Departing from the script
Page 2: Hermeking also has plans to work with so-called spheroids in future. Spheroids are three-dimensional cell cultures consisting of various cell types, which are organized in ways that reproduce important aspects of the structure of the kind of tumor one wants to study. They can be derived from mice but Hermeking also collaborates with specialists who generate them from patients’ tissues. “This allows us to significantly reduce the number of animal experiments we do,” he says, “and in many cases we get the results quicker.”
In addition, Hermeking and his co-workers make use of all the standard molecular biological methods to reconstruct what goes on in tumor cells. State-of-the-art sequencing machines that perform Next Generation Sequencing now enable researchers to identify the genes that drive the growth of an individual patient’s tumor, while a variety of molecular histological methods and imaging techniques are used to characterize tumor tissue. Many patients consent to the use of their tissue samples for research purposes. This allows Hermeking and his colleagues to check whether their laboratory findings in mouse are also hold for tumor growth in humans. He has no favorite method, he says. “All are necessary to give us the complete picture.” But from the aesthetic point of view, he adds, confocal laser microscopy is in a class of its own. And this tribute to the continuing relevance of light microscopy places him firmly in the long tradition of his predecessors in the Institute.
Hermeking and his team are now particularly interested in the question of how some tumor cells manage to leave their sites of origin, enter the circulation and find their way to another tissue where they seed a new tumor, a metastatic tumor. “To do so, tumor cells make use of a sort of tumor mimicry“, Hermeking explains. The tumor cell adopts a disguise, so to speak, by exploiting biological programs that are otherwise activated only during the growth and development of the embryo in the womb. At this point in development, many organs and tissues have not yet fully differentiated. Their cells are in a labile state, and can be induced to take on any one of a variety of forms and functions. This, incidentally, confirms that tumors are opportunists. They make use of the mechanisms open to them – and this is what makes them so difficult to fight.
For example, tumor cells can change their character by undergoing an epithelial-mesenchymal transition (EMT). An epithelial cell in a mucous membrane can “forget” that it is part of a flat sheet of cells and turn into a mobile fibroblast. Hermeking and his team recently identified a regulatory program that triggers this transformation, which can prove lethal unless tightly controlled.
At the heart of this program are two transcription factors – proteins that regulate the activity of specific genes or sets of genes – called Myc and p53. Hermeking refers to them as master switches. Myc promotes cell division, while p53 is a “tumor suppressor” and acts as a brake on cell proliferation. But, being master switches, they actually regulate a wide range of processes within cells, not only those that are directly related to carcinogenesis
Take p53, which is named for its molecular weight. Among other things, p53 helps to inhibit cardiac hypertrophy, the pathological replacement of injured muscle cells by scar tissue that often occurs following a heart attack. “p53 is a central component in the organism’s response to stress, and its function is not confined to specific cell types,” says Hermeking. However, unlike Myc, it is not essential for survival of the developing organism. Mice that lack p53 due to a mutation develop normally. However, they are highly sensitive to all forms of stress, such as DNA damage or induced ischemia. Mutant mice in which Myc is missing, on the other hand, die before birth.
There’s a poster on the wall behind Hermeking‘s desk that looks about as complicated as a street-map of Tokyo. What it actually shows is a kind of circuit diagram of carcinogenesis. Each node represents a switch in the program that controls how cells behave, and the edges depict how the switches are connected. In this scheme, p53 and Myc stand out as central hubs, and have been extensively investigated. Indeed, according to Hermeking, literature searches now turn up around 30,000 publications that refer to Myc, while p53 is cited in some 80,000 research papers.
We owe the recognition of some of the salient connections and central junctions in this network to Hermeking and his coworkers. But the road map that describes the many routes to malignancy consists of more than links between proteins. So-called micro-RNAs, i.e., short fragments derived from longer ribonucleic acid molecules, which are both structurally related to, and derived from the genomic DNA, also play a role in carcinogenesis. By interacting with the messenger RNAs that direct the assembly of proteins, specific micro-RNAs can inhibit the synthesis of certain proteins. Moreover, some years ago, Hermeking and his team showed that p53 and Myc are involved in regulating the production of specific micro-RNAs. This is another of the complex interaction networks that Hermeking hopes to dissect.
More recently, Hermeking‘s group recently uncovered a molecular interaction that links inflammation reactions to the formation of metastases. In this context, the synthesis of a specific micro-RNA, miR-34a, is turned off by signals that originate in the tumor’s environment and are responsible for provoking local inflammation. Synthesis of miR-34a is activated by the tumor suppressor p53, which in turn initiates a process that serves to localize the tumor. However, if inflammation processes inhibit the production of miR-34a, this brake on tumor growth is disabled, allowing cells to escape from the primary tumor and form metastases. It is particularly important to understand how such secondary tumors form, because they are what actually cause 90% of all cancer deaths.
Hermeking compares the progress of his field of research with what one sees through the viewfinder of a camera: As one adjusts the focus, the picture gradually becomes sharper, and one can recognize ever finer details. Discoveries that completely alter the landscape and make it necessary to rewrite the textbooks are very rare.
Can carcinogenesis be prevented? Hermeking doesn’t yet have a final answer to this question. But experiments in animals suggest that a healthy, balanced diet can suppress the growth of tumors. Conversely, eating too much sugar or fat can provoke inflammation, which in turn promotes tumorigenesis. “A healthy lifestyle probably cannot prevent the appearance of tumorous cells, but it looks as if lifestyle factors can have an impact on their further development.”
At least in mice, there is evidence that, in addition to dietary factors, lack of exercise, too much weight and chronic inflammation promote the growth of tumors. Is that also true of people? “That may well be so,” Hermeking replies. “But one thing’s for sure. In these respects, people exhibit far more diversity than mice do.” Hanno Carisius
Prof. Dr. Heiko Hermeking. Now Professor of Experimental and Molecular Pathology at LMU, Hermeking (b.1966) studied Biology at LMU, where he also obtained his doctorate and completed his Habilitation in Cell Biology. After his PhD, he worked as a postdoc in the Oncology Center at Johns Hopkins University Medical School in Baltimore (Maryland), and as a Research Associate at the Howard Hughes Medical Institute. On his return to Germany, Hermeking headed a research group in Molecular Oncology at the Max Planck Institute for Biochemistry in Martinsried, and later served as Professor of Molecular Tumor Pathology at the University of the Ruhr in Bochum, before moving back to LMU in 2009.