Contributed Talk

State of Cell Unjamming correlates with distant Metastasis in Cancer Patients

Pablo Gottheil¹, Jürgen Lippoldt¹, Steffen Grosser², Frederic Renner¹, Dimitrij Tschodu¹, Anne-Sophie Wegscheider³, Christoph Engel⁴, Markus Löffler⁴, Benjamin Wolf⁵, Bahriye Aktas⁵, Hans Kubitschke¹, Axel Niendorf³, Josef Käs¹

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Pathological morphological changes in tumor tissue enable collective cancer cell unjamming, a cellular motility transition. However, fundamental questions remain: Is unjamming essential for tumor progression? Which different unjamming states can be found in patients?
Here, vital cell tracking in patient-derived solid tumor explants reveals that states of cell unjamming can be recognized by elongated cell and nucleus shape (CeNuS) and low nucleus number density. These static variables serve as a morphodynamic
link to map the broad range of morphologies and associated motility states found in histological slides of 1380 breast cancer patients to generate a comprehensive state diagram of cancer cell unjamming. An increase in predicted cell motility in primary tumors through unjamming significantly correlates with distant metastases that may even occur a decade later. Patient risk groups are quantified via a decision boundary in the state space found by support vector machine classification. The resulting clinical prognostic potential is evaluated using a range of quantifiers, including Harrel’s concordance index. Using multivariable Cox models, we find that cell unjamming as a prognostic parameter adds a 26% information gain in the concordance index when combined with the established prognostic criteria (tumor diameter, tumor grade, lymph node status) used in the Nottingham index. Furthermore, it is independent of the chemotherapy status.
The derived state diagram of cancer cell unjamming reconciles conflicting observations regarding shape- or density-induced unjamming and stresses the nuclei’s mechanical importance, which is not considered in current theories of cell unjamming. We
conclude that cancer cell unjamming is part of the metastatic cascade and contributes to tumor progression.