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 cancer cell clusters cells collectively become motile through a novel unjamming transition and fluidize the tissue. Our publication has been chosen by Nature Review Physics as one of the ten most important publications in 2021 and by Physical Review X as one of the ten most important publications of the last ten years. Based on previous findings cell unjamming was either interpreted shape or density induced (Blauth et al, Frontiers in Physics (2021)) my state diagram resolves this conflict (Fig 2). Cancer cell unjamming is based on elongated cell and nucleus shapes (CeNuS) as well as a decrease in nucleus number density. 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 3. 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 (Fuhs et al, Nature Physics (2022)). 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 (see Fig 4). A change from cortical contractility to stress fiber based contractility plays a role in the unjamming process (Warmt et al, New J. Phys. (2021)). Other drivers of unjamming and cancer cell escape from the tumor mass are stroma density and cadherin expression (Ilina et al, Nature Cell Biol. (2020)). Cancer cell unjamming is one of the earliest events in the metastatic cascade. I have investigated the prognostic value of cancer cell unjamming for distant metastasis. Our retrospective study of histological slides from 1,380 breast cancer patients demonstrates that cancer cell unjamming is of prognostic relevance concerning distant metastasis (Gottheil et al, Physical Review X (2023)) (Fig 5). 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 prognostic marker for 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. Moreover, on a bulk level cancer cell unjamming causes an increase in tissue fluidity. In collaboration with Prof Sack’s lab at the Charité I have shown for a broad range of tumor entities that tumor progression leads to tissue fluidization, which can be used a prognostic criterion in magnetic resonance elastography (MRE) (Sauer et al, Adv. Science, in press).
