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May 16, 2017

Tumors Hold Stiff Upper Lip Before Malignancy

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    This is an accumulation of cytoskeleton fibers (magenta) in benign breast tumor cells. The cell nucleus is seen in blue. [Sandra Tavares/IGC.]

    While tumors alone can present a host of problems for the body, it’s the transition to malignancy that enables cancer cells to persist and wreak havoc on tissues and organs distant from the original tumor. For decades, scientists have been trying to understand what triggers cancerous cells into malignancy, and now it would seem that investigators at the Instituto Gulbenkian de Ciência (IGC) in Portugal may have struck upon some key insights. Findings from the new study—published recently in Nature Communications in an article entitled “Actin Stress Fiber Organization Promotes Cell Stiffening and Proliferation of Pre-Invasive Breast Cancer Cells”—show that breast cancer cells undergo a stiffening state prior to acquiring malignant features and becoming invasive.

    "Previously, it had been shown that cancer cell invasion requires cell softening,” explained lead study investigator Sandra Tavares, a doctoral candidate at the IGC. “What we observed now is that prior to becoming invasive cells undergo a transient stiffening state caused by the accumulation of cytoskeleton fibers.”

    The progression of breast cancer takes several stages from a benign lesion to an invasive carcinoma, with possible metastasis. Yet, 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 according to the severity of the disease. In the current study, the research team identified a new signal in tumor cells that they hope will be further explored when designing cancer-targeted therapies.

    The IGC investigators had been looking for signals within cells that could help predict when benign tumors would progress toward invasive carcinoma. The focus of much of their work has centered on the cytoskeleton—the 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 configure cells into a more rigid or soft structure.

    The research team discovered that cell stiffening induces the activity of proteins that promote cell proliferation, driving the growth of benign tumors. Most importantly, this cell rigidity state also triggers the subsequent progression of invasive cancer.

    “Using a human breast cell line with conditional Src induction, we demonstrate that cells undergo a stiffening state prior to acquiring malignant features,” the authors wrote. “This state is characterized by the transient 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.”

    The proteins involved in this mechanism were identified by studies on a human breast cell line, which recapitulates the multistep development of breast cancer, and biopsies of breast cancers. The importance of these proteins for the formation of tumors was further confirmed in the fruit fly.

    "Our work adds an important piece to the intricate puzzle of breast tumor progression,” concluded senior study author Florence Janody, Ph.D., principal investigator at IGC. “Knowing what happens inside the cell before a cell becomes preinvasive 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."

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