Cell softness regulates tumorigenicity and stemness of cancer cells

Abstract

Identifying and sorting highly tumorigenic and metastatic tumor cells from a heterogeneous cell population is a daunting challenge. Here, we show that microfluidic devices can be used to sort marker‐based heterogeneous cancer stem cells (CSC) into mechanically stiff and soft subpopulations. The isolated soft tumor cells (< 400 Pa) but not the stiff ones (> 700 Pa) can form a tumor in immunocompetent mice with 100 cells per inoculation. Notably, only the soft, but not the stiff cells, isolated from CD133+, ALDH+, or side population CSCs, are able to form a tumor with only 100 cells in NOD‐SCID or immunocompetent mice. The Wnt signaling protein BCL9L is upregulated in soft tumor cells and regulates their stemness and tumorigenicity. Clinically, BCL9L expression is correlated with a worse prognosis. Our findings suggest that the intrinsic softness is a unique marker of highly tumorigenic and metastatic tumor cells.

Single-cell physical phenotyping of mechanically dissociated tissue biopsies for fast diagnostic assessment

“…Previous studies on cancer cells have shown a strong correlation between malignancy and the mechanical properties of cells [10][11][12]42,45,49 . Here, we exploit this correlation for detecting malignancy in human tissue biopsies.…”

“…Previous studies have found differences between the mechanical properties of cancer cells and their healthy counterparts 11,12,[42][43][44][45] . A major drawback of these studies is laborious sample preparation and low throughput that limits the conversion of these studies to actual diagnostic approaches.…”

Cytoskeletal prestress: The cellular hallmark in mechanobiology and mechanomedicine

“…An ex vivo analysis of cells from metastatic cancer patient samples using AFM also shows a low stiffness profile (Cross, Jin, Rao, & Gimzewski, 2007 ). A recent report that utilizes the softness trait to separate soft tumor cells from stiff tumor cell population using a microfluidic‐based method reveals that these soft cells are much more tumorigenic and metastatic than stiff tumor cells (Lv et al, 2020 ), suggesting that the cell softness is a physical marker for malignant solid tumors (Figure 2 ), adding a new physical trait to the known four physical traits (tumor tissue solid stress, interstitial fluid pressure, tumor tissue stiffness, and tumor microarchitecture) of solid tumors that may hamper successful treatment of malignant tumors (Nia, Munn, & Jain, 2020 ). The stiffness of these malignant soft tumor cells in suspension is only one‐third of the stiffness of those differentiated tumor cells (Lv et al, 2020 ), suggesting that their intrinsic cytoskeletal prestress is much lower than that in those stiff tumor cells.…”

“…Based on such biomechanical understanding, a tumor cell‐derived, drug‐loaded MP treatment platform has been developed. Highly tumorigenic tumor‐repopulating cells are very soft (Lv et al, 2020 ) and preferable to take up drug‐packing MPs via their high deformability. In turn, MPs mobilize the endo‐lysosomal systems, allowing the drug molecules to be delivered to the nucleus, thus killing tumor‐repopulating cells and reversing their drug resistance (Jin et al, 2017 ; Ma et al, 2016 ).…”

TAB2 Promotes the Stemness and Biological Functions of Cervical Squamous Cell Carcinoma Cells

“…Knockdown of TAB2 in Siha and MS751 cells significantly downregulated sphere-forming efficiency (Figures 4(c) – 4(e) ). Furthermore, aldehyde dehydrogenase (ALDH) activity, a reliable marker for CSCs, mediated by TAB2 in CC cells was determined [ 14 , 15 ]. The ALDH activity was significantly reduced in CC cells transfected with si-TAB2 compared with that of negative controls (Figures 4(f) and 4(g) ).…”