Cancer cells can spread to distant locations of the body by degrading their surrounding scaffold, which is known as the extracellular matrix (ECM). Now, researchers at the Francis Crick Institute have identified a key mechanism that controls this process and that they believe could inspire the development of new drugs to stop cancer metastasis.
The organization of ECM fibers is caused by collisions between cells, and fibroblasts are largely responsible for maintaining the structure of the matrix. In cancerous tissue, highly aligned collagen fibers can create a “highway” along which tumor cells spread to new locations. Scientists have observed that the orientation of the matrix perpendicular to a tumor's edge is linked to poor patient outcomes. But not enough is known about what controls its formation.
Using experimental and computational modeling, the Crick scientists showed that a protein called TFAP2C regulates these collisions and helps create different tissue structures, some of which allow cancer to escape. The results are published in two studies in Nature Materials and PLOS Computational Biology.
“These super-highways provide roads for cancer cells to travel out of tumors and spread more widely in the tissue, having potentially disastrous consequences for the patient,” said Crick's Danielle Park, Ph.D., first author of the Nature Materials study, in a statement. “By understanding more about how this type of structure is formed, we can then look at finding ways to stop it and impose a road block on the spread of cancer cells.”
The alignment of fibroblasts is influenced by how cells collide with each other, the Francis Crick researchers have found. They selected 37 genes with increased expression in aligning fibroblasts and pinpointed the transcription factor TFAP2C as required for the generation of these matrices.
Once they settled on TFAP2C, the scientists looked for drugs that inhibit this protein in hopes of disrupting the creation of super-highways for cancer progression. Using existing data, the team suggested that TFAP2C suppression might be achieved by inhibiting the known targets MEK, PI3K, mTOR, EGFR, Src-family kinases and Hsp90.
Five drugs emerged as good candidates for disrupting the formation of matrix alignment, with MEK inhibitor PD184352 (CI-1040) and Novartis’ Hsp90 drug luminespib having the strongest effects, according to the researchers.
Finding ways to restrict the degradation of the ECM is a popular strategy to stop cancer progression. A team led by the Garvan Institute of Medical Research recently found that pancreatic tumors overproduce a protein called perlecan to change the ECM. In mouse studies, lowering perlecan levels led to a drop in the spread of pancreatic cancer and improved response to chemotherapy, that team found.
Park and colleagues at Crick believe their discovery of the role TFAP2C plays in the “social behavior” of fibroblasts could be used to identify new drugs to alter ECM organization and hence block the spread of the cancer cells.