Summary by: Arooba Ahmed (CC '23)
Dr. Califano’s lab recognizes that the cell’s transcriptional state (which identifies phenotype) is implemented by a few proteins called master regulators (MR). These MRs are affected by signals from either endogenous perturbation (viruses), or signals from the environment. MRs can induce inactivation or activation of protein to maintain a cellular state. His studies on MRs have led to trials to control them in breast cancer. Currently, their goal is to see whether MR activation or repression can be applied to control other diseases (particularly, developmental ones such as diabetes). They also use this approach to see what the virus does to the human cells it infects.
To identify master regulators, they have created algorithms to reconstruct regulatory networks of cells, take the target of proteins, use them as gene reporter assays to measure their activity, and then turn the RNA profile into protein activity profiles. They apply this to cancer and viruses by using the profile to identify master regulators and looking to see whether there are drugs that can reverse the activity of MRs.
This approach is being remodelled in order to study drug mediated reversal of viral infection master regulators. They looked at profiles for perturbations in lung cancer cells and found that their protein activity very specifically changed from non-infected to infected cells. This change in activity was related to well established viral pathways. They observed a time dependent migration in cells in response to infection, which created an environment that is hospitable to viruses.
The group then asked if the MRs utilized in virally infected cells were the same in cancer cells, and they found high overlap in master regulators. The overlapping is consistent with rapid transitions between cell cycle phases that promote a response that allows for viral RNA transcription and translation. So, they took 150,000 gene expression profiles from many cell lines and different drug perturbations and looked to see if any showed the ability to completely reverse the activation of MR of the SARS infection. They found that Selinexor has a potent antiviral effect.