Open Access
Analysis of copy number alterations reveals the lncRNA ALAL-1 as a regulator of lung cancer immune evasion
(Rockefeller University Press, 2020) Athie, Alejandro; Marchese, Francesco P.; González, Jovanna; Lozano, Teresa; Raimondi, Ivan; Juvvuna, Prasanna Kumar; Abad, Amaya ; Marin-Béjar, Oskar; Serizay, Jacques; Martínez, Dannys; Ajona, Daniel; Pajares Villandiego, María Josefa; Sandoval, Juan; Montuenga, Luis M.; Kanduri, Chandrasekhar ; Lasarte, Juan José; Huarte, Maite ; Ciencias de la Salud; Osasun Zientziak
Cancer is characterized by genomic instability leading to deletion or amplification of oncogenes or tumor suppressors. However, most of the altered regions are devoid of known cancer drivers. Here, we identify lncRNAs frequently lost or amplified in cancer. Among them, we found amplified lncRNA associated with lung cancer-1 (ALAL-1) as frequently amplified in lung adenocarcinomas. ALAL-1 is also overexpressed in additional tumor types, such as lung squamous carcinoma. The RNA product of ALAL-1 is able to promote the proliferation and tumorigenicity of lung cancer cells. ALAL-1 is a TNFα− and NF-κB–induced cytoplasmic lncRNA that specifically interacts with SART3, regulating the subcellular localization of the protein deubiquitinase USP4 and, in turn, its function in the cell. Interestingly, ALAL-1 expression inversely correlates with the immune infiltration of lung squamous tumors, while tumors with ALAL-1 amplification show lower infiltration of several types of immune cells. We have thus unveiled a pro-oncogenic lncRNA that mediates cancer immune evasion, pointing to a new target for immune potentiation.
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 Zientziak
Rationale: 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.
Open Access
Whole exome sequencing characterization of individuals presenting extreme phenotypes of high and low risk of developing tobacco-induced lung adenocarcinoma
(AME Publishing, 2021) Patiño García, Ana; Guruceaga, Elizabeth; Segura, Víctor; Sánchez Bayona, Rodrigo; Andueza, María Pilar; Tamayo Uria, Ibon; Serrano, Guillermo; Fusco, Juan Pablo; Pajares Villandiego, María Josefa; Gúrpide, Alfonso; Ocón, Marimar; Sanmamed, Miguel F.; Rodríguez Ruiz, María; Melero, Ignacio; Lozano, María Dolores; Andrea, Carlos de; Pita, Guillermo; González Neira, Anna; González, Alvaro; Zulueta, Javier J.; Montuenga, Luis M.; Pío, Rubén; Pérez Gracia, José Luis; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua
Background: tobacco is the main risk factor for developing lung cancer. Yet, some heavy smokers do not develop lung cancer at advanced ages while others develop it at young ages. Here, we assess for the first time the genetic background of these clinically relevant extreme phenotypes using whole exome sequencing (WES). Methods: we performed WES of germline DNA from heavy smokers who either developed lung adenocarcinoma at an early age ( extreme cases, n=50) or did not present lung adenocarcinoma or other tumors at an advanced age (extreme controls, n=50). We selected non-synonymous variants located in exonic regions and consensus splice sites of the genes that showed significantly different allelic frequencies between both cohorts. We validated our results in all the additional extreme cases (i.e., heavy smokers who developed lung adenocarcinoma at an early age) available from The Cancer Genome Atlas (TCGA). Results: the mean age for the extreme cases and controls was respectively 49.7 and 77.5 years. Mean tobacco consumption was 43.6 and 56.8 pack-years. We identified 619 significantly different variants between both cohorts, and we validated 108 of these in extreme cases selected from TCGA. Nine validated variants, located in relevant cancer related genes, such as PARP4, HLA-A or NQO1, among others, achieved statistical significance in the False Discovery Rate test. The most significant validated variant (P=4.48x10(-5)) was located in the tumor-suppressor gene ALPK2. Conclusions: we describe genetic variants associated with extreme phenotypes of high and low risk for the development of tobacco-induced lung adenocarcinoma. Our results and our strategy may help to identify high-risk subjects and to develop new therapeutic strategies.
Open Access
TMPRSS4: a novel tumor prognostic indicator for the stratification of stage ia tumors and a liquid biopsy biomarker for NSCLC patients
(MDPI, 2019-12-03) Villalba, María; Expósito, Francisco; Pajares Villandiego, María Josefa; Sáinz, Cristina; Redrado, Miriam; Remírez, Ana; Wistuba, Ignacio; Behrens, Carmen; Jantus-Lewintre, Eloisa; Camps, Carlos; Montuenga, Luis M.; Pío, Rubén; Lozano, María Dolores; Andrea, Carlos de; Calvo, Alfonso; Ciencias de la Salud; Osasun Zientziak
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.

Pajares Villandiego, María Josefa

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