The Secretome Gets a Seat at the Drug Discovery Table

Jeffrey S. Buguliskis Ph.D. Technical Editor Genetic Engineering & Biotechnology News

Researchers Are Beginning to See the Therapeutic Potential in Understanding the Mechanisms that Regulate Cells’ Repertoire of Secreted Biomolecules

The “omics” suffix has seen its fair share of usage over the past several years, from the widely encompassing field of genomics to the esoteric discipline of foodomics. The secretome represents an array of cell-secreted molecules—such as cytokines, growth factors, and neurotransmitters—with tremendous potential as targets for novel drug development. While it’s not a newcomer to the omics game, novel technologies and renewed interest have begun to push the secretome field to the research forefront.

Interestingly, the term secretome has been around since early 2000, when a group of Dutch researchers coined the phrase while reviewing protein transport mechanisms in the bacterium Bacillus subtilis. Subsequently, a lot of research has been done to discern the genomic basis for secreted molecules, as well as the intracellular events that take place to eject these molecules out of the cell. Studying these primarily proteinaceous compounds, once they have been secreted into the extracellular environment, has presented a particular set of problems for many investigators.

Typically the secreted compounds are analyzed from in vitro culture media, which often contain background contaminants that can make detection extraordinarily difficult. Mitigating the secretome analysis difficulties is that simply removing the various factors from the culture media that skew the analysis often changes the environment in which the cell is residing, and can result in a cascade of global cellular changes.

Getting a Clear Signal

For most investigators, the secretome begins with the translation of the secreted protein repertoire. All secretory proteins contain a signal peptide sequence at one end of the biomolecule—usually between 5 and 45 amino acids in length—that dictates the ultimate ending location and directs its circuitous path through the cell organelles.

The pathway begins in the endoplasmic reticulum (ER), were the signal peptide binds to an internal receptor that is anchored to the inner ER membrane. This binding initiates a cascade of events that precipitate the formation of a coated protein vesicle, which is shuttled to the Golgi apparatus. Once inside the Golgi, the protein is ferried though the Golgi stacks into a new set of coated vesicles that are bound for the cell’s surface membrane. In transit out of the cell, the protein is cleaved from its membrane tether so it can actively diffuse outward into the extracellular milieu when the vesicle fuses with the cell membrane.

The importance of the pathway was underscored in 2013 when the Nobel Prize in Physiology or Medicine was awarded to researchers who contributed to elucidating the mechanisms regulating vesicle trafficking within our cells.

While still the focus of a very broad area of research, secretory proteins—and hence the secretome—constitute a bulk of the workload for this pathway. Over the years, there have been numerous attempts at developing therapies that block secretory protein pathways. Many of the drugs have been successful at treating disease, though the developed compounds are often broad in their mechanism of actions, leading to increased side effects and contraindications. A greater understanding of the molecular mechanisms that underscore the secretome could allow for the design of more specific therapies and possibly the precise blockage of secreted proteins that have some deleterious effect.

Secretion as Big Business

Because the secretome accounts for close to one-third of all the proteins coded for by the human genome, it would follow that many of these proteins are involved in critical processes associated with various disease states. As such, the secretome’s potential as a resource for pharmaceutical research remains largely unexplored.

Companies such as AstraZeneca are now collaborating with scientists and research centers that have secretome expertise with the hope of discovering new drug targets for diseases ranging from cancer to cardiovascular disorders. Specifically, AstraZeneca has entered into a three-year collaboration with the newly established Wallenberg Center for Protein Research in Sweden—a partnership that at the very least could help the pharma giant tap into various new types of cell cultures better suited for large-scale production (other than the current gold standard CHO cells).

Academic institutions are also getting involved in this exciting area of translational research. For example, investigators from the Medical University of Vienna, Austria have begun to look at secretome fractions from stem cell culture media as starting material in the development of cell-free therapies for regenerative medicine. Previous work has shown that stem cell transplantation triggers the release of paracrine factors that stimulate endogenous regeneration signals in cells surrounding the transplant site. Hence, the use of these secreted factors in lieu of or in addition to administering live stem cell populations holds great therapeutic potential and could, in certain instances, alleviate various regulatory safety concerns.

Finally, mammalian cell culture is not the only area in which secretome research is valuable. Plants secrete a host of proteins and other factors into the extracellular space. Biotech companies have been attempting to take advantage and manipulate these pathways for years as various plant models are used for drug and vaccine development. Moreover, new methodologies to improve insecticide and fungicide delivery within engineered plants are influencing pathways within the secretome.

As the importance of the secretome steadily continues to be recognized, we should expect to see a larger section of the life science industry dedicate resources to aiding researchers to visualize, detect, and identify therapeutically relevant secretome molecules. Over the next several years, expect interest in the secretome field to continue to expand through investments from the biopharmaceutical industry. Greater understanding of the secretome is poised to have a positive effect on drug discovery and development.