| Laboratory of Rosario Perona Abellón |
Role of DUSP1 phosphatase in carcinogenesis, tumor progression and chemotherapy response
DUSP1 is a dual phosphatase that dephosphorylates the JNK, p38 and ERK1/2 MAP kinases. We have previously report that this phosphatase plays a relevant role in cancer and its function may depend on the tumor type. In non-small cell lung cancer (NSCLC) DUSP1 expression protects from the cytotoxic activity from cisplatin since it blocks JNK and p38 MAP Kinase activities that are necessary for cell death induction by cisplatin. Further, DUSP1 is overexpressed in 75-80% of NSCLC patient biopsies in early stages of the disease. In this tumor type DUSP1 is necessary for tumor growth, angiogenesis induction and metastasis since blocking the expression of this gene we observed a decrease in these functions in NSCLC cell lines. In patient biopsies of NSCLC, DUSP1 is expressed in those areas surrounding blood vessels and expressing the vascular growth factor VEGF. On the other hand in a DUSP1/KO mice model we have used a two-step skin carcinogenesis protocol (DMBA/TPA) for induction of papilomas and carcinomas. We have found that DUSP1 KO mice develop more frequently invasive carcinomas while WT mice developed preferentially papilomas. Interestingly, biopsies from skin from human control tissues and those from basal and invasive carcinomas showed a decrease in DUSP1 expression (by Q-RT-PCR) both in basal and invasive carcinomas when compared with control skin. This apparently contradictory finding for DUSP1 indicates that that its functions may depend on the tissue type acting as a tumor suppressor (skin) and carcinogenesis, and inductor of tumor progression, angiogenesis and metastasis (lung). We are currently obtaining of conditional KO mice model for DUSP1 in collaboration with Sagrario Ortega at CNIO, and this model will be useful to clarify the role of DUSP1 in cancer. Preliminary data indicates that DSUP1 plays an important role in pancreatic cancer and high-grade gliomas and these will be the first models to use with our conditional KO model.
Development of new approaches for telomeropaties based in reactivation of telomerase activity by expression of GSE24.2
In 2007 we published that an internal fragment of dyskerin that we termed GSE24.2 was able to reactivate telomerase activity in cells derived from Dyskeratosis congenita patients (DC). This is a rare disease consequence of mutations in telomerase complex genes: dyskerin (DKC1) telomerase reverse transcriptase (hTERT) or telomerase RNA (hTR) among others. This finding was patented and the patent licensed to the spin-off Advanced Medical projects. In November 2012 EMA give the status of orphan drug to GSE24-2 for the treatment of dyskeratosis congenita. We are currently making the preclinical assays optimizing the delivery and stability of the peptide (nanoparticles, pegylation, etc). We have also recently reported silica mesoporous nanoparticles that harbor a molecular gate consisting on a sugar, substrate for acid-b-galactosidase, an enzyme that is preferentially expressed in senescent cells. These nanoparticles empty their content only in senescent cells. We are currently assaying the biological activity of GSE24.2 released by these nanoparticles in senescent cells.
In parallel our group is a national reference for the detection of mutations in telomerase genes in DC patients and as a consequence of this work we have recently published new mutations in DC Spanish patients