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Cancer cells face many challenges: their rapid cell division leads to defective proteins in the long run. Their nutritional status and their oxygen supply are often precarious, the toxins of chemotherapy threatening: scientists speak of such a situation of "cellular stress". The different stress stimuli in the cell activate the JNK enzyme (N-terminal c-Jun kinases) as a central stress switch. In cancer cells, this can have many effects. Depending on the environment, the activity of JNK triggers a cell suicide or survival program.
Side effects of chemotherapy
"We wanted to know exactly what is happening in bad cancer cells after JNK activation," said Thordur Oskarsson, stem cell researcher at DKFZ. In this study, he and his team discovered a direct link between JNK activation and metastasis formation. The researchers also found that standard chemotherapy treatments administered in bad cancer also activated JNK, which limited the effectiveness of the treatment.
"The drugs do their job and destroy the cancer cells, but obviously they also have adverse effects that need to be taken into account," said Oskarsson. He pointed out that his new findings nevertheless offer new opportunities: "We have identified three unprecedented approaches that new drugs could target to slow the spread of cancer and prevent resistance."
JNK promotes metastasis
Oskarsson and his team first studied tissue samples from patients with metastatic bad cancer. The more they detected JNK activity in bad cancer tissue, the less the disease course was favorable. Metastases contained more JNK-active cells than primary tumors.
This was also confirmed in mice in which bad cancer cells had become metastatic tumors. The researchers found particularly striking differences between tiny micrometastases, which contained up to 50% of JNK-active cells, and advanced metastases, in which JNK was active only in about 15% of cells. "JNK promotes mobility and invasion, a typical behavior of aggressive cancer cells, essential for the colonization of new tissues and will be closed once metastasis is established," said Jacob Insua-Rodriguez, the first author of the work.
In mice to which they had transferred bad cancer cells, scientists studied the effect of known and often successfully used chemotherapeutic products. Paclitaxel or doxorubicin drugs activated JNK in bad cancer cells and triggered the stem cell program. In pulmonary metastases in animals, the proportion of cells active in the JNK increased considerably from 20 to 80%. However, when scientists used anti-cancer drugs in combination with a JNK inhibitor, the number of metastases formed in the lungs of mice was greatly reduced.
Stop JNK, throttle the metastases
But the aggressive behavior of bad cancer cells relies on both JNK-stimulated SPP1 and TNC proteins: If the mice received bad cancer cells in which SPP1 or TNC were genetically deactivated, JNK activity remained inconsequential. negative. When these animals were treated with chemotherapy, tumor growth and lung metastasis were significantly lower than in mice to which bad cancer cells had been transferred.
SPP1 or TNC are extracellular matrix proteins, which are more or less the microenvironment of tumor cells. The researchers therefore see their results as further evidence of the considerable influence of the so-called niche on the evolution of cancer.
"We now know that we are disabling JNK as a key switch of bad cancer cell aggression with specific drugs, so that the production of the two key molecular players SPP1 and TNC can stop, thus reducing metastasis" Oskarsson concluded. "In this way, we will be able to study even better in the future what leads to metastasis and resistance to bad cancer treatment – and we have discovered promising new approaches to treatment development."
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