Agorreta Arrazubi, Jackeline
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Agorreta Arrazubi
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Jackeline
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Ciencias de la Salud
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Publication Open Access Two cell line models to study multiorganic metastasis and immunotherapy in lung squamous cell carcinoma(The Company of Biologists, 2022) Valencia, Karmele; Sáinz, Cristina; Bértolo, Cristina; Biurrun, Gabriel de; Agorreta Arrazubi, Jackeline; Azpilikueta, Arantza; Larrayoz, Marta; Bosco, Graziella; Zandueta, Carolina; Redrado, Miriam; Redin, Esther; Expósito, Francisco; Serrano, Diego; Echepare, Mirari; Ajona, Daniel; Melero, Ignacio; Pío, Rubén; Thomas, Roman; Calvo, Alfonso; Montuenga, Luis M.; Ciencias de la Salud; Osasun ZientziakThere is a paucity of adequate mouse models and cell lines available to study lung squamous cell carcinoma (LUSC). We have generated and characterized two models of phenotypically different transplantable LUSC cell lines, i.e. UN-SCC679 and UN-SCC680, derived from A/J mice that had been chemically induced with N-nitroso-tris-chloroethylurea (NTCU). Furthermore, we genetically characterized and compared both LUSC cell lines by performing whole-exome and RNA sequencing. These experiments revealed similar genetic and transcriptomic patterns that may correspond to the classic LUSC human subtype. In addition, we compared the immune landscape generated by both tumor cells lines in vivo and assessed their response to immune checkpoint inhibition. The differences between the two cell lines are a good model for the remarkable heterogeneity of human squamous cell carcinoma. Study of the metastatic potential of these models revealed that both cell lines represent the organotropism of LUSC in humans, i.e. affinity to the brain, bones, liver and adrenal glands. In summary, we have generated valuable cell line tools for LUSC research, which recapitulates the complexity of the human disease.Publication Open Access DSTYK inhibition increases the sensitivity of lung cancer cells to T cell-mediated cytotoxicity(Rockefeller University Press, 2022) Valencia, Karmele; Echepare, Mirari; Teijeira, Álvaro; Pasquier, Andrea; Bértolo, Cristina; Sáinz, Cristina; Tamayo Uria, Ibon; Picabea, Beñat; Bosco, Graziella; Thomas, Roman; Agorreta Arrazubi, Jackeline; López-Picazo, José María; Frigola, Joan; Amat, Ramón; Calvo, Alfonso; Felip, Enriqueta; Melero, Ignacio; Montuenga, Luis M.; Ciencias de la Salud; Osasun ZientziakLung cancer remains the leading cause of cancer-related death worldwide. We identify DSTYK, a dual serine/threonine and tyrosine non-receptor protein kinase, as a novel actionable target altered in non-small cell lung cancer (NSCLC). We also show DSTYK's association with a lower overall survival (OS) and poorer progression-free survival (PFS) in multiple patient cohorts. Abrogation of DSTYK in lung cancer experimental systems prevents mTOR-dependent cytoprotective autophagy, impairs lysosomal biogenesis and maturation, and induces accumulation of autophagosomes. Moreover, DSTYK inhibition severely affects mitochondrial fitness. We demonstrate in vivo that inhibition of DSTYK sensitizes lung cancer cells to TNF-α–mediated CD8+-killing and immune-resistant lung tumors to anti–PD-1 treatment. Finally, in a series of lung cancer patients, DSTYK copy number gain predicts lack of response to the immunotherapy. In summary, we have uncovered DSTYK as new therapeutic target in lung cancer. Prioritization of this novel target for drug development and clinical testing may expand the percentage of NSCLC patients benefiting from immune-based treatments.Publication Open Access YES1 drives lung cancer growth and progression and predicts sensitivity to dasatinib(American Thoracic Society, 2019-06-04) Garmendia, Irati; Pajares Villandiego, María Josefa; Hermida-Prado, Francisco; Ajona, Daniel; Bértolo, Cristina; Sáinz, Cristina; Lavín, Amaya; Remírez, Ana; Valencia, Karmele; Moreno, Haritz; Ferrer, Irene; Behrens, Carmen; Cuadrado, Myriam; Paz-Ares, Luis; Bustelo, Xosé R.; Gil-Bazo, Ignacio; Alameda, Daniel; Lecanda, Fernando; Calvo, Alfonso; Felip, Enriqueta; Sánchez-Céspedes, Montse; Wistuba, Ignacio; Granda-Diaz, Rocío; Rodrigo, Juan Pablo; García-Pedrero, Juana María; Pío, Rubén; Montuenga, Luis M.; Agorreta Arrazubi, Jackeline; Ciencias de la Salud; Osasun ZientziakRationale: the characterization of new genetic alterations is essential to assign effective personalized therapies in non-small cell lung cancer (NSCLC). Furthermore, finding stratification biomarkers is essential for successful personalized therapies. Molecular alterations of YES1, a member of the SRC (proto-oncogene tyrosine-protein kinase Src) family kinases (SFKs), can be found in a significant subset of patients with lung cancer. Objectives: to evaluate YES1 (v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1) genetic alteration as a therapeutic target and predictive biomarker of response to dasatinib in NSCLC. Methods: functional significance was evaluated by in vivo models of NSCLC and metastasis and patient-derived xenografts. The efficacy of pharmacological and genetic (CRISPR [clustered regularly interspaced short palindromic repeats]/Cas9 [CRISPR-associated protein 9]) YES1 abrogation was also evaluated. In vitro functional assays for signaling, survival, and invasion were also performed. The association between YES1 alterations and prognosis was evaluated in clinical samples. Measurements and Main Results: we demonstrated that YES1 is essential for NSCLC carcinogenesis. Furthermore, YES1 overexpression induced metastatic spread in preclinical in vivo models. YES1 genetic depletion by CRISPR/Cas9 technology significantly reduced tumor growth and metastasis. YES1 effects were mainly driven by mTOR (mammalian target of rapamycin) signaling. Interestingly, cell lines and patient-derived xenograft models with YES1 gene amplifications presented a high sensitivity to dasatinib, an SFK inhibitor, pointing out YES1 status as a stratification biomarker for dasatinib response. Moreover, high YES1 protein expression was an independent predictor for poor prognosis in patients with lung cancer. Conclusions: YES1 is a promising therapeutic target in lung cancer. Our results provide support for the clinical evaluation of dasatinib treatment in a selected subset of patients using YES1 status as predictive biomarker for therapy.