A study published now on Nature Communications* shows that breast cancer cells undergo a stiffening state prior to acquiring malignant features and becoming invasive. The discovery identifies a new signal in tumor cells that can be further explored when designing cancer-targeting therapies.

The progression of breast cancer disease takes several stages, from a benign lesion to an invasive carcinoma, possibly with metastasis. But actually, only 20 to 50% of benign tumors end up as invasive cancer. Predicting what lesions are within this group could result in a better use of therapeutics accordingly to the severity of the disease.

The group has been looking for signals inside the cells that could help predicting benign tumors that will progress to invasive carcinoma. Their attention focus on the cell skeleton - the cytoskeleton --, an intricate network of fibers that can either exert or resist forces, and that may have an impact on tumor invasion and malignancy. These fibers can be organized into distinct architectures to confer cells a more rigid or soft structure.

"Previously, it had been shown that cancer cell invasion requires cell softening. What we observed now is that prior to becoming invasive cells undergo a transient stiffening state caused by the accumulation of cytoskeleton fibers ", explains first author of this study.

The research team discovered that cell stiffening induces the activity of proteins that promote cell proliferation, driving the growth of benign tumors. The process involves accumulation of stress fibres and upregulation of Ena/VASP-like (EVL). EVL, in turn, organizes stress fibres leading to transient cell stiffening, ERK-dependent cell proliferation, as well as enhancement of Src activation and progression towards a fully transformed state. Accordingly, EVL accumulates predominantly in premalignant breast lesions and is required for Src-induced epithelial overgrowth in Drosophila. Most importantly, this cell rigidity state also triggers the subsequent progression into invasive cancer.

Senior author says: "Our work adds an important piece to the intricate puzzle of breast tumor progression. Knowing what happens inside the cell before a cell becomes pre-invasive and acquires malignant features may help us predict, in the future, which tumors may result in metastasis. Also, it may help designing therapeutics better tailored for each type of lesion."

http://www.igc.gulbenkian.pt/pages/article.php/A=400___collection=pressReleases___year=2017

https://www.nature.com/articles/ncomms15237