Zhifei Zeng ’23
Many breast cancer (BC) patients suffer from complications of metastatic disease. In order to form metastasis, cancer cells must switch from a proliferative to an invasive state and overcome several physical barriers to reach another site. Interestingly, increased invasiveness of the tumor is accompanied by a decrease in its cell proliferation capacity. For breast cancer, some proteins may help this proliferative-to-invasive switch by facilitating tumor extravasation from blood vessels while attenuating tumor growth. A group led by Dr. Benjamin L. Martin at Stony Brook University found that srGAP1, an enzyme-activating protein, may mediate the switch from proliferative to invasive in breast cancer cells.
Researchers injected labeled breast cancer cells into the bloodstream of transparent zebrafish embryos, including cancer cells with normal amounts of srGAP1 and low srGAP1. After 24 hours, they observed the movement of cancer cells in blood vessels under the microscope. Most of the breast cancer cells still circulated in the blood, but few cancer cells close to the blood vessels formed dynamic actin-rich finger-like protrusions, followed by extravasating out of the blood vessels. Also, srGAP1low cells were more likely to form protrusions, thus more likely to extravasate from the blood vessels and enter other tissues. Next, the researchers cultured breast cancer cells and labeled the extracellular matrix. They found that srGAP1low cells degraded the extracellular matrix more efficiently than control cells, which facilitated the movement of cancer cells in vivo. To determine how srGAP1 restricts the growth of primary tumors and promotes metastasis, they labeled a cell division related protein- Cdk2, which can be detected in the cytoplasm of dividing cells, while Cdk2 accumulates in the nucleus of cells that do not divide. Sensors show prolonged accumulation of Cdk2 in the nucleus of cells with low srGAP1, which demonstrated that cells with low srGAP1 levels have restricted proliferation. They also found that srGAP1 low cells secrete more TGF𝛃2 protein than control cells. Treating cells with TGF𝛃2 demonstrated increased matrix degradation, which increases the invasion of cancer cells.
Overall, the researchers found that srGAP1 low cell displayed a highly motile phenotype and restricted proliferation state. These cells also secreted more TGF𝛃2 proteins to promote their invasion. This study cautioned that current treatments that target only dividing cells may not stop cancer metastasis. Future research could focus on blocking the metastatic pathway of non-dividing invasive cells to increase the long-term survival of cancer patients.
 C. Mondal, et al., A proliferative to invasive switch is mediated by srGAP1 downregulation through the activation of TGF𝛃2 signaling. SSRN, (2021).
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