In cases of malignant melanoma, the effectiveness of targeted treatment can diminish over time. Researchers have found that a factor secreted by tumor cells is responsible for this resistance, offering hope for more successful therapies.
Malignant melanoma is a highly aggressive form of cancer. Despite advancements in treatment, many patients’ tumors either do not respond initially or develop resistance during therapy.
Understanding the mechanism behind resistance in melanoma is crucial, according to Lukas Sommer, a stem cell biology professor at the University of Zurich (UZH). A study led by Sommer has identified a mechanism that hampers treatment effectiveness, providing new avenues for therapies to combat resistance. The research was a collaborative effort with Mitch Levesque and Reinhard Dummer from the University Hospital Zurich (USZ).
Comparing resistant and non-resistant tumor cells
The research team used innovative fine-needle biopsies to sample tumor cells before and during treatment, enabling individual cell analysis. Samples were obtained from patients undergoing targeted therapy for malignant melanoma, which targets signaling pathways crucial for tumor growth.
“It was crucial to have both responsive and resistant tumors to compare the metabolic and environmental differences between them,” explained Sommer.
Interaction between tumor factor and immune cells
A significant finding was the involvement of the POSTN gene, which encodes a secreted factor critical in resistant tumors. Tumors in patients with rapidly progressing disease exhibited elevated levels of POSTN. These tumors’ microenvironment harbored an increased number of a specific type of macrophage, an immune cell subtype that supports cancer growth.
Subsequent experiments with human cancer cells and mice elucidated how increased POSTN levels interact with these macrophages to induce resistance. POSTN binds to macrophage receptors, causing them to shield melanoma cells from death, rendering targeted therapy ineffective.
No resistance without cancer-promoting macrophages
The team views this mechanism as a promising target for intervention. Sommer stated, “Targeting specific macrophages within the tumor microenvironment could enhance treatment success in patients with malignant melanoma when combined with existing therapies.”
