Five genes enable prediction of survival in head and neck tumors
Surface molecules EGFR and Integrin beta 4 play a key role in this process
Frequently, cancer patients do not die because of their “initial tumor” in a specific organ. Only when individual cells of the primary tumor transform, migrate or colonize into other tissues and form life-threatening metastases, then the tumor becomes a deadly threat for the patient. How this process takes place in tumors of the ear, nose and throat, has now been studied by a team of scientists from the Helmholtz Munich, the Klinik und Poliklinik für Hals-Nasen-Ohren-Heilkunde (Clinic and Polyclinic for Otorhinolaryngology) of the LMU hospital as well as the Klinik für Strahlentherapie (Clinic for Radiation) of the LMU hospital. The researchers discovered five genes, whose activity may predict survival of patients with these tumors. In addition, they could forecast patients who profited from receiving the drug Cetuximab at an advanced stage of the disease later. The results were published in the scientific journal “Molecular Cancer”.
Locally advanced head and neck tumors are among the deadliest forms of cancer: Five years after diagnosis, fewer than 35 percent of patients are still alive. After the first therapy, they usually suffer relapses – either at the same site of the initial tumor or in the neighboring lymph nodes. Chemo- and radiation therapy can hardly help anymore. In this late state of the disease the patients receive in addition Cetuximab. This drug slows down the activity of the so-called EGF receptor (EGFR), a molecule that sits on the surface of cancer cells and triggers molecular signaling pathways in tumor cells and that causes cells to migrate. In other words: The cells detach themselves from the original malignant tissue and settle elsewhere. But even Cetuximab has only limited effect on late-stage patients. “We therefore wanted to know what the EGFR and its associated signaling pathways do in the course of therapy”, says Prof. Oliver Gires from the Klinik und Poliklinik für Hals-Nasen-Ohren-Heilkunde (Clinic and Polyclinic for Otorhinolaryngology) of the LMU hospital.
For this purpose, researchers of the Helmholtz Munich research group “Radiation Cytogenetics” (ZYTO) generated and analyzed transcriptome data from various treatments in head and neck cell lines.
5 of 170 genes are particularly informative
In a first place, the researchers had shown that the receptor can trigger both the proliferation of cancer cells as well as a process called epithelial-mesenchymal transition (EMT). Tumor cells in EMT cut cell-to-cell contacts and break away from a composite to colonize new tissue.
Then, in cell culture experiments with EMT cells, the scientist found around 170 genes that are preferentially regulated after EGFR activation. With this knowledge, they searched large databases listing all sorts of scientific and clinical information about patients with head and neck tumors. By comparing their cell culture data with patient data, the researchers found that 5 of the 170 genes provided information on whether or not a patient would survive for a long time. “The activity pattern of these five genes was best at predicting patient survival”, says Gires.
Drug-induced blockade of the surface molecule Integrin
One of these genes carries the blueprint for an Integrin, a surface molecule that is important for the migratory behavior of cancer cells. In a tree-dimensional laboratory model, the researchers simulated the local invasion behavior of the tumor cells. “That’s where we showed that EMT causes the cells to grow invasively and also contact each other. If we then block Integrin beta 4, the invasion of the cells is also inhibited.” The Integrin could therefore be a starting point for a new drug, that slows down the migratory behavior of tumor cells.
Last but not least, the research team used databases to check which patients with head and neck tumors benefit from Cetuximab. The result: Patients with high Integrin beta 4 activity benefited most from the drug.
All results need to be tested for validity in larger patient studies. The questions to be addressed are: Is the activity of EGFR or the five “predictor genes” really useful in forecasting, which patients with head and neck tumors will best benefit from Cetuximab? And which ones do not profit? The latter could be spared a treatment with several side effects.
Schinke, H., E. Shi, Z. Lin, T. Quadt, G. Kranz, J. Zhou, H. Wang, J. Hess, S. Heuer, C. Belka, H. Zitzelsberger, U. Schumacher, S. Genduso, K. Riecken, Y. Gao, Z. Wu, C. A. Reichel, C. Walz, M. Canis, K. Unger, P. Baumeister, M. Pan and O. Gires (2022). "A transcriptomic map of EGFR-induced epithelial-to-mesenchymal transition identifies prognostic and therapeutic targets for head and neck cancer." Mol Cancer 21(1): 178.