Thomas, R. (Roman)

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    Two cell line models to study multiorganic metastasis and immunotherapy in lung squamous cell carcinoma
    (2022) Expósito, F. (Francisco); Pio, R. (Rubén); Sainz, C. (Cristina); Agorreta, J. (Jackeline); Bosco, G. (Graziella); Thomas, R. (Roman); Larrayoz, M. (Marta); Azpilicueta, A. (Arantza); Montuenga-Badia, L.M. (Luis M.); Biurrun, G. (Gabriel) de; Bertolo, C. (Cristina); Melero, I. (Ignacio); Redrado, M. (Miriam); Valencia, K. (Karmele); Redín, E. (Esther); Echepare, M. (Mirari); Serrano-Tejero, D. (Diego); Calvo-González, A. (Alfonso); Ajona, D. (Daniel); Zandueta, C. (Carolina)
    There 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.
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    DSTYK inhibition increases the sensitivity of lung cancer cells to T cell-mediated cytotoxicity
    (Rockefeller University Press, 2022) Valencia, K. (Karmele); Echepare, M. (Mirari); Teijeira, A. (Álvaro); Pasquier, F. (Florence); Bertolo, C. (Cristina); Sainz, C. (Cristina); Tamayo, I. (Ibon); Picabea, B. (Beñat); Bosco, G. (Graziella); Thomas, R. (Roman); Agorreta, J. (Jackeline); Lopez-Picazo, J.M. (José M.); Frigola, J. (Joan); Amat, R. (Ramon); Calvo-González, A. (Alfonso); Felip, E. (Enriqueta); Melero, I. (Ignacio); Montuenga-Badia, L.M. (Luis M.)
    Lung 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.