Liquid biopsy represents a minimally invasive procedure that can provide similar information from body fluids to what is usually obtained from a tissue biopsy sample. Its implementation in the clinical setting might significantly renew the field of medical oncology, facilitating the introduction of the concepts of precision medicine and patient-tailored therapies. These advances may be useful in the diagnosis of brain tumors that currently require surgery for tissue collection, or to perform genetic tumor profiling for disease classification and guidance of therapy. In this review, we will summarize the most recent advances and putative applications of liquid biopsy in glioblastoma, the most common and malignant adult brain tumor. Moreover, we will discuss the remaining challenges and hurdles in terms of technology and biology for its clinical application.

Myotonic dystrophy type 1 (DM1; MIM #160900) is an autosomal dominant disorder, clinically characterized by progressive muscular weakness and multisystem degeneration. The broad phenotypes observed in patients with DM1 resemble the appearance of a multisystem accelerated aging process. However, the molecular mechanisms underlying these phenotypes remain largely unknown. In this study, we characterized the impact of metabolism and mitochondria on fibroblasts and peripheral blood mononuclear cells (PBMCs) derived from patients with DM1 and healthy individuals. Our results revealed a decrease in oxidative phosphorylation system (OXPHOS) activity, oxygen consumption rate (OCR), ATP production, energy metabolism, and mitochondrial dynamics in DM1 fibroblasts, as well as increased accumulation of reactive oxygen species (ROS). PBMCs of DM1 patients also displayed reduced mitochondrial dynamics and energy metabolism. Moreover, treatment with metformin reversed the metabolic and mitochondrial defects as well as additional accelerated aging phenotypes, such as impaired proliferation, in DM1-derived fibroblasts. Our results identify impaired cell metabolism and mitochondrial dysfunction as important drivers of DM1 pathophysiology and, therefore, reveal the efficacy of metformin treatment in a pre-clinical setting.

Frailty represents a state of vulnerability and increases the risk of negative health outcomes, which is becoming an important public health problem. Over recent years, multiple independent studies have attempted to identify biomarkers that can predict, diagnose, and monitor frailty at the biological level. Among them, several promising candidates have been associated with frailty status including antioxidants and free radicals, and also inflammatory response biomarkers. In this review, we will summarize the more recent advances in this field. Moreover, the identification of scales and measurements to detect and quantify frailty in aged mice, as well as the generation of mouse models, have started to unravel the underlying biological and molecular mechanisms of frailty. We will discuss them here with an emphasis on murine models with overexpression of glucose-6phosphate dehydrogenase and loss of function of superoxide dismutase and interleukin 10, which reveal that altered oxidative stress and inflammation pathways are involved in the physiopathology of frailty. In summary, we provide the current available evidence, from both human cohorts and experimental animal models, that highlights oxidative damage and inflammation as relevant biomarkers and drivers of frailty.

Histone deacetylase 6 (HDAC6) is an epigenetic modifier that is an attractive pharmacological target in cancer. In this work, we show that HDAC6 is elevated in glioblastoma, the most malignant and common brain tumor in adults, in which its high levels correlate with poor patient survival and is more abundant in glioma stem cell subpopulation. Moreover, we identified a new small-molecule inhibitor of HDAC6, which presents strong sensitivity for HDAC6 inhibition and exerts high cytotoxic activity, alone or in combination with temozolomide. It is also able to significantly reduce tumor growth in vivo. Transcriptomic analysis of patient-derived glioma stem cells revealed an increase in cell differentiation and cell death pathways, as well as a decrease in cell-cycle activity and cell division by the treatment with the compound. Finally, the comparison with a pan-HDAC inhibitor, Vorinostat (SAHA), or HDAC6-specific inhibitor, Tubastatin A, showed higher target specificity and antitumor activity of the new HDAC6 inhibitor. In conclusion, our data reveal the efficacy of a novel HDAC6 inhibitor in glioblastoma preclinical setting.

The developmental regulator SOX9 is linked to cancer progression mainly as a result of its role in the regulation of cancer stem cells (CSCs). However, its activity in the differentiated cells that constitute the heterogeneous tumor bulk has not been extensively studied. In this work, we addressed this aspect in gastric cancer, glioblastoma and pancreatic adenocarcinoma. SOX9 silencing studies revealed that SOX9 is required for cancer cell survival, proliferation and evasion of senescence in vitro and tumor growth in vivo. Gain of-SOX9 function showed that high levels of SOX9 promote tumor cell proliferation in vitro and in vivo. Mechanistically, the modulation of SOX9 changed the expression of the transcriptional repressor BMI1 in the same direction in the three types of cancer, and the expression of the tumor suppressor p21 cip in the opposite direction. In agreement with this, SOX9 expression positively correlated with BMI1 levels and inversely with p21 cip in clinical samples of the different cancers. Moreover, BMI1 re-establishment in SOX9-silenced tumor cells restored cell viability and proliferation as well as decreased p21 cip in vitro and tumor growth in vivo. These results indicate that BMI1 is a critical effector of the pro-tumoral activity of SOX9 in tumor bulk cells through the repression of p21 cip. Our results highlight the relevance of the SOX9-BMI1-p21 cip axis in tumor progression, shedding novel opportunities for therapeutic development. Some types of cancer exhibit a dismal prognosis, mainly due to its late diagnosis, its aggressive progression and the resistance to the available chemotherapy, in which inter and intra-tumoral heterogeneity play a major role 1,2. One of these types of cancer is pancreatic ductal adenocarcinoma (PDAC), with a 5-year survival rate of less than 6% 3 and very similar rates of incidence and mortality (458,918 new diagnoses and 432,242 deaths worldwide in 2018) 4. Glioblastoma (GBM), the most malignant primary brain tumor, also represents a challenge in oncology despite having a low incidence (less than 5 cases per 100,000 people), as exhibits a 5-year survival rate of 5.6% 5 and a median survival of 14.6 months 6. For its part, gastric cancer (GC) is the third leading cause of cancer deaths worldwide, with an estimated 783,000 deaths in 2018 4. SOX9 [SRY (Sex determining region Y)-box 9] is a member of the SOX family of transcription factors, which are developmental regulators characterized by a conserved high mobility group (HMG) DNA-binding domain 7. SOX9 regulates stem cell maintenance and instruction of cell fate, and exerts relevant roles during development, such as sex determination, neural crest development, chondrogenesis or pancreas development 8-10. During embryogenesis, SOX9 is expressed and regulates progenitor proliferation and differentiation, being required for maintaining tissue identity in different contexts, but mainly in the brain and gastrointestinal system 10-12. Likewise, in the adulthood, SOX9 also plays a relevant role in the maintenance of t...