In Grosser et al, Physical Review X (2021), my lab has shown in patient derived tumor explants of cervix and breast carcinoma by vital cell tracking that in the cancer cell clusters found in a solid tumor cancer cells collectively become motile through a novel unjamming transition and fluidize the tissue. My publication in Physical Review X on this topic has been chosen by Nature Review Physics as one of the ten most important physics publications in 2021 and by Physical Review X as one of the ten most important experimental publications of the last ten years. Unlike cell jamming in embryonic development, which is driven by an increase in cell density, cancer cell unjamming is based on elongated cell and nucleus shapes (CeNuS) as well as a decrease in nucleus density (Blauth et al, Frontiers in Physics (2021)). The phenomenon of cancer cell unjamming allows me to develop the first clinical cell motility marker that can be used in static images such as histological slides. As illustrated in Fig 1 I have shown that the cancer cell clusters embedded in stroma within solid tumors need jammed regions of stiff cancer cells to behave like a mechanically stable solid and unjammed regions of soft, motile cells to foster motility and proliferation (manuscript submitted to Nature Physics,
https://doi.org/10.21203/rs.3.rs-1114106/v1). The cancer cell clusters assume a unique heterogeneous solid state, where the soft unjammed cells are the majority and tension percolation generates a solid behavior. Jammed and unjammed cells differ by a decrease in cell stiffness. A change from cortical contractility to stress fiber based contractility also plays a role in the unjamming process (Warmt et al, New Jour. of Phys. (2021)). Other key drivers of unjamming and cancer cell escape from the tumor mass are stroma density and cadherin expression (Ilina et al, Nature Cell Bio. (2020)). Since cancer cell unjamming is probably the earliest event of the metastatic cascade. I have investigated its prognostic value for distant metastasis. My clinical data obtained in a retrospective study of histological slides from 1,380 breast cancer patients demonstrate that cancer cell unjamming is of prognostic relevance concerning distant metastasis (manuscript submitted to Nature Materials,
Fig 2. The Nottingham index is currently the gold standard in prognostic indices, relying on histopathology. It uses the invasion of nearby lymph nodes as the sole indicator of cancer cell motility. Thus, lymph node status constitutes the most important marker for the prognosis of distant metastases. Cancer cell unjamming distinctively complements the lymph node status. Unjamming seems to support pathways for distant metastasis that bypass the lymph nodes. Thus, jamming may help to avoid overtreatment of patients with false-positive lymph nodes and under treatment of patients with false-negative lymph nodes with regard to metastatic risk.