mechanisms by which reduced caloric intake modulates inflammation are poorly understood. Here we show that short-term fasting reduced monocyte metabolic and inflammatory activity and drastically reduced the number of circulating monocytes. Regulation of peripheral monocyte numbers was dependent on dietary glucose and protein levels. Specifically, we found that activation of the low-energy sensor 5'-AMP-activated protein kinase (AMPK) in hepatocytes and suppression of systemic CCL2 production by peroxisome proliferator-activator receptor alpha (PPARα) reduced monocyte mobilization from the bone marrow. Importantly, we show that fasting improves chronic inflammatory diseases without compromising monocyte emergency mobilization during acute infectious inflammation and tissue repair. These results reveal that caloric intake and liver energy sensors dictate the blood and tissue immune tone and link dietary habits to inflammatory disease outcome.
Macrophages orchestrate breast cancer early dissemination and metastasis.
(NATURE PORTFOLIO, 2018-01-02) Linde, Nina; Casanova-Acebes, Maria; Sosa, Maria Soledad; Mortha, Arthur; Rahman, Adeeb; Farias, Eduardo; Harper, Kathryn; Tardio, Ethan; Reyes Torres, Ivan; Jones, Joan; Condeelis, John; Merad, Miriam; Aguirre-Ghiso, Julio A
Cancer cell dissemination during very early stages of breast cancer proceeds through poorly understood mechanisms. Here we show, in a mouse model of HER2 breast cancer, that a previously described sub-population of early-evolved cancer cells requires macrophages for early dissemination. Depletion of macrophages specifically during pre-malignant stages reduces early dissemination and also results in reduced metastatic burden at end stages of cancer progression. Mechanistically, we show that, in pre-malignant lesions, CCL2 produced by cancer cells and myeloid cells attracts CD206/Tie2 macrophages and induces Wnt-1 upregulation that in turn downregulates E-cadherin junctions in the HER2 early cancer cells. We also observe macrophage-containing tumor microenvironments of metastasis structures in the pre-malignant lesions that can operate as portals for intravasation. These data support a causal role for macrophages in early dissemination that affects long-term metastasis development much later in cancer progression. A pilot analysis on human specimens revealed intra-epithelial macrophages and loss of E-cadherin junctions in ductal carcinoma in situ, supporting a potential clinical relevance.
Rhythmic modulation of the hematopoietic niche through neutrophil clearance.
(Cell Press, 2013-05-23) Casanova-Acebes, Maria; Pitaval, Christophe; Weiss, Linnea A; Nombela-Arrieta, César; Chèvre, Raphaël; A-González, Noelia; Kunisaki, Yuya; Zhang, Dachuan; van Rooijen, Nico; Silberstein, Leslie E; Weber, Christian; Nagasawa, Takashi; Frenette, Paul S; Castrillo, Antonio; Hidalgo, Andrés
Unique among leukocytes, neutrophils follow daily cycles of release from and migration back into the bone marrow, where they are eliminated. Because removal of dying cells generates homeostatic signals, we explored whether neutrophil elimination triggers circadian events in the steady state. Here, we report that the homeostatic clearance of neutrophils provides cues that modulate the physiology of the bone marrow. We identify a population of CD62L(LO) CXCR4(HI) neutrophils that have "aged" in the circulation and are eliminated at the end of the resting period in mice. Aged neutrophils infiltrate the bone marrow and promote reductions in the size and function of the hematopoietic niche. Modulation of the niche depends on macrophages and activation of cholesterol-sensing nuclear receptors and is essential for the rhythmic egress of hematopoietic progenitors into the circulation. Our results unveil a process that synchronizes immune and hematopoietic rhythms and expand the ascribed functions of neutrophils beyond inflammation. PAPERFLICK:
Melanoma-derived extracellular vesicles mediate lymphatic remodelling and impair tumour immunity in draining lymph nodes.
(Wiley, 2022-02) Leary, Noelle; Walser, Sarina; He, Yuliang; Cousin, Nikola; Pereira, Paulo; Gallo, Alessandro; Collado-Diaz, Victor; Halin, Cornelia; Garcia-Silva, Susana; Peinado Selgas, Hector; Dieterich, Lothar C
Tumour-draining lymph nodes (LNs) undergo massive remodelling including expansion of the lymphatic sinuses, a process that has been linked to lymphatic metastasis by creation of a pre-metastatic niche. However, the signals leading to these changes have not been completely understood. Here, we found that extracellular vesicles (EVs) derived from melanoma cells are rapidly transported by lymphatic vessels to draining LNs, where they selectively interact with lymphatic endothelial cells (LECs) as well as medullary sinus macrophages. Interestingly, uptake of melanoma EVs by LN-resident LECs was partly dependent on lymphatic VCAM-1 expression, and induced transcriptional changes as well as proliferation of those cells. Furthermore, melanoma EVs shuttled tumour antigens to LN LECs for cross-presentation on MHC-I, resulting in apoptosis induction in antigen-specific CD8 T cells. In conclusion, our data identify EV-mediated melanoma-LN LEC communication as a new pathway involved in tumour progression and tumour immune inhibition, suggesting that EV uptake or effector mechanisms in LECs might represent a new target for melanoma therapy.
CD9 inhibition reveals a functional connection of extracellular vesicle secretion with mitophagy in melanoma cells.
(WILEY, 2021-05) Suárez, Henar; Andreu, Zoraida; Mazzeo, Carla; Toribio, Víctor; Pérez-Rivera, Aldo Emmanuel; López-Martín, Soraya; García-Silva, Susana; Hurtado, Begoña; Morato, Esperanza; Peláez, Laura; Arribas, Egoitz Astigarraga; Tolentino-Cortez, Tarson; Barreda-Gómez, Gabriel; Marina, Ana Isabel; Peinado, Héctor; Yáñez-Mó, María
Tetraspanins are often used as Extracellular Vesicle (EV) detection markers because of their abundance on these secreted vesicles. However, data on their function on EV biogenesis are controversial and compensatory mechanisms often occur upon gene deletion. To overcome this handicap, we have compared the effects of tetraspanin CD9 gene deletion with those elicited by cytopermeable peptides with blocking properties against tetraspanin CD9. Both CD9 peptide or gene deletion reduced the number of early endosomes. CD9 peptide induced an increase in lysosome numbers, while CD9 deletion augmented the number of MVB and EV secretion, probably because of compensatory CD63 expression upregulation. , CD9 peptide delayed primary tumour cell growth and reduced metastasis size. These effects on cell proliferation were shown to be concomitant with an impairment in mitochondrial quality control. CD9 KO cells were able to compensate the mitochondrial malfunction by increasing total mitochondrial mass reducing mitophagy. Our data thus provide the first evidence for a functional connection of tetraspanin CD9 with mitophagy in melanoma cells.
Studying the Fate of Tumor Extracellular Vesicles at High Spatiotemporal Resolution Using the Zebrafish Embryo.
(2019-02-25) Hyenne, Vincent; Ghoroghi, Shima; Collot, Mayeul; Bons, Joanna; Follain, Gautier; Harlepp, Sébastien; Mary, Benjamin; Bauer, Jack; Mercier, Luc; Busnelli, Ignacio; Lefebvre, Olivier; Fekonja, Nina; Garcia-Leon, Maria J; Machado, Pedro; Delalande, François; López, Ana Amor; Silva, Susana Garcia; Verweij, Frederik J; van Niel, Guillaume; Djouad, Farida; Peinado, Héctor; Carapito, Christine; Klymchenko, Andrey S; Goetz, Jacky G
Tumor extracellular vesicles (EVs) mediate the communication between tumor and stromal cells mostly to the benefit of tumor progression. Notably, tumor EVs travel in the bloodstream, reach distant organs, and locally modify the microenvironment. However, visualizing these events in vivo still faces major hurdles. Here, we describe an approach for tracking circulating tumor EVs in a living organism: we combine chemical and genetically encoded probes with the zebrafish embryo as an animal model. We provide a first description of tumor EVs' hemodynamic behavior and document their intravascular arrest. We show that circulating tumor EVs are rapidly taken up by endothelial cells and blood patrolling macrophages and subsequently stored in degradative compartments. Finally, we demonstrate that tumor EVs activate macrophages and promote metastatic outgrowth. Overall, our study proves the usefulness and prospects of zebrafish embryo to track tumor EVs and dissect their role in metastatic niches formation in vivo.
C/EBPalpha and beta couple interfollicular keratinocyte proliferation arrest to commitment and terminal differentiation.
(NATURE PORTFOLIO, 2009-10) Lopez, Rodolphe G; Garcia-Silva, Susana; Moore, Susan J; Bereshchenko, Oksana; Martinez-Cruz, Ana B; Ermakova, Olga; Kurz, Elke; Paramio, Jesus M; Nerlov, Claus
The transcriptional regulators that couple interfollicular basal keratinocyte proliferation arrest to commitment and differentiation are yet to be identified. Here we report that the basic region leucine zipper transcription factors C/EBPalpha and C/EBPbeta are co-expressed in basal keratinocytes, and are coordinately upregulated as keratinocytes exit the basal layer and undergo terminal differentiation. Mice lacking both C/EBPalpha and beta in the epidermis showed increased proliferation of basal keratinocytes and impaired commitment to differentiation. This led to ectopic expression of keratin 14 (K14) and DeltaNp63 in suprabasal cells, decreased expression of spinous and granular layer proteins, parakeratosis and defective epidermal water barrier function. Knock-in mutagenesis revealed that C/EBP-E2F interaction was required for control of interfollicular epidermis (IFE) keratinocyte proliferation, but not for induction of spinous and granular layer markers, whereas C/EBP DNA binding was required for DeltaNp63 downregulation and K1/K10 induction. Finally, loss of C/EBPalpha/beta induced stem cell gene expression signatures in the epidermis. C/EBPs, therefore, couple basal keratinocyte cell cycle exit to commitment to differentiation through E2F repression and DNA binding, respectively, and may act to restrict the epidermal stem cell compartment.
Thyroid hormone receptor beta1 acts as a potent suppressor of tumor invasiveness and metastasis.
(AMER ASSOC CANCER RESEARCH, 2009-01-15) Martínez-Iglesias, Olaia; Garcia-Silva, Susana; Tenbaum, Stephan P; Regadera, Javier; Larcher, Fernando; Paramio, Jesus M; Vennström, Bjorn; Aranda, Ana
Loss of thyroid hormone receptors (TR) is a common feature in some tumors, although their role in tumor progression is currently unknown. We show here that expression of TRbeta1 in hepatocarcinoma and breast cancer cells reduces tumor growth, causes partial mesenchymal-to-epithelial cell transition, and has a striking inhibitory effect on invasiveness, extravasation, and metastasis formation in mice. In cultured cells, TRbeta1 abolishes anchorage-independent growth and migration, blocks responses to epidermal growth factor, insulin-like growth factor-I, and transforming growth factor beta, and regulates expression of genes that play a key role in tumorigenicity and metastatic growth. The receptor disrupts the mitogenic action of growth factors by suppressing activation of extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling pathways that are crucial for cell proliferation and invasiveness. Furthermore, increased aggressiveness of skin tumors is found in genetically modified mice lacking TRs, further demonstrating the role of these receptors as inhibitors of tumor progression. These results define a novel role for the thyroid hormone receptor as a metastasis suppressor gene, providing a starting point for the development of novel therapeutic strategies for the treatment of human cancer.
An element in the region responsible for premature termination of transcription mediates repression of c-myc gene expression by thyroid hormone in neuroblastoma cells.
(Elsevier, 2000-01-14) Pérez-Juste, G; García-Silva, S; Aranda, A
The thyroid hormone (T3) blocks proliferation and induces differentiation of neuroblastoma N2a-beta cells that express the thyroid hormone receptor (TR) beta1 isoform. c-Myc is required for cell cycle progression, and this study shows that T3-induced neuronal differentiation is preceded by a rapid decrease of c-myc gene expression. A negative T3 responsive element (TRE), arranged as an inverted palindrome spaced by three nucleotides, has been identified within the first exon between nucleotides +237 and +268. The TRE is adjacent to the binding site for the transcriptional repressor CCCTC binding factor and maps precisely within the region of RNA polymerase II pausing and release, suggesting a direct implication of TR on premature termination of transcription. Furthermore, the TRE confers repression by T3 to an heterologous promoter only when inserted downstream of the transcription initiation site. Binding of CCCTC binding factor and TR to their cognate sites in the region of transcriptional attenuation, as well as direct interactions between both factors, could facilitate the formation of a repressor complex and the inhibition of c-myc gene expression. These studies provide insight into mechanisms by which TR mediate transcriptional repression and contribute to the understanding of the important effects of thyroid hormones on growth and differentiation of neuronal cells.
Type VII secretion systems: structure, functions and transport models.
(Springuer Nature, 2021-09) Rivera Calzada, Angel; Famelis, Nikolaos; Llorca Blanco, Oscar Antonio; Geibel, Sebastian; EUROPEAN REGIONAL DEVELOPMENT FUND; INSTITUTO DE SALUD CARLOS III; MINISTERIO DE CIENCIA, INNOVACION Y UNIVERSIDADES
Type VII secretion systems (T7SSs) have a key role in the secretion of effector proteins in non-pathogenic mycobacteria and pathogenic mycobacteria such as Mycobacterium tuberculosis, the main causative agent of tuberculosis. Tuberculosis-causing mycobacteria, still accounting for 1.4 million deaths annually, rely on paralogous T7SSs to survive in the host and efficiently evade its immune response. Although it is still unknown how effector proteins of T7SSs cross the outer membrane of the diderm mycobacterial cell envelope, recent advances in the structural characterization of these secretion systems have revealed the intricate network of interactions of conserved components in the plasma membrane. This structural information, added to recent advances in the molecular biology and regulation of mycobacterial T7SSs as well as progress in our understanding of their secreted effector proteins, is shedding light on the inner working of the T7SS machinery. In this Review, we highlight the implications of these studies and the derived transport models, which provide new scenarios for targeting the deathly human pathogen M. tuberculosis.
Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF-mutant thyroid carcinomas.
(American Association for Cancer Research, 2013-05) Montero-Conde, Cristina; Ruiz-Llorente, Sergio; Dominguez, Jose M; Knauf, Jeffrey A; Viale, Agnes; Sherman, Eric J; Ryder, Mabel; Ghossein, Ronald A; Rosen, Neal; Fagin, James A
The RAF inhibitor vemurafenib (PLX4032) increases survival in patients with BRAF-mutant metastatic melanoma, but has limited efficacy in patients with colorectal cancers. Thyroid cancer cells are also comparatively refractory to RAF inhibitors. In contrast to melanomas, inhibition of mitogen-activated protein kinase (MAPK) signaling by PLX4032 is transient in thyroid and colorectal cancer cells. The rebound in extracellular signal-regulated kinase (ERK) in thyroid cells is accompanied by increased HER3 signaling caused by induction of ERBB3 (HER3) transcription through decreased promoter occupancy by the transcriptional repressors C-terminal binding protein 1 and 2 and by autocrine secretion of neuregulin-1 (NRG1). The HER kinase inhibitor lapatinib prevents MAPK rebound and sensitizes BRAF-mutant thyroid cancer cells to RAF or MAP-ERK kinase inhibitors. This provides a rationale for combining ERK pathway antagonists with inhibitors of feedback-reactivated HER signaling in this disease. The determinants of primary resistance to MAPK inhibitors vary between cancer types, due to preferential upregulation of specific receptor tyrosine kinases, and the abundance of their respective ligands.
Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine.
(American Society for Clinical Investigation, 2016-11-01) Nagarajah, James; Le, Mina; Knauf, Jeffrey A; Ferrandino, Giuseppe; Montero-Conde, Cristina; Pillarsetty, Nagavarakishore; Bolaender, Alexander; Irwin, Christopher; Krishnamoorthy, Gnana Prakasam; Saqcena, Mahesh; Larson, Steven M; Ho, Alan L; Seshan, Venkatraman; Ishii, Nobuya; Carrasco, Nancy; Rosen, Neal; Weber, Wolfgang A; Fagin, James A
Radioiodide (RAI) therapy of thyroid cancer exploits the relatively selective ability of thyroid cells to transport and accumulate iodide. Iodide uptake requires expression of critical genes that are involved in various steps of thyroid hormone biosynthesis. ERK signaling, which is markedly increased in thyroid cancer cells driven by oncogenic BRAF, represses the genetic program that enables iodide transport. Here, we determined that a critical threshold for inhibition of MAPK signaling is required to optimally restore expression of thyroid differentiation genes in thyroid cells and in mice with BrafV600E-induced thyroid cancer. Although the MEK inhibitor selumetinib transiently inhibited ERK signaling, which subsequently rebounded, the MEK inhibitor CKI suppressed ERK signaling in a sustained manner by preventing RAF reactivation. A small increase in ERK inhibition markedly increased the expression of thyroid differentiation genes, increased iodide accumulation in cancer cells, and thereby improved responses to RAI therapy. Only a short exposure to the drug was necessary to obtain a maximal response to RAI. These data suggest that potent inhibition of ERK signaling is required to adequately induce iodide uptake and indicate that this is a promising strategy for the treatment of BRAF-mutant thyroid cancer.
Overexpression of the S-phase kinase-associated protein 2 in thyroid cancer.
(BIOSCIENTIFICA LTD, 2007-06) Chiappetta, Gennaro; De Marco, Carmela; Quintiero, Alfina; Califano, Daniela; Gherardi, Simona; Malanga, Donatella; Scrima, Marianna; Montero-Conde, Cristina; Cito, Letizia; Monaco, Mario; Motti, Maria Letizia; Pasquinelli, Rosa; Agosti, Valter; Robledo, Mercedes; Fusco, Alfredo; Viglietto, Giuseppe; Montero-Conde, Cristina
Loss of expression of the cyclin-dependent kinase inhibitor p27 through enhanced protein degradation frequently occurs in human cancer. Degradation of p27 requires ubiquitination by the S-phase kinase-associated protein 2 (Skp2), a member of the F-box family of Skp1-Cullin-F-box protein ubiquitin ligases. In the present study, we have investigated the role of Skp2 in human thyroid tumours. Immunohistochemistry analysis showed that Skp2 was overexpressed significantly in thyroid carcinomas (26 out of 51) compared with goitres (0 out of 12, P<0.001) or adenomas (1 out of 10, P<0.05), and that high Skp2 expression was detected more often in anaplastic thyroid (ATC; 83%, n=12) than follicular thyroid (FTC; 40%, n=20) or papillary thyroid (PTC; 42%, n=19) carcinomas (P<0.05). Thyroid cancer cell lines and tissues with high levels of Skp2 protein presented high p27 degradation activity and there was an inverse correlation between Skp2 and p27 expression in thyroid cancer tissues (n=68; P<0.05). In most cases, the observed overexpression of Skp2 protein was paralleled by an increase in the levels of Skp2 mRNA, and we observed Skp2 gene amplification at 5p13 in 2 out of 6 cell lines and in 9 out of 23 primary tumours (six out of eight ATCs, two out of nine PTCs and one out of six FTCs) using Q-PCR and/or fluorescence in situ hybridization analysis. Finally, in vitro experiments demonstrated that suppression of Skp2 expression drastically reduced proliferation of thyroid cancer cells and, conversely, forced expression of Skp2 circumvented serum dependency and contact inhibition in Skp2-negative cells by promoting p27 degradation. These findings indicate that Skp2 plays an important role for the development of thyroid cancer.
The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.
(PUBLIC LIBRARY SCIENCE, 2009-09) Montero-Conde, Cristina; Landa, Iñigo; Ruiz-Llorente, Sergio; Montero-Conde, Cristina; Inglada-Pérez, Lucía; Schiavi, Francesca; Leskelä, Susanna; Pita, Guillermo; Milne, Roger; Maravall, Javier; Ramos, Ignacio; Andía, Víctor; Rodríguez-Poyo, Paloma; Jara-Albarrán, Antonino; Meoro, Amparo; del Peso, Cristina; Arribas, Luis; Iglesias, Pedro; Caballero, Javier; Serrano, Joaquín; Picó, Antonio; Pomares, Francisco; Giménez, Gabriel; López-Mondéjar, Pedro; Castello, Roberto; Merante-Boschin, Isabella; Pelizzo, Maria-Rosa; Mauricio, Didac; Opocher, Giuseppe; Rodriguez Antona, Cristina; Gonzalez-Neira, Anna; Matías-Guiu, Xavier; Santisteban, Pilar; Robledo, Mercedes; Robledo Batanero, Mercedes; Ministry of Science & Innovation (ESPAÑA); Instituto de Salud Carlos III
In order to identify genetic factors related to thyroid cancer susceptibility, we adopted a candidate gene approach. We studied tag- and putative functional SNPs in genes involved in thyroid cell differentiation and proliferation, and in genes found to be differentially expressed in thyroid carcinoma. A total of 768 SNPs in 97 genes were genotyped in a Spanish series of 615 cases and 525 controls, the former comprising the largest collection of patients with this pathology from a single population studied to date. SNPs in an LD block spanning the entire FOXE1 gene showed the strongest evidence of association with papillary thyroid carcinoma susceptibility. This association was validated in a second stage of the study that included an independent Italian series of 482 patients and 532 controls. The strongest association results were observed for rs1867277 (OR[per-allele] = 1.49; 95%CI = 1.30-1.70; P = 5.9x10(-9)). Functional assays of rs1867277 (NM_004473.3:c.-283G>A) within the FOXE1 5' UTR suggested that this variant affects FOXE1 transcription. DNA-binding assays demonstrated that, exclusively, the sequence containing the A allele recruited the USF1/USF2 transcription factors, while both alleles formed a complex in which DREAM/CREB/alphaCREM participated. Transfection studies showed an allele-dependent transcriptional regulation of FOXE1. We propose a FOXE1 regulation model dependent on the rs1867277 genotype, indicating that this SNP is a causal variant in thyroid cancer susceptibility. Our results constitute the first functional explanation for an association identified by a GWAS and thereby elucidate a mechanism of thyroid cancer susceptibility. They also attest to the efficacy of candidate gene approaches in the GWAS era.
Transposon mutagenesis identifies chromatin modifiers cooperating with in thyroid tumorigenesis and detects as a cancer gene.
(NATL ACAD SCIENCES, 2017-06-20) Montero-Conde, Cristina; Leandro-Garcia, Luis J; Chen, Xu; Oler, Gisele; Ruiz-Llorente, Sergio; Ryder, Mabel; Landa, Iñigo; Sanchez-Vega, Francisco; La, Konnor; Ghossein, Ronald A; Bajorin, Dean F; Knauf, Jeffrey A; Riordan, Jesse D; Dupuy, Adam J; Fagin, James A; United States Department of Health & Human Services National Institutes of Health (NIH) - USA; Weiner Family Foundation; David Linn family; Frank D. Cohen Fund; Cole Family Fund; ASOCIACIÓN ESPAÑOLA CONTRA EL CÁNCER
Oncogenic mutations are present in 15-30% of thyroid carcinomas. Endogenous expression of mutant Ras is insufficient to initiate thyroid tumorigenesis in murine models, indicating that additional genetic alterations are required. We used Sleeping Beauty (SB) transposon mutagenesis to identify events that cooperate with Hras in thyroid tumor development. Random genomic integration of SB transposons primarily generated loss-of-function events that significantly increased thyroid tumor penetrance in mice. The thyroid tumors closely phenocopied the histological features of human RAS-driven, poorly differentiated thyroid cancers. Characterization of transposon insertion sites in the SB-induced tumors identified 45 recurrently mutated candidate cancer genes. These mutation profiles were remarkably concordant with mutated cancer genes identified in a large series of human poorly differentiated and anaplastic thyroid cancers screened by next-generation sequencing using the MSK-IMPACT panel of cancer genes, which we modified to include all SB candidates. The disrupted genes primarily clustered in chromatin remodeling functional nodes and in the PI3K pathway. , a component of a multiprotein complex with histone acetylase activity, scored as a significant SB hit. It was recurrently mutated in advanced human cancers and significantly co-occurred with or mutations. Expression of mutants cooperated with oncogenic RAS to induce thyroid cell proliferation, pointing to as a previously unrecognized cancer gene.
CD133 Expression in Medullary Thyroid Cancer Cells Identifies Patients with Poor Prognosis.
(Endocrine Society, 2020-11-01) Cordero-Barreal, Alfonso; Caleiras, Eduardo; López de Maturana, Evangelina; Monteagudo, María; Martínez-Montes, Ángel M; Letón, Rocío; Gil, Eduardo; Álvarez-Escolá, Cristina; Regojo, Rita M; Andía, Víctor; Marazuela, Mónica; Guadalix, Sonsoles; Calatayud, María; Robles-Díaz, Luis; Aguirre, Miguel; Cano, Juana M; Díaz, José Ángel; Saavedra, Pilar; Lamas, Cristina; Azriel, Sharona; Sastre, Julia; Aller, Javier; Leandro-García, Luis J; Calsina, Bruna; Roldán-Romero, Juan María; Santos, María; Lanillos, Javier; Cascon Soriano, Alberto; Robledo Batanero, Mercedes; Montero-Conde, Cristina; Rodriguez Antona, Cristina; Instituto de Salud Carlos; European Union (EU); Comunidad de Madrid; AECC
The identification of markers able to determine medullary thyroid cancer (MTC) patients at high-risk of disease progression is critical to improve their clinical management and outcome. Previous studies have suggested that expression of the stem cell marker CD133 is associated with MTC aggressiveness.
Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation.
(Cell Press, 2022-09-15) García-Alonso, Sara; Mesa, Pablo; Ovejero, Laura de la Puente; Aizpurua, Gonzalo; Lechuga, Carmen G; Zarzuela, Eduardo; Santiveri, Clara M; Sanclemente, Manuel; Muñoz, Javier; Musteanu, Mónica; Campos-Olivas, Ramón; Martínez-Torrecuadrada, Jorge; Barbacid, Mariano; Montoya, Guillermo; European Research Council (ERC); Asociación Española contra el Cáncer; Ministerio de Ciencia, Innovación y Universidades (España); CRIS Cancer Foundation; Comunidad de Madrid (Esapña); Novo Nordisk Foundation
RAF kinases are RAS-activated enzymes that initiate signaling through the MAPK cascade to control cellular proliferation, differentiation, and survival. Here, we describe the structure of the full-length RAF1 protein in complex with HSP90 and CDC37 obtained by cryoelectron microscopy. The reconstruction reveals a RAF1 kinase with an unfolded N-lobe separated from its C-lobe. The hydrophobic core of the N-lobe is trapped in the HSP90 dimer, while CDC37 wraps around the chaperone and interacts with the N- and C-lobes of the kinase. The structure indicates how CDC37 can discriminate between the different members of the RAF family. Our structural analysis also reveals that the folded RAF1 assembles with 14-3-3 dimers, suggesting that after folding RAF1 follows a similar activation as B-RAF. Finally, disruption of the interaction between CDC37 and the DFG segment of RAF1 unveils potential vulnerabilities in attempting the pharmacological degradation of RAF1 for therapeutic purposes.

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