BENGALURU: Cells and spacing between them plays a crucial role for a healthy body. A team of researchers from the Indian Institute of Science shows that tweaking the spacing between the cells’ binding domain on the extracellular matrix (ECM) helps improve the efficiency of ultrasound treatment, which is used to kill cancer cells.
Researchers of the study ‘Nanoscale Ligand Spacing Regulates Mechanical Force - Induced Cancer Cell Killing’ explained that cells have surface receptors called integrins that bind to repetitive domains present on the ECM surrounding the cells, allowing them to grow and spread. The study by researchers from the Department of Bioengineering (BE), IISc, was also published in Nano Letters, on January 30, 2025.
Explaining the study paper, released on Tuesday, researchers noted that in a normal tissue, the spacing on the ECM is around 50-70 nanometres (nm), but in the tumour micro-environment, severe choking occurs due to excessive ECM secretion, which reduces the binding spacing to below 50nm.
Ajay Tijore, Assistant Professor in BE and co-author of the paper said: “We found more cancer cells being killed when the binding spacing is increased to around 50-70 nm.”
Similar to how people touch a surface to feel its texture, cancer cells need to ‘pinch’ the ECM by applying myosin forces to sense the ECM architecture. It was then realised that if there was a way to increase this spacing or mimic its effect, cancer cells might respond better to treatments, Tijore said.
The researchers collaborated with clinicians to test various medical combinations on oral cancer tissue samples. “Oral cancer is a major problem in India. There is a lot of ECM deposition, leading to swelling and inflammation, an extreme choking of the tumour micro-environment, which we are currently working on,” Tijore said.
S Manasa Veena, PhD student in BE and co-author, added, “While conducting experiments, we found literature on a drug called Cilengitide. It works by blocking integrin-ECM binding. It was one of the most widely studied drug and went to Phase III clinical trials, but failed.
Using the same setup, the team decided to test what happens when a very low dose of Cilengitide – about 1,000 times lower than used in the trials – was given along with ultrasound treatment. When the dose is very low, there are not enough drug molecules to bind all the integrin receptors. The cancer cells then started thinking that the 35nm spacing has increased.”
Tijore said: “We are fooling the cancer cell to think that the spacing changed. The cells started developing myosin forces, pumped more calcium and this triggered cancer cell killing.”
To mimic the integrin-ECM binding, they constructed an array of gold nanodots separated by different distances (35, 50 and 70nm) and allowed highly invasive cancer cells to attach to them. They then applied pulsed ultrasound waves to the cancer cells grown on the 50nm and 70nm platforms, their cell membranes were found to stretch due to forces exerted by a filament protein called myosin.
More extracellular calcium was then pumped into the cytoplasm, which damaged the mitochondria and promoted cell death. Reducing spacing to 35nm prevented the cells from binding more efficiently to the nanodots, and generating sufficient myosin forces to trigger cell death, the release said.