María Abad, who joined VHIO last summer from the Department of Molecular Biology, the University of Texas Southwestern Medical Center, as Principal Investigator of our newly established Cellular Plasticity and Cancer Group, is first and co-corresponding author of a recent open access study published in Stem Cell Reports* revealing the preclinical promise of the inhibition of the Notch signalling pathway in enhancing cardiac reprogramming.
The Notch signaling pathway is commonly activated in cancer and plays a key role in the progression of cancer, whose inhibition via novel agents -- either alone or in combo with chemotherapeutics, is proving clinically important across different tumor types. Several groups including VHIO´s Early Clinical Drug Development Group headed by Jordi Rodón, are currently leading pioneering clinical studies aimed at targeting developmental pathways including Notch.
Now, thanks to a study led by María in collaboration with her former colleagues at the Department of Molecular Biology at UT Southwestern Medical Center, inhibiting Notch with DAPT, a γ-secretase inhibitor, can potentiate the conversion of mouse fibroblasts into induced cardiac-like myocytes by a GHMT quad set of transcription factors (GATA4, HAND2, MEF2C, and TBX5). The researchers have also evidenced that DAPT cooperates with the AKT1 kinase to further boost cardiac reprogramming, resulting in up to 70% of conversion efficiency.
Not only does Notch activation therefore hamper GHMT-induced cardiac cell reprogramming, its blockade has now been shown to improve this reprogramming. Importantly, results also show that DAPT increases cardiomyocytes features such as sarcomere organization, calcium flux, and spontaneous beating. Mechanistically, they demonstrate that Notch inhibition enhances the transcriptional activity of the cardiogenic transcription factor MEF2C in this process, thus enhancing expression of cardiac genes.
Considering the limited capacity of heart tissue to regenerate and therefore compensate for the mass loss of cardiomyocytes that occurs upon myocardial infarction (MI) -- one of the most common causes of mortality at global level, this study provides important insights into the cardiac reprogramming process and may have important implications for regenerative medicine in cardiology.
Further advancing discovery into cardiac cellular reprogramming and achieving a better understanding of the molecular mechanisms governing this process, will ultimately spur the development of more effective approaches aimed at repairing cardiac function after injury.
At VHIO, María´s Cellular Plasticity & Cancer Group will focus on exploring the interplay between reprogramming, cellular plasticity and cancer, deciphering the molecular mechanisms governing the acquisition of cellular plasticity during tumorigenesis, as well as determining the impact of inducing cellular de-differentiation in various stages of tumorigenesis (tumor initiation, maintenance and metastasis), and in the resistance of cancer cells to chemotherapeutic agents.
She will also lead research aimed at identifying chemical compounds that specifically target cancer stem cells.
* Notch Inhibition Enhances Cardiac Reprogramming by Increasing MEF2C Transcriptional Activity, Maria Abad, Hisayuki Hashimoto, Huanyu Zhou, Maria Gabriela Morales, Beibei Chen, Rhonda Bassel-Duby, and Eric N. Olson. DOI:http://dx.doi.org/10.1016/j.stemcr.2017.01.025.