Redrado, M. (Miriam)
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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.
- SRC family kinase (SFK) inhibitor dasatinib improves the antitumor activity of anti-PD-1 in NSCLC models by inhibiting Treg cell conversion and proliferation(2021) Expósito, F. (Francisco); Pio, R. (Rubén); Sainz, C. (Cristina); Senent, Y. (Yaiza); Garmendia, I. (Irati); Remirez, A. (Ana); Agorreta, J. (Jackeline); Lozano-Moreda, T. (Teresa); García-Pedrero, J.M. (Juana M.); Montuenga-Badia, L.M. (Luis M.); Bertolo, C. (Cristina); Villalba-Esparza, M. (María); Redrado, M. (Miriam); Redín, E. (Esther); Andrea, C.E. (Carlos Eduardo) de; Ortiz-Espinosa, S. (Sergio); Serrano-Tejero, D. (Diego); Calvo-González, A. (Alfonso); Ajona, D. (Daniel); Lasarte, J.J. (Juan José)Introduction The use of immune-checkpoint inhibitors has drastically improved the management of patients with non-small cell lung cancer (NSCLC), but innate and acquired resistances are hurdles needed to be solved. Immunomodulatory drugs that can reinvigorate the immune cytotoxic activity, in combination with antiprogrammed cell death 1 (PD-1) antibody, are a great promise to overcome resistance. We evaluated the impact of the SRC family kinases (SFKs) on NSCLC prognosis, and the immunomodulatory effect of the SFK inhibitor dasatinib, in combination with anti-PD-1, in clinically relevant mouse models of NSCLC. Methods A cohort of patients from University Clinic of Navarra (n=116) was used to study immune infiltrates by multiplex immunofluorescence (mIF) and YES1 protein expression in tumor samples. Publicly available resources (TCGA, Km Plotter, and CIBERSORT) were used to study patient's survival based on expression of SFKs and tumor infiltrates. Syngeneic NSCLC mouse models 393P and UNSCC680AJ were used for in vivo drug testing. Results Among the SFK members, YES1 expression showed the highest association with poor prognosis. Patients with high YES1 tumor levels also showed high infiltration of CD4+/FOXP3+ cells (regulatory T cells (Tregs)), suggesting an immunosuppressive phenotype. After testing for YES1 expression in a panel of murine cell lines, 393P and UNSCC680AJ were selected for in vivo studies. In the 393P model, dasatinib+anti-PD-1 treatment resulted in synergistic activity, with 87% tumor regressions and development of immunological memory that impeded tumor growth when mice were rechallenged. In vivo depletion experiments further showed that CD8+ and CD4+ cells are necessary for the therapeutic effect of the combination. The antitumor activity was accompanied by a very significant decrease in the number of Tregs, which was validated by mIF in tumor sections. In the UNSCC680AJ model, the antitumor effects of dasatinib+anti-PD-1 were milder but similar to the 393P model. In in vitro assays, we demonstrated that dasatinib blocks proliferation and transforming growth factor beta-driven conversion of effector CD4+ cells into Tregs through targeting of phospholymphocyte-specific protein tyrosine kinase and downstream effectors pSTAT5 and pSMAD3. Conclusions YES1 protein expression is associated with increased numbers of Tregs in patients with NSCLC. Dasatinib synergizes with anti-PD-1 to impair tumor growth in NSCLC experimental models. This study provides the preclinical rationale for the combined use of dasatinib and PD-1/programmed death-ligand 1 blockade to improve outcomes of patients with NSCLC.
- TMPRSS4 regulates levels of integrin α5 in NSCLC through miR-205 activity to promote metastasis(Cancer Research UK, 2014) Rodriguez, M.J. (María José); Rueda, P. (Paloma); Montuenga-Badia, L.M. (Luis M.); Bodegas-Frías, E. (Elena); Aberasturi, A.L. (A. L.) de; Redrado, M. (Miriam); Larzabal, L. (Leyre); Calvo-González, A. (Alfonso)TMPRSS4 is a membrane-anchored protease involved in cell migration and invasion in different cancer types including lung cancer. TMPRSS4 expression is increased in NSCLC and its inhibition through shRNA reduces lung metastasis. However, molecular mechanisms leading to the protumorigenic regulation of TMPRSS4 in lung cancer are unknown. METHODS: miR-205 was identified as an overexpressed gene upon TMPRSS4 downregulation through microarray analysis. Cell migration and invasion assays and in vivo lung primary tumour and metastasis models were used for functional analysis of miR-205 overexpression in H2170 and H441 cell lines. Luciferase assays were used to identify a new miR-205 direct target in NSCLC. RESULTS: miR-205 overexpression promoted an epithelial phenotype with increased E-cadherin and reduced fibronectin. Furthermore, miR-205 expression caused a G0/G1 cell cycle arrest and inhibition of cell growth, migration, attachment to fibronectin, primary tumour growth and metastasis formation in vivo. Integrin α5 (a proinvasive protein) was identified as a new miR-205 direct target in NSCLC. Integrin α5 downregulation in lung cancer cells resulted in complete abrogation of cell migration, a decreased capacity to adhere to fibronectin and reduced in vivo tumour growth, compared with control cells. TMPRSS4 silencing resulted in a concomitant reduction of integrin α5 levels. CONCLUSION: We have demonstrated for the first time a new molecular pathway that connects TMPRSS4 and integrin α5 through miR-205 to regulate cancer cell invasion and metastasis. Our results will help designing new therapeutic strategies to inhibit this novel pathway in NSCLC.
- Nivolumab plus ipilimumab for treatment-naïve metastatic uveal melanoma: An open-label, multicenter, phase II trial by the spanish multidisciplinary melanoma group (GEM-1402)(Asco, 2020) Varela, M. (Mar); Rodríguez-Abreu, D. (Delvys); Rullan, A.J. (Antonio J.); Martin-Algarra, S. (Salvador); Goma, M. (Montserrat); López-Castro, R. (Rafael); Curiel, T. (Teresa); Carrión, L.A. (Lorenzo Alonso); Redrado, M. (Miriam); Espinosa, E. (Enrique); Piulats, J.M. (José María); Cruz-Merino, L. (Luis) de la; Berrocal, A. (Alfonso); Calvo-González, A. (Alfonso)Purpose: This study aimed to assess the efficacy of the combination of nivolumab (nivo) plus ipilimumab (ipi) as a first-line therapy with respect to the 12-month overall survival (OS) in patients with metastatic uveal melanoma (MUM) who are not eligible for liver resection. Methods: This was a single-arm, phase II trial led by the Spanish Multidisciplinary Melanoma Group (GEM) on nivo plus ipi for systemic treatment-naïve patients of age > 18 years, with histologically confirmed MUM, Eastern Cooperative Oncology Group-PS 0/1, and confirmed progressive metastatic disease (M1). Nivo (1 mg/kg once every 3 weeks) and ipi (3 mg/kg once every 3 weeks) were administered during four inductions, followed by nivo (3 mg/kg once every 2 weeks) until progressive disease, toxicity, or withdrawal. The primary end point was 12-month OS. OS, progression-free survival (PFS), and overall response rate were evaluated every 6 weeks using RECIST (v1.1). Safety was also evaluated. Logistic regression and Cox proportional hazard models comprising relevant clinical factors were used to evaluate the potential association with response to treatment and survival. Cytokines were quantified in serum samples for their putative role in immune modulation/angiogenesis and/or earlier evidence of involvement in immunotherapy. Results: A total of 52 patients with a median age of 59 years (range, 26-84 years) were enrolled. Overall, 78.8%, 56%, and 32% of patients had liver M1, extra-liver M1, and elevated lactate dehydrogenase. Stable disease was the most common outcome (51.9%). The primary end point was 12-month OS, which was 51.9% (95% CI, 38.3 to 65.5). The median OS and PFS were 12.7 months and 3.0 months, respectively. PFS was influenced by higher LDH values. Conclusions: Nivo plus ipi in the first-line setting for MUM showed a modest improvement in OS over historical benchmarks of chemotherapy, with a manageable toxicity profile.
- TMPRSS4: a novel tumor prognostic indicator for the stratification of stage IA tumors and a liquid biopsy biomarker for NSCLC patients(MDPI AG, 2019) Behrens, C. (C.); Pajares, M.J. (María José); Expósito, F. (Francisco); Pio, R. (Rubén); Sainz, C. (Cristina); Lozano, M.D. (María Dolores); Remirez, A. (Ana); Jantus-Lewintre, E. (Eloisa); Camps, C. (Carlos); Montuenga-Badia, L.M. (Luis M.); Villalba-Esparza, M. (María); Redrado, M. (Miriam); Andrea, C.E. (Carlos Eduardo) de; Wistuba, I.I. (Ignacio I.); Calvo-González, A. (Alfonso)Relapse rates in surgically resected non-small-cell lung cancer (NSCLC) patients are between 30% and 45% within five years of diagnosis, which shows the clinical need to identify those patients at high risk of recurrence. The eighth TNM staging system recently refined the classification of NSCLC patients and their associated prognosis, but molecular biomarkers could improve the heterogeneous outcomes found within each stage. Here, using two independent cohorts (MDA and CIMA-CUN) and the eighth TNM classification, we show that TMPRSS4 protein expression is an independent prognostic factor in NSCLC, particularly for patients at stage I: relapse-free survival (RFS) HR, 2.42 (95% CI, 1.47–3.99), p < 0.001; overall survival (OS) HR, 1.99 (95% CI, 1.25–3.16), p = 0.004). In stage IA, high levels of this protein remained associated with worse prognosis (p = 0.002 for RFS and p = 0.001 for OS). As TMPRSS4 expression is epigenetically regulated, methylation status could be used in circulating tumor DNA from liquid biopsies to monitor patients. We developed a digital droplet PCR (ddPCR) method to quantify absolute copy numbers of methylated and unmethylated CpGs within the TMPRSS4 and SHOX2 (as control) promoters in plasma and bronchoalveolar lavage (BAL) samples. In case-control studies, we demonstrated that TMPRSS4 hypomethylation can be used as a diagnostic tool in early stages, with an AUROC of 0.72 (p = 0.008; 91% specificity and 52% sensitivity) for BAL and 0.73 (p = 0.015; 65% specificity and 90% sensitivity) for plasma, in early stages. In conclusion, TMPRSS4 protein expression can be used to stratify patients at high risk of relapse/death in very early stages NSCLC patients. Moreover, analysis of TMPRSS4 methylation status by ddPCR in blood and BAL is feasible and could serve as a non-invasive biomarker to monitor surgically resected patients.
- Biomarkers and polymorphisms in pancreatic neuroendocrine tumors treated with sunitinib(Impact Journals, 2018) Fuster, J. (Josep); Jiménez-Fonseca, P. (Paula); Grande, E. (Enrique); Raquel; Martín, M. (Miguel); Martínez-Lago, N. (Nieves); Muñarriz, J. (Javier); Cruz-Hernández, J.J. (Juan Jesús); Llanos, M. (Marta); Fernández-Mateos, J. (Javier); La-Casta-Muñoa, A. (Adelaida); Carmona-Bayonas, A. (Alberto); Barón, F. (Francisco); Redrado, M. (Miriam); Calvo-González, A. (Alfonso); Segura, Á. (Ángel); Castillo, A. (Alfredo); Capdevila, J. (Jaume)Several circulating biomarkers and single nucleotide polymorphisms (SNPs) have been correlated with efficacy and tolerability to antiangiogenic agents. These associations remain unexplored in well-differentiated, metastatic pancreatic neuroendocrine tumors treated with the multitargeted tyrosine kinase inhibitor sunitinib. We have assessed the effect on tumor response at 6 months, overall survival, progression-free survival and safety of 14 SNPs, and 6 soluble proteins. Forty-three patients were recruited. Two SNPs in the vascular endothelial growth factor receptor 3 (VEGFR-3) gene predicted lower overall survival: rs307826 with hazard ratio (HR) 3.67 (confidence interval [CI] 95%, 1.35-10.00) and rs307821 with HR 3.84 (CI 95%, 1.47-10.0). Interleukin-6 was associated with increased mortality: HR 1.06 (CI 95%, 1.01-1.12), and osteopontin was associated with shorter PFS: HR 1.087 (1.01-1.16), independently of Ki-67. Furthermore, levels of osteopontin remained higher at the end of the study in patients considered non-responders: 38.5 ng/mL vs. responders: 18.7 ng/mL, p-value=0.039. Dynamic upward variations were also observed with respect to IL-8 levels in sunitinib-refractory individuals: 28.5 pg/mL at baseline vs. 38.3 pg/mL at 3 months, p-value=0.024. In conclusion, two VEGFR-3 SNPs as well as various serum biomarkers were associated with diverse clinical outcomes in patients with well-differentiated pancreatic neuroendocrine tumors treated with sunitinib.
- Pilot clinical trial of type 1 dendritic cells loaded with autologous tumor lysates combined with GM-CSF, pegylated IFN, and cyclophosphamide for metastatic cancer patients(American Association of Immunologists, 2011) Benito-Boilos, A. (Alberto); Martinez-Forero, I. (Iván); Alfaro, C. (Carlos); Perez-Gracia, J.L. (Jose Luis); Peñuelas-Sanchez, I. (Ivan); Martin-Algarra, S. (Salvador); Rodriguez, I. (Inmaculada); Bolaños, E. (Elixabet); Agliano, A. (Alice); Rodriguez, J. (Javier); Sangro, B. (Bruno); Gonzalez-Hernandez, A. (Alvaro); Richter, J.A. (José Ángel); Perez-Calvo, J. (Javier); Hervas-Stubbs, S. (Sandra); Melero, I. (Ignacio); Vigil, C. (Carmen); Redrado, M. (Miriam); Suarez, N. (Natalia); Calvo-González, A. (Alfonso); Fernandez-Sanmamed, M. (Miguel)Twenty-four patients with metastatic cancer received two cycles of four daily immunizations with monocyte-derived dendritic cells (DC). DC were incubated with preheated autologous tumor lysate and subsequently with IFN-α, TNF-α, and polyinosinic:polycytidylic acid to attain type 1 maturation. One DC dose was delivered intranodally, under ultrasound control, and the rest intradermally in the opposite thigh. Cyclophosphamide (day -7), GM-CSF (days 1-4), and pegIFN alpha-2a (days 1 and 8) completed each treatment cycle. Pretreatment with cyclophosphamide decreased regulatory T cells to levels observed in healthy subjects both in terms of percentage and in absolute counts in peripheral blood. Treatment induced sustained elevations of IL-12 in serum that correlated with the output of IL-12p70 from cultured DC from each individual. NK activity in peripheral blood was increased and also correlated with the serum concentration of IL-12p70 in each patient. Circulating endothelial cells decreased in 17 of 18 patients, and circulating tumor cells markedly dropped in 6 of 19 cases. IFN-γ-ELISPOT responses to DC plus tumor lysate were observed in 4 of 11 evaluated cases. Tracing DC migration with [(111)In] scintigraphy showed that intranodal injections reached deeper lymphatic chains in 61% of patients, whereas with intradermal injections a small fraction of injected DC was almost constantly shown to reach draining inguinal lymph nodes. Five patients experienced disease stabilization, but no objective responses were documented. This combinatorial immunotherapy strategy is safe and feasible, and its immunobiological effects suggest potential activity in patients with minimal residual disease. A randomized trial exploring this hypothesis is currently ongoing.
- Identification of novel synthetic lethal vulnerability in non small cell lung cancer by co targeting TMPRSS4 and DDR1(Springer Science and Business Media LLC, 2019) Pajares, M.J. (María José); Expósito, F. (Francisco); Pio, R. (Rubén); Sainz, C. (Cristina); Jantus-Lewintre, E. (Eloisa); Camps, C. (Carlos); Montuenga-Badia, L.M. (Luis M.); Villalba-Esparza, M. (María); Guruceaga, E. (Elizabeth); López-López, R. (Rafael); Redrado, M. (Miriam); Valencia, K. (Karmele); Redín, E. (Esther); Lahoz, A. (Agustín); Andrea, C.E. (Carlos Eduardo) de; Calvo-González, A. (Alfonso); Sandoval, J. (Juan); Cirauqui, C. (Cristina); Hervas, D. (D.); Diaz-Lagares, A. (Ángel)Finding novel targets in non-small cell lung cancer (NSCLC) is highly needed and identification of synthetic lethality between two genes is a new approach to target NSCLC. We previously found that TMPRSS4 promotes NSCLC growth and constitutes a prognostic biomarker. Here, through large-scale analyses across 5 public databases we identified consistent co-expression between TMPRSS4 and DDR1. Similar to TMPRSS4, DDR1 promoter was hypomethylated in NSCLC in 3 independent cohorts and hypomethylation was an independent prognostic factor of disease-free survival. Treatment with 5-azacitidine increased DDR1 levels in cell lines, suggesting an epigenetic regulation. Cells lacking TMPRSS4 were highly sensitive to the cytotoxic effect of the DDR1 inhibitor dasatinib. TMPRSS4/DDR1 double knock-down (KD) cells, but not single KD cells suffered a G0/G1 cell cycle arrest with loss of E2F1 and cyclins A and B, increased p21 levels and a larger number of cells in apoptosis. Moreover, double KD cells were highly sensitized to cisplatin, which caused massive apoptosis (~40%). In vivo studies demonstrated tumor regression in double KD-injected mice. In conclusion, we have identified a novel vulnerability in NSCLC resulting from a synthetic lethal interaction between DDR1 and TMPRSS4.
- YES1 is a druggable oncogenic target in SCLC(Elsevier, 2022) Redín, E. (Esther); Garrido-Martín, E. (Eva); Valencia, K. (Karmele); Redrado, M. (Miriam); Solórzano-Rendón, J.L. (José Luis); Carias, R. (Rafael); Echepare, M. (Mirari); Expósito, F. (Francisco); Serrano-Tejero, D. (Diego); Ferrer, I. (Irene); Nunez-Buiza, A. (Angel); Garmendia, I. (Irati); García-Pedrero, J.M. (Juana M.); Gurpide, A. (Alfonso); Paz-Ares, L. (Luis); Politi, K. (Katerina); Montuenga-Badia, L.M. (Luis M.); Calvo-González, A. (Alfonso)Introduction: SCLC is an extremely aggressive subtype of lung cancer without approved targeted therapies. Here we identified YES1 as a novel targetable oncogene driving SCLC maintenance and metastasis. Methods: Association between YES1 levels and prognosis was evaluated in SCLC clinical samples. In vitro functional experiments for proliferation, apoptosis, cell cycle, and cytotoxicity were performed. Genetic and pharmacologic inhibition of YES1 was evaluated in vivo in cell- and patientderived xenografts and metastasis. YES1 levels were evaluated in mouse and patient plasma-derived exosomes. Results: Overexpression or gain/amplification of YES1 was identified in 31% and 26% of cases, respectively, across molecular subgroups, and was found as an independent predictor of poor prognosis. Genetic depletion of YES1 dramatically reduced cell proliferation, three-dimensional organoid formation, tumor growth, and distant metastasis, leading to extensive apoptosis and tumor regressions. Mechanistically, YES1-inhibited cells revealed alterations in the replisome and DNA repair processes, that conferred sensitivity to irradiation. Pharmacologic blockade with the novel YES1 inhibitor CH6953755 or dasatinib induced marked antitumor activity in organoid models and cell- and patient-derived xenografts. YES1 protein was detected in plasma exosomes from patients and mouse models, with levels matching those of tumors, suggesting that circulating YES1 could represent a biomarker for patient selection/ monitoring. Conclusions: Our results provide evidence that YES1 is a new druggable oncogenic target and biomarker to advance the clinical management of a subpopulation of patients with SCLC.
- Short-term starvation reduces IGF-1 levels to sensitize lung tumors to PD-1 immune checkpoint blockade(Nature, 2020) Ajona, D. (Daniel); Ortiz-Espinosa, S. (Sergio); Lozano-Moreda, T. (Teresa); Expósito, F. (Francisco); Calvo-González, A. (Alfonso); Valencia, K. (Karmele); Redrado, M. (Miriam); Remirez, A. (Ana); Lecanda, F. (Fernando); Alignani, D. (Diego); Lasarte, J.J. (Juan José); Macaya, I. (Irati); Senent, Y. (Yaiza); Bertolo, C. (Cristina); Sainz, C. (Cristina); Gil-Bazo, I. (Ignacio); Eguren-Santamaría, I. (Iñaki); Lopez-Picazo, J.M. (José M.); Perez-Gracia, J.L. (Jose Luis); Andrea, C.E. (Carlos Eduardo) de; Vicent, S. (Silvestre); Fernandez-Sanmamed, M. (Miguel); Montuenga-Badia, L.M. (Luis M.); Pio, R. (Rubén); González, Á. (Álvaro)Harnessing the immune system by blocking the programmed cell death protein 1 (PD-1) pathway has been a major breakthrough in non-small-cell lung cancer treatment. Nonetheless, many patients fail to respond to PD-1 inhibition. Using three syngeneic models, we demonstrate that short-term starvation synergizes with PD-1 blockade to inhibit lung cancer progression and metastasis. This antitumor activity was linked to a reduction in circulating insulin-like growth factor 1 (IGF-1) and a downregulation of IGF-1 receptor (IGF-1R) signaling in tumor cells. A combined inhibition of IGF-1R and PD-1 synergistically reduced tumor growth in mice. This effect required CD8 cells, boosted the intratumoral CD8/Treg ratio and led to the development of tumor-specific immunity. In patients with non-small-cell lung cancer, high plasma levels of IGF-1 or high IGF-1R expression in tumors was associated with resistance to anti-PD-1–programmed death-ligand 1 immunotherapy. In conclusion, our data strongly support the clinical evaluation of IGF-1 modulators in combination with PD-1 blockade.