Abstract
Tissue, cell, and nucleus morphology change during tumor progression. In 2D confluent cell cultures, different tissue states, such as fluid (unjammed) and solid (jammed), are correlated with cell shapes. These results do not have to apply a priori to three dimensions. Cancer cell motility requires and corresponds to a fluidization of the tumor tissue on the bulk level. Here, we investigate bulk tissue fluidity in 3D and determine how it correlates with cell and nucleus shape. In patient samples of mamma and cervix carcinoma, we find areas where cells can move or are immobile. We compare 3D cell spheroids composed of cells from a cancerous and a noncancerous cell line. Through bulk mechanical spheroid-fusion experiments and single live-cell tracking, we show that the cancerous sample is fluidized by active cells moving through the tissue. The healthy, epithelial sample with immobile cells behaves more solidlike. 3D segmentations of the samples show that the degree of tissue fluidity correlates with elongated cell and nucleus shapes. This correlation links cell shapes to cell motility and bulk mechanical behavior. We find two active states of matter in solid tumors: an amorphous glasslike state with characteristics of 3D cell jamming and a disordered fluid state. Individual cell and nucleus shape may serve as a marker for metastatic potential to foster personalized cancer treatment.
Highlights
Epithelial tissues develop into malignant tumors that are densely packed with cancer cells
Since we focus on solid tumors that originate from epithelial tissue, cell clusters may be directly interconnected by cadherins or through extracellular matrix (ECM) interspersed between the cells
We investigate the influence of imaging noise, optical resolution, and refractive index mismatches [53] on our results, finding that they are surprisingly stable and that the values are no artifacts of our imaging methods
Summary
Epithelial tissues develop into malignant tumors that are densely packed with cancer cells. Tumor grading classifies tumors by tissue histology based on shape variation of cell nuclei and tissue morphology [2,3]. This classification is nowadays complemented by molecular markers [4], but it remains elusive how morphology and biochemistry relate to the biomechanics. While genes and signaling pathways exert exquisite control over cell properties, mechanical interactions and the emerging collective behavior of cells play a critical role in sculpting collections of cells into functional three-dimensional (3D) tissues and organs [1,5,7,8,9,10,11], raising the question of how cells collectively shape the mechanical state of a tumor [5,6]. The ability of cancer cells to move in a specific tumor may be a predictive marker of a tumor’s metastatic potential
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