Helpful Hijacking: A System to Rewire Cancer-causing Signals

Written by Alexander Egipto and Edited by Catherine Zhang

When a cell speaks, it does so not through words but through molecules, sending signals that travel between and through cells to convey meaning and intent. A cell perceives and reacts to its environment through the use of surface receptors that pick up a variety of molecules capable of producing complex signaling pathways [1]. Due to the language of the cells remaining as complex as many of our own languages, miscommunication often happens and carries potential consequences. Cancer is an example of one such consequence, in which the characteristic uncontrolled proliferation, or multiplication, of cells results from cellular miscommunication. Specifically, the signaling pathways for proliferation are permanently left on because of mutations in the pathway [2]. These mutations can occur in a number of different proteins within the pathway, but a particular group known as the ErbB protein family is regarded as a common starting point for the growth of many tumors [2].

The receptors of this protein family activate a multitude of complex signaling pathways that ultimately tell the cell to perform a wide variety of important processes, which include movement, growth, and even death [3]. Mutations that cause an overproduction of specific ErbB receptors have been linked to the presence of tumors, particularly breast and lymph node tumors [4]. In addition to promoting proliferation, ErbB receptors also trigger the activation of pro-survival genes for the cell, perpetuating its lifespan when needed [5]. So, between controlling cell growth and cell survival, the ErbB protein family becomes a dangerous group for mutations to occur in; as a result, many researchers have created treatments focused on these receptors, such as a group of researchers from Stanford University. These researchers chose the ErbB family of proteins to work with, but instead of working to suppress or eliminate the mutated versions of these proteins, the scientists chose to harness their overactive signaling to trigger therapeutic responses in afflicted cells with a system they have dubbed Rewiring of Aberrant Signaling to Effector Release, or RASER [2].

What the researchers designed is a synthetic protein composed of two regular proteins—a protease (a protein designed to cut other proteins) and a protein carrying molecular cargo that elicits different effects depending on the researchers’ discretion [2]. The protease becomes activated by binding to an active ErbB receptor and subsequently cutting the cargo to be released into the tumor cell [2]. With ErbB receptors being perpetually active in tumor cells, the protease will continuously cause the release of the molecular cargo, which could push the tumor cell towards death, or even re-activate genes designed to control proliferation. However, to establish the RASER system’s clinical viability, the researchers had to optimize parts of the system. To ensure the molecular cargo isn’t prematurely released, they tied the activity of the protease to the activity of ErbB proteins: if ErbB activity was high like it is in tumor cells, then the protease would activate, but it would otherwise remain inactive [2]. The researchers then confirmed the system would only be active in a wide variety of tumor cells characterized by overactive ErbB proteins [2]. Finally, they wanted to ensure that their system could not only cause different outcomes, but also only target tumor cells. This was verified through the use of different molecular cargo that each had therapeutically useful effects, which became apparent in just cancer cells [2]. With a system that is both selective in its targeting and flexible in its response, the researchers are excited for RASER’s potential as they look to implement the treatment in a manner compatible with the immune system [6].

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