Prostate cancer cells of increasing metastatic potential exhibit diverse contractile forces, cell stiffness, and motility in a microenvironment stiffness-dependent manner

Abstract

During metastasis, all cancer types must migrate through crowded multicellular environments. Simultaneously, cancers appear to change their biophysical properties. Indeed, cell softening and increased contractility are emerging as seemingly ubiquitous biomarkers of metastatic progression which may facilitate metastasis. Cell stiffness and contractility are also influenced by the microenvironment. Stiffer matrices resembling the tumor microenvironment cause metastatic cells to contract more strongly, further promoting contractile tumorigenic phenotypes. Prostate cancer (PCa), however, appears to deviate from these common cancer biophysics trends; aggressive metastatic PCa cells appear stiffer, rather than softer, to their lowly metastatic PCa counterparts. Although metastatic PCa cells have been reported to be more contractile than healthy cells, how cell contractility changes with increasing PCa metastatic potential has remained unknown. Here, we characterize the biophysical changes of PCa cells of various metastatic potential as a function of microenvironment stiffness. Using a panel of progressively increasing metastatic potential cell lines (22RV1, LNCaP, DU145, and PC3), we quantified their contractility using traction force microscopy (TFM), and measured their cortical stiffness using optical magnetic twisting cytometry (OMTC) and their motility using time-lapse microscopy. We found that PCa contractility, cell stiffness, and motility do not universally scale with metastatic potential. Rather, PCa cells of various metastatic efficiencies exhibit unique biophysical responses that are differentially influenced by substrate stiffness. Despite this biophysical diversity, this work concludes that mechanical microenvironment is a key determinant in the biophysical response of PCa with variable metastatic potentials. The mechanics-oriented focus and methodology of the study is unique and complementary to conventional biochemical and genetic strategies typically used to understand this disease, and thus may usher in new perspectives and approaches.

Prostate cancer cells synergistically defend against CD8+ T cells by secreting exosomal PD‐L1

“…However, PC3 and DU145 cells expressed more exosomal PD‐L1 than LNCaP and 22RV1 cells (Figure 1C). It is important to note that PC3 and DU145 cells are more aggressive than the latter two types 25,26 . Immunofluorescence staining revealed that PD‐L1 co‐localized with a well‐established exosome marker (CD63) in PC3 and DU145 cells (Figure 1D,E).…”

“…It is important to note that PC3 and DU145 cells are more aggressive than the latter two types. 25 , 26 Immunofluorescence staining revealed that PD‐L1 co‐localized with a well‐established exosome marker (CD63) in PC3 and DU145 cells (Figure 1D,E ). Taken together, these data suggest that exosomal PD‐L1 is widely present in prostate cancer cell lines and increases in more malignant cells.…”

Altered Mechanobiology of PDAC Cells with Acquired Chemoresistance to Gemcitabine and Paclitaxel

“…To closely emulate native settings, we indeed cultured cells on ECM-coated substrates and controlled near-native stiffness conditions EMT and cellular force generation are believed to be closely correlated. For example, metastatic/mesenchymal cancer cells of different tumor types (prostate, breast and lung) showed higher contractile forces [7,12] compared to non-metastatic phenotypes. The correlation between EMT and traction forces in PDAC was first investigated by Nguyen and collaborators, who reported that in PDAC the metastatic potential does not correlate with increased traction forces [5].…”

“…Cellular mechano-transduction, the process by which mechanical cues are converted into intracellular molecular signals, along with interactions with the surrounding extracellular matrix (ECM) play a pivotal role in cell homeostasis and signaling. Increasing evidence show that this phenomenon is particularly critical in cancers that develop abnormal ECM, causing tumor progression, increased metastatic potential and drug resistance [5][6][7]. PDAC is characterized by a drastic change in the ECM reflected by tissue stiffening.…”

Membrane tension-mediated stiff and soft tumor subtypes closely associated with prognosis for prostate cancer patients

“…However, PCa appears to deviate from the cell-softening trends described in other cancer models, in which with the increasing of stiffness of PCa cells, the metastasis potential is also increasing [ 49 – 53 ]. In addition, a recent study found that the cell and tissue mechanic characteristics of different metastatic potential cells were diverse, which meant the relationship between the metastatic ability and membrane tension and tissue stiffness of PCa cells was not necessarily linear [ 54 ]. These confounding results indicate that microenvironment mechanics are a significant yet nuanced factor in the progression of PCa.…”