cAMP, a molecule modulating metastasis formation.

Cellular processes are the result of the tightly regulated interaction of a number of small molecules, such as cAMP. Fluctuations of cAMP concentration, modulating downstream effectors, regulate a wide range of cell processes, such as neuronal development, cell migration, proliferation and differentiation.

cAMP plays also a key role in modulating the ability to form metastases –meaning seeding new tumors at distant sites from the original- by a subset of cancer cells: the Tumor Initiating Cells (TICs). TICs possess specific properties i) endowing them with the ability to metastatize, thus driving clinical relapse of patients after chemotherapy, and ii) making them resistant to conventional chemotherapeutic drugs, de facto preventing a complete recovery of cancer patients.

Evidence suggests that cells acquire these properties by undergoing a process called EMT -namely the Transition from a more differentiated Epithelial state to an undifferentiated Mesenchymal state-. Reasonably, triggering the opposite process -the Mesenchymal to Epithelial Transition, MET- by inducing cells’ loss of mesenchymal features, would i) reduce their ability to migrate and seed new tumors, and ii) make them vulnerable to conventional chemotherapeutic treatments.

The rationale. Uncovering the cell mechanism responsible for MET induction in TICs would enable to manipulate the process, pushing TICs to exit the mesenchymal state and enter the epithelial state.

  The mechanism. The mechanism underlying MET is a cAMP-related process. Indeed, the pharmacological increase of intracellular cAMP concentration, activating one of the main cAMP effectors –PKA protein-, results into the activation (by removing the repression) of genes involved in maintaining the epithelial phenotype. This means that cAMP-elicited PKA activation, by modulating MET-inducing genes that trigger loss of mesenchymal traits in favor of epithelial traits, prevents cells’ acquisition of aggressive features, thereby impairing their ability to form metastases.

  The implications. What is the end result? When TICs are pushed into an epithelial state, conventional chemotherapeutic treatment is 20 times more effective, and TICs elimination ultimately results in preventing metastatization. Translating these findings into a therapeutic application is appealing. One could argue that being cAMP involved in such a wide range of cell processes, its modulation would bring highly toxic side effects. However, uncovering the whole mechanism enables to bypass cAMP and act downstream, directly modulating gene activation required for the maintenance of an epithelial state, possibly making the treatment more specific. Would then this approach be free of significant side effects? Probably not, but after all, no approach is ever completely free of side effects. As long as the balance between adverse and beneficial effect leans towards the latter one, it might be worth a try.

Reference. Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability. Pattabiraman DR, Bierie B, Kober KI, Thiru P, Krall JA, Zill C, Reinhardt F, Tam WL, Weinberg RA. Science, 2016.