Recent research spearheaded by Dr. Tanmay Lele, a joint faculty member in chemical engineering, along with Ph.D. candidate Ting-Ching Wang, is contributing to the development of new cancer therapies by exploring how the mechanical properties of tissue can impact the behavior of tumor cells. Their work, published in the Proceedings of the National Academy of Sciences, delves into the relationship between the stiffness of the extracellular matrix (ECM) and the progression of cancer, offering insights that could lead to more effective treatments.
The ECM is a complex network of proteins that provides structural and biochemical support to surrounding cells. In healthy tissues, the ECM maintains a specific stiffness that supports normal cellular function. However, in tumors, this stiffness changes, often becoming more rigid as the disease progresses. According to Wang, this alteration in ECM stiffness plays a crucial role in the evolution of tumors. “Tumors evolve through a process of mutation and selection, driven in part by changes in the tumor’s ECM,” said Wang. “One key feature of this changing ECM is that its stiffness becomes progressively altered in tumors, which is why many solid tumors are initially detected as stiff lumps. We investigated whether changes in ECM stiffness can impose selective pressure on tumor cells.”
This research seeks to understand how cancer cells respond to the altered environment within a stiffening ECM. Such an understanding could potentially enable scientists to target cancer cells that thrive in these conditions, which often pose the greatest challenge in treatment. Wang emphasizes that cancer’s notorious difficulty to treat arises from its genetic heterogeneity—the fact that cancer cells can vary significantly even within a single tumor. “Whenever the environment of the tumor changes, variant cancer cells best adapted to the changed environment outcompete the rest of the cells and over time, dominate the population,” Wang explained. This ability of cancer cells to adapt quickly to shifting environments makes them particularly hard to eradicate with conventional treatments.
The team’s experiments focused on observing how cancer cell populations, with inherent genetic variability, react to changes in ECM stiffness. Over several weeks, they observed that specific subpopulations of cells outcompeted others in response to the stiffened ECM. These dominant cells exhibited unique characteristics that differentiated them from the rest, and, according to Dr. Lele, they were especially mobile. “When we first analyzed these variant cells, we found that they were extremely migratory,” said Lele. This finding is significant because the spread of cancer to other parts of the body—known as metastasis—is driven by highly migratory cancer cells. The results imply that as the ECM becomes stiffer, it may select for these more aggressive and mobile cells, increasing the likelihood of metastasis.
Understanding how ECM stiffness influences cancer cell behavior is essential for devising targeted therapies. The researchers believe that future treatments could potentially disrupt this selective advantage, making it harder for aggressive cancer cells to dominate and spread. If scientists can identify which cancer cells are most suited to a stiffened ECM, they may be able to develop drugs that specifically target those cells, halting the progression of the disease.
The next phase of the research will involve directly observing the selection of these variant cells under a microscope to track their response to changing ECM conditions. This detailed visual analysis could provide deeper insights into how cancer cells adapt and evolve in real-time, further refining therapeutic strategies. Wang and Lele aim to understand the fundamental dynamics of cancer development, potentially unveiling new opportunities for early intervention.
Lele points out that this research highlights the importance of understanding cancer as a dynamic and evolving disease. Traditional cancer treatments often focus on eliminating the bulk of tumor cells, but if the most adaptable and aggressive cells survive, they can lead to recurrence and metastasis. “Our studies are shedding light into the fundamental dynamic changes that occur during cancer development,” Lele said. “Cancer is a very difficult disease that we’ve been trying to treat for decades. We hope to better understand how tumors evolve and develop, in order to improve therapies that target these evolving tumors.”
This research also underscores the significance of the ECM as a potential target in cancer therapy. Instead of solely focusing on the tumor cells themselves, modifying the ECM or interfering with how cancer cells interact with their altered environment could provide a new approach to therapy. For instance, drugs that limit ECM stiffening or change the mechanical signals sent to cells might prevent cancer cells from gaining migratory advantages. Alternatively, therapies that exploit the vulnerabilities of cells that thrive in a stiff ECM environment could make them more susceptible to existing treatments.