Research from Cornell University has revealed that cellular changes associated with melanoma can potentially be reversed with existing drugs, paving the way for more effective treatments for this aggressive form of skin cancer. Published on August 22, 2023, in the journal Advanced Science, the study highlights how the extracellular matrix (ECM), which provides structural support to cells, often becomes denser during cancer treatment, contributing to treatment resistance.
Understanding Treatment Resistance
The study was led by Andrew White, an associate professor in the Department of Biomedical Science at the College of Veterinary Medicine. White noted that while melanoma patients often initially respond well to targeted therapies, most eventually experience a relapse as their tumors develop resistance. “We wanted to understand what causes this resistance,” he explained.
Researchers observed significant changes in collagen, the main protein in the ECM, during treatment. The ECM tends to thicken and overproduce collagen, leading to a physical barrier that hinders the effectiveness of therapies. Chia-Hsin Hsu, a doctoral student and the study’s first author, stated, “What we wanted to know is whether the changes in the ECM were just a side effect of therapy, or if they actually contributed to drug resistance.”
Reversing ECM Changes to Enhance Immunotherapy
The research produced two critical findings. First, the team established that the thickened ECM acts as a barrier that prevents cytotoxic T cells—immune cells responsible for killing cancer cells—from reaching the tumor. Hsu noted, “It changes the way we think about cancer treatment, from focusing only on the cancer cells themselves to understanding and treating the entire tissue environment around them.”
Secondly, the study demonstrated that drugs capable of reducing the ECM’s density could allow T cells to infiltrate the tumor environment and resume their attack on cancer cells. Hsu described the observation as “thrilling,” stating, “Under the microscope, we could literally see cytotoxic T cells spreading more evenly once the ECM was reduced.”
This breakthrough suggests the potential for new treatment strategies that combine existing targeted drugs or immunotherapies with agents that modify the ECM. Some of these ECM-modifying drugs are currently under investigation for their effectiveness in treating tissue scarring, indicating a possible avenue for repurposing these treatments for cancer therapy.
The research team is now exploring whether other ECM molecules, beyond collagen, contribute to therapy resistance. Hsu emphasized the importance of recognizing that treatment does not occur in isolation, but rather within a dynamic ecosystem of the tumor microenvironment. “Our study reminds us that curing cancer isn’t just about killing cancer cells. It’s also about restoring the body’s own environment so that the immune system can fight back effectively,” he said.
This study represents a significant advance in the understanding of melanoma treatment and its complexities, offering hope for the development of more effective therapies that could reduce relapse rates and improve patient outcomes.
