| Laboratory of Ignacio Palmero Rodríguez |
SIX1 and senescence in cancer
We have recently shown that the SIX1 homeoprotein is an essential repressor of cellular senescence, mainly via the regulation of the senescence effector p16INK4A (Adrados et al, Oncogene, 2016. PMID 26500063). SIX1 is also an oncogene, frequently activated in different types of human tumors such as lung and brain cancer or sarcomas. We have explored the role of senescence in the protumorigenic role of SIX1, studying mouse fibrosarcoma tumors derived from transformed fibroblasts. Our results show that SIX1 has a protumorigenic effect in this model, which is accompanied by the blunting of the expression signature associated to SIX1 in senescence. This is consistent with the role of cell senescence as a tumor barrier and suggests that opposing senescence plays a role in the oncogenic role of SIX1. These studies have also shown that SIX1 promotes an undifferentiated phenotype in these tumors, mainly mediated by the transcrptional activation of the stemness regulator SOX2. Our results have identified new mechanisms that may underpin the oncogenic role of SIX1: blocking the tumor suppressive action of senescence and promoting stem-cell features via SOX2 (De Lope et al, Scientific Reports, 2019. PMID 30723235).
SIX1 and senescence in development
Developmental senescence is a form of programmed, physiological senescence that occurs transiently in specific embryo locations and contributes to patterning during embryonic development. SIX1 is a key transcriptional regulator of development, essential for the formation of organs such as inner ear, kidney, muscle and thymus, among others. Interestingly, alterations in the SIX/EYA pathway are linked to the Branquio-Oto-Renal (BOR) syndrome, a human rare congenital disorder with defects in the ear and kidney and branchial arch anomalies. Based on our recent finding that SIX1 is a senescence regulator, we are currently testing the hypothesis that aberrant activation of senescence can underpin the developmental defects associated with SIX1 deficiency in mice and humans. For this, we are focusing on the developing inner ear, an organ where physiological developmental senescence is found and is also severely affected in Six1-deficient mice and in BOR patients.
Senescence and cell plasticity
One of our interests is to understand the link between cell senescence and plasticity. Emerging evidence has uncovered a complex connection between senescence, differentiation and regeneration in different contexts, with examples of both inhibitory and activating effects of senescence. In this context, our recent results have identified a gene signature related to differentiation in cellular models of senescence triggered either by oncogenic stress or SIX1 loss (Adrados et al, Oncogene, 2016. PMID 26500063). To investigate further this link, we are exploring the impact of senescence on the differentiation potential of fibroblasts. During these studies, we have observed the differential regulation of myofibroblastic phenotype in primary fibroblasts undergoing diverse forms of senescence. Our results show that this phenotype is transmitted in a paracrine manner and it is dynamically regulated during senescence. We are currently investigating the functional implications of these findings in the context of normal and pathological myofibroblast differentiation.