Cancer cells that disseminate from a tumor can enter a period of dormancy that may persist from months to decades before metastasis. Efforts to improve adjuvant therapy to remove residual cancer cells are hindered by an insufficient understanding of the long-term viability of cancer dormancy. Identifying these mechanisms can greatly improve treatments and prevent relapse.
In a study published in Nature Cancer titled, “TGFβ induces an atypical EMT to evade immune mechanosurveillance in lung adenocarcinoma dormant metastasis,” researchers from Memorial Sloan Kettering Cancer Center (MSK) have uncovered how cancer cells evade the immune system by changing their shape in a mouse model.
“When cancer cells are round, they have much lower surface tension, and it’s harder for the immune cells to attack them and pop them like a balloon,” said Joan Massagué, PhD, director of MSK’s Sloan Kettering Institute and corresponding author of the study.
“Our research suggests that if we can stop cancer cells from entering this soft state, or re-stiffen them, we might help the immune system find and clear dormant metastases before they can seed a new tumor,” said Zhenghan Wang, PhD, a senior research scientist in the Massagué Lab and first author on the paper.
Different forms of epithelial-to-mesenchymal transition (EMT) occur during tumor progression. Transforming Growth Factor (TGF) is a family of proteins crucial for cell growth, differentiation, and tissue repair.
The phenotypic plasticity of EMTs has important roles in development, injury repair, cancer invasion, and metastasis. During EMT, epithelial cells remodel cell adhesion contacts, assemble contractile actin stress fibers, adopt a spindly morphology, gain anteroposterior polarity, and become motile.
During dormancy, solitary cells persist despite immune surveillance. In large tumors, TGFβ acts as a direct suppressor of immune effector cells. In this context, the spindly architecture induced by TGFβ-dependent EMT would be expected to increase cell stiffness, thereby sensitizing metastatic cells to killing by cytotoxic T lymphocytes (CTLs). How dormant metastatic cells evade this fate has remained unclear.
Results showed that the TGFβ response in disseminated cancer cells leads to growth arrest and a full EMT, eventually transitioning into a round morphology that lacks actin stress fibers. This transition lowers the biomechanical stiffness of cancer cells and protects them from being killed by the immune system.
Additionally, this biomechanical transition is driven by gelsolin, which breaks down the cell’s actin fibers to reduce stiffness. Long exposure to TGFβ causes increased gelsolin production, which contributes to the round morphology.
While blocking TGFβ reduced gelsolin and prevented cells from becoming soft, the dormant cancer cells were still more effectively eliminated by immune cells. This demonstrates that TGFβ was crucial for facilitating dormant metastatic cells to evade immune defenders over months and years.
“We hope that with continuing research into dormant metastasis, we can ultimately prevent metastatic cancer by helping the body eliminate its dormant seeds,” said Massagué.
