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29 results on '"Almagro, Jorge"'

2. Examining tumour heterogeneity and progression in three dimensions

Author

Almagro, Jorge, Behrens, Axel Johannes, and Grigoriadis, Anita

Abstract

Tumours are intrinsically heterogeneous at a genetic and phenotypic level. This complexity conditions tumour progression and the long-term effectiveness of cancer therapy, since the acquired diversity of tumour cells favours the selection of aggressive and resistant phenotypes along tumour evolution. Studying the mechanisms of therapy resistance and metastasis is critical in oncology, as these phenomena account for most cancer-related deaths. However, conventional histopathology and cell culture techniques, used in the past century in cancer research, simplify our perception of tumour biology, often not representing the full heterogeneity or molecular complexity of cancer cells. Novel tools such as tissue clearing and fluorescence 3D imaging and the use of organoids for tissue culture allow a complete visualisation of tumours or a better recapitulation of cancer signalling cues respectively. In this thesis, I contributed to the development of FLASH, a new technique for tissue permeabilization, clearing and 3D immunofluorescence, and I established technical adaptations to image a wide range of samples. I applied FLASH to visualise the heterogeneity of mammary tumours. FLASH unmasked the presence of rare mammary gland chemoresistant cancer stem cells (CSCs) in established mouse tumours. Using organoids and molecular biology techniques, I discovered a new mechanism of resistance against anthracyclines, a family of chemotherapeutic agents widely used for cancer treatment. Resistance was driven by CSCs through Wnt-mediated downregulation of anthracycline influx transporters. In addition, FLASH revealed mouse mammary cancer cells seeding intravascular epithelial metastases in the lung, challenging the notion that epithelial-tomesenchymal transition and extravasation are necessary steps in metastatic seeding. Together, these observations demonstrate how visualising tumours in their native 3D architecture can reveal important cancer biology processes and expand our understanding of tumour evolution and progression.

Published
2022

3. Antibodies against endogenous retroviruses promote lung cancer immunotherapy

Author

Ng, Kevin W., Boumelha, Jesse, Enfield, Katey S. S., Almagro, Jorge, Cha, Hongui, Pich, Oriol, Karasaki, Takahiro, Moore, David A., Salgado, Roberto, Sivakumar, Monica, Young, George, Molina-Arcas, Miriam, de Carné Trécesson, Sophie, Anastasiou, Panayiotis, Fendler, Annika, Au, Lewis, Shepherd, Scott T. C., Martínez-Ruiz, Carlos, Puttick, Clare, Black, James R. M., Watkins, Thomas B. K., Kim, Hyemin, Shim, Seohee, Faulkner, Nikhil, Attig, Jan, Veeriah, Selvaraju, Magno, Neil, Ward, Sophia, Frankell, Alexander M., Al Bakir, Maise, Lim, Emilia L., Hill, Mark S., Wilson, Gareth A., Cook, Daniel E., Birkbak, Nicolai J., Behrens, Axel, Yousaf, Nadia, Popat, Sanjay, Hackshaw, Allan, Hiley, Crispin T., Litchfield, Kevin, McGranahan, Nicholas, Jamal-Hanjani, Mariam, Larkin, James, Lee, Se-Hoon, Turajlic, Samra, Swanton, Charles, Downward, Julian, and Kassiotis, George

Published
2023
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4. GREM1 is required to maintain cellular heterogeneity in pancreatic cancer

Author

Lan, Linxiang, Evan, Theodore, Li, Huafu, Hussain, Aasia, Ruiz, E. Josue, Zaw Thin, May, Ferreira, Rute M. M., Ps, Hari, Riising, Eva M., Zen, Yoh, Almagro, Jorge, Ng, Kevin W., Soro-Barrio, Pablo, Nelson, Jessica, Koifman, Gabriela, Carvalho, Joana, Nye, Emma L., He, Yulong, Zhang, Changhua, Sadanandam, Anguraj, and Behrens, Axel

Published
2022
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14. GREM1 is required to maintain cellular heterogeneity in pancreatic cancer

Author

Lan, Linxiang, Evan, Theodore, Li, Huafu, Hussain, Aasia, Ruiz, E. Josue, Zaw Thin, May, Ferreira, Rute M. M., Ps, Hari, Riising, Eva M., Zen, Yoh, Almagro, Jorge, Ng, Kevin W., Soro-Barrio, Pablo, Nelson, Jessica, Koifman, Gabriela, Carvalho, Joana, Nye, Emma L., He, Yulong, Zhang, Changhua, Sadanandam, Anguraj, and Behrens, Axel

Abstract

Pancreatic ductal adenocarcinoma (PDAC) shows pronounced epithelial and mesenchymal cancer cell populations1–4. Cellular heterogeneity in PDAC is an important feature in disease subtype specification3–5, but how distinct PDAC subpopulations interact, and the molecular mechanisms that underlie PDAC cell fate decisions, are incompletely understood. Here we identify the BMP inhibitor GREM16,7as a key regulator of cellular heterogeneity in pancreatic cancer in human and mouse. Grem1inactivation in established PDAC in mice resulted in a direct conversion of epithelial into mesenchymal PDAC cells within days, suggesting that persistent GREM1 activity is required to maintain the epithelial PDAC subpopulations. By contrast, Grem1overexpression caused an almost complete ‘epithelialization’ of highly mesenchymal PDAC, indicating that high GREM1 activity is sufficient to revert the mesenchymal fate of PDAC cells. Mechanistically, Grem1was highly expressed in mesenchymal PDAC cells and inhibited the expression of the epithelial–mesenchymal transition transcription factors Snai1(also known as Snail) and Snai2(also known as Slug) in the epithelial cell compartment, therefore restricting epithelial–mesenchymal plasticity. Thus, constant suppression of BMP activity is essential to maintain epithelial PDAC cells, indicating that the maintenance of the cellular heterogeneity of pancreatic cancer requires continuous paracrine signalling elicited by a single soluble factor.

Published
2024
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15. Antibodies against endogenous retroviruses promote lung cancer immunotherapy

Author

Ng, Kevin W, Boumelha, Jesse, Enfield, Katey SS, Almagro, Jorge, Cha, Hongui, Pich, Oriol, Karasaki, Takahiro, Moore, David A, Salgado, Roberto, Sivakumar, Monica, Young, George, Molina-Arcas, Miriam, de Carné Trécesson, Sophie, Anastasiou, Panayiotis, Fendler, Annika, Au, Lewis, Shepherd, Scott TC, Martínez-Ruiz, Carlos, Puttick, Clare, Black, James RM, Watkins, Thomas BK, Kim, Hyemin, Shim, Seohee, Faulkner, Nikhil, Attig, Jan, Veeriah, Selvaraju, Magno, Neil, Ward, Sophia, Frankell, Alexander M, Al Bakir, Maise, Lim, Emilia L, Hill, Mark S, Wilson, Gareth A, Cook, Daniel E, Birkbak, Nicolai J, Behrens, Axel, Yousaf, Nadia, Popat, Sanjay, Hackshaw, Allan, Consortium, TRACERx, Consortium, CAPTURE, Hiley, Crispin T, Litchfield, Kevin, McGranahan, Nicholas, Jamal-Hanjani, Mariam, Larkin, James, Lee, Se-Hoon, Turajlic, Samra, Swanton, Charles, Downward, Julian, and Kassiotis, George

Subjects
Model organisms, Lung Neoplasms, Immunology, Gene Expression, Adenocarcinoma of Lung, Infectious Disease, Antibodies, Cohort Studies, Mice, Signalling & Oncogenes, Ecology,Evolution & Ethology, Carcinoma, Non-Small-Cell Lung, Tumor Microenvironment, Animals, Humans, Lung, Computational & Systems Biology, Chemical Biology & High Throughput, B-Lymphocytes, Human Biology & Physiology, Stem Cells, FOS: Clinical medicine, Endogenous Retroviruses, Genome Integrity & Repair, Cell Biology, Tumour Biology, Disease Models, Animal, Cell Cycle & Chromosomes, Immunotherapy, Genetics & Genomics
Abstract

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)1,2. Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive1,2. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma3. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response. ispartof: NATURE vol:616 issue:7957 ispartof: location:England status: Published online

Published
2023
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19. Deficient adaptation to centrosome duplication defects in neural progenitors causes microcephaly and subcortical heterotopias

Author

González-Martínez, José, primary, Cwetsch, Andrzej W., additional, Martínez-Alonso, Diego, additional, López-Sainz, Luis R., additional, Almagro, Jorge, additional, Melati, Anna, additional, Gómez, Jesús, additional, Pérez-Martínez, Manuel, additional, Megías, Diego, additional, Boskovic, Jasminka, additional, Gilabert-Juan, Javier, additional, Graña-Castro, Osvaldo, additional, Pierani, Alessandra, additional, Behrens, Axel, additional, Ortega, Sagrario, additional, and Malumbres, Marcos, additional

Published
2021
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21. The ubiquitin ligase HOIL-1L regulates immune responses by interacting with linear ubiquitin chains

Author

Gomez-Diaz, Carlos, primary, Jonsson, Gustav, additional, Schodl, Katrin, additional, Deszcz, Luiza, additional, Bestehorn, Annika, additional, Eislmayr, Kevin, additional, Almagro, Jorge, additional, Kavirayani, Anoop, additional, Fennell, Lilian M, additional, Hagelkruys, Astrid, additional, Kovarik, Pavel, additional, Penninger, Josef M, additional, and Ikeda, Fumiyo, additional

Published
2021
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26. Lack of adaptation to centriolar defects leads to p53-independent microcephaly in the absence of Cep135

Author

González-Martínez, José, primary, Cwetsch, Andrzej W, additional, Martínez-Alonso, Diego, additional, López-Sainz, Luis Rodrigo, additional, Almagro, Jorge, additional, Megías, Diego, additional, Boskovic, Jasminka, additional, Gilabert-Juan, Javier, additional, Graña-Castro, Osvaldo, additional, Pierani, Alessandra, additional, Behrens, Axel, additional, Ortega, Sagrario, additional, and Malumbres, Marcos, additional

Published
2020
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27. Enoxaparin does not ameliorate liver fibrosis or portal hypertension in rats with advanced cirrhosis

Author

Fortea, José I., primary, Zipprich, Alexander, additional, Fernandez‐Mena, Carolina, additional, Puerto, Marta, additional, Bosoi, Cristina R., additional, Almagro, Jorge, additional, Hollenbach, Marcus, additional, Bañares, Juan, additional, Rodríguez‐Sánchez, Belén, additional, Cercenado, Emilia, additional, Clément, Marc‐André, additional, Rose, Christopher F., additional, Bañares, Rafael, additional, Vaquero, Javier, additional, and Ripoll, Cristina, additional

Published
2017
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28. Linear ubiquitination byLUBELhas a role inDrosophilaheat stress response

Author

Asaoka, Tomoko, primary, Almagro, Jorge, additional, Ehrhardt, Christine, additional, Tsai, Isabella, additional, Schleiffer, Alexander, additional, Deszcz, Luiza, additional, Junttila, Sini, additional, Ringrose, Leonie, additional, Mechtler, Karl, additional, Kavirayani, Anoop, additional, Gyenesei, Attila, additional, Hofmann, Kay, additional, Duchek, Peter, additional, Rittinger, Katrin, additional, and Ikeda, Fumiyo, additional

Published
2016
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29. Linear ubiquitination by LUBEL has a role in Drosophila heat stress response.

Author

Asaoka, Tomoko, Almagro, Jorge, Ehrhardt, Christine, Tsai, Isabella, Schleiffer, Alexander, Deszcz, Luiza, Junttila, Sini, Ringrose, Leonie, Mechtler, Karl, Kavirayani, Anoop, Gyenesei, Attila, Hofmann, Kay, Duchek, Peter, Rittinger, Katrin, and Ikeda, Fumiyo

Abstract

The HOIP ubiquitin E3 ligase generates linear ubiquitin chains by forming a complex with HOIL-1L and SHARPIN in mammals. Here, we provide the first evidence of linear ubiquitination induced by a HOIP orthologue in Drosophila. We identify Drosophila CG11321, which we named Linear Ubiquitin E3 ligase ( LUBEL), and find that it catalyzes linear ubiquitination in vitro. We detect endogenous linear ubiquitin chain-derived peptides by mass spectrometry in Drosophila Schneider 2 cells and adult flies. Furthermore, using CRISPR/Cas9 technology, we establish linear ubiquitination-defective flies by mutating residues essential for the catalytic activity of LUBEL. Linear ubiquitination signals accumulate upon heat shock in flies. Interestingly, flies with LUBEL mutations display reduced survival and climbing defects upon heat shock, which is also observed upon specific LUBEL depletion in muscle. Thus, LUBEL is involved in the heat response by controlling linear ubiquitination in flies. [ABSTRACT FROM AUTHOR]

Published
2016
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