Peritumoral activation of the Hippo pathway effectors YAP and TAZ suppresses liver cancer in mice.

The Hippo signaling pathway and its two downstream effectors, the YAP and TAZ transcriptional coactivators, are drivers of tumor growth in experimental models. Studying mouse models, we show that YAP and TAZ can also exert a tumor-suppressive function. We found that normal hepatocytes surrounding liver tumors displayed activation of YAP and TAZ and that deletion of Yap and Taz in these peritumoral hepatocytes accelerated tumor growth. Conversely, experimental hyperactivation of YAP in peritumoral hepatocytes triggered regression of primary liver tumors and melanoma-derived liver metastases. Furthermore, whereas tumor cells growing in wild-type livers required YAP and TAZ for their survival, those surrounded by Yap- and Taz-deficient hepatocytes were not dependent on YAP and TAZ. Tumor cell survival thus depends on the relative activity of YAP and TAZ in tumor cells and their surrounding tissue, suggesting that YAP and TAZ act through a mechanism of cell competition to eliminate tumor cells.

Empagliflozin in type 1 diabetes.

There is a clear unmet need in people living with type 1 diabetes (T1D). Although the quality of life of people with T1D has improved, issues like hypoglycemia, weight gain and variability in glucose profiles remain. In this review, the clinical efficacy and safety of empagliflozin, a sodium-glucose cotransporter type 2 (SGLT2) inhibitor in T1D, is described based on a review of phase 2 and 3 studies to date. Empagliflozin and SGLT2 inhibitors, in general, are effective glucose-lowering drugs, which also work in people with T1D. Recent phase II and III studies, including the EASE trials for empagliflozin, showed a clear beneficial effect on HbA1c, body weight, glucose variability and total daily insulin use in people with T1D. No increase in hypoglycemia risk, in particular severe hypoglycemia, was observed, but genital infections were more prevalent. The use of SGLT2 inhibitors comes with a decrease in insulin doses, making individuals more prone to diabetic ketoacidosis (DKA). The uniqueness of the EASE program is that here, a very low dose of empagliflozin was used, with less, but still present, effects on metabolic outcomes, but interestingly a lower risk of DKA. Importantly, even in the higher doses of empagliflozin, it is clear that the overall risk for DKA remains low, most likely by educating patients and caretakers intensively on this subject. In conclusion, evidence is building on the potential of using empagliflozin, like other SGLT2 inhibitors, in T1D. However, to date, the use of empagliflozin is not approved in people with T1D. Clinicians will have to weigh the potential short- and long-term benefits of these adjunct therapies versus the potential acute side effects, in particular, the small but real risk of DKA in the individual T1D patient.

Efficacy of dapagliflozin as an adjunct therapy in patients with inadequately controlled type 1 diabetes mellitus.

INTRODUCTION: There is a clear unmet clinical need in people with Type 1 diabetes (T1DM) considering present day insulin therapy. New insulin analogues and novel technologies allowing more tailored insulin administration have improved the quality of life of people with T1DM, but issues like hypoglycemia, weight gain and variability in glucose profiles remain problematic. Areas covered: In this review, the clinical efficacy, safety and tolerability of dapagliflozin, a sodium-glucose cotransporter type 2 inhibitor, in type 1 diabetes (T1DM) is described based on a review of phase 2 and 3 studies to date. Expert opinion: Dapagliflozin has shown promising results as an adjunct therapy in T1DM, resulting in better glucose control, weight loss and lower blood pressure. No increase in hypoglycemia risk, in particular severe hypoglycemia, was observed, but, in comparison with reports in Type 2 diabetes (T2DM), genital infections were more prevalent. Dapagliflozin use was accompanied with decreases in insulin doses, but, to date, only a low risk of diabetic ketoacidosis (DKA) was reported. However, caution is needed when interpreting this data, arising from well controlled clinical trials, with intensive education programs around ketone measurements and DKA prevention. Further studies will need to establish how high the DKA risk is and how to mitigate this in a real-world setting.

Decoding the regulatory landscape of melanoma reveals TEADS as regulators of the invasive cell state.

Transcriptional reprogramming of proliferative melanoma cells into a phenotypically distinct invasive cell subpopulation is a critical event at the origin of metastatic spreading. Here we generate transcriptome, open chromatin and histone modification maps of melanoma cultures; and integrate this data with existing transcriptome and DNA methylation profiles from tumour biopsies to gain insight into the mechanisms underlying this key reprogramming event. This shows thousands of genomic regulatory regions underlying the proliferative and invasive states, identifying SOX10/MITF and AP-1/TEAD as regulators, respectively. Knockdown of TEADs shows a previously unrecognized role in the invasive gene network and establishes a causative link between these transcription factors, cell invasion and sensitivity to MAPK inhibitors. Using regulatory landscapes and in silico analysis, we show that transcriptional reprogramming underlies the distinct cellular states present in melanoma. Furthermore, it reveals an essential role for the TEADs, linking it to clinically relevant mechanisms such as invasion and resistance.