Tissue mechanics in stem cell fate, development, and cancer

Abstract

Cells in tissues experience a plethora of forces that regulate their fate and modulate development and homeostasis. Cells sense mechanical cues through localized mechanoreceptors or by influencing cytoskeletal or plasma membrane organization. Cells translate force and modulate their behavior through a process termed mechanotransduction. Cells tune their tension upon exposure to chronic force by engaging cellular machinery that modulates actin tension, which in turn stimulates matrix remodeling and stiffening and alters cell-cell adhesions until cells achieve a state of tensional homeostasis. Loss of tensional homeostasis can be induced through oncogene activity and/or tissue fibrosis, accompanies tumor progression, and is associated with increased cancer risk. The mechanical stresses that develop in tumors can also foster the mesenchymal-like transdifferentiation of cells to induce a stem-like phenotype that contributes to their aggression, metastatic dissemination, and treatment resistance. Thus, strategies that ameliorate tumor mechanics may comprise an effective strategy to prevent aggressive tumor behavior.

Figure 1.. Mechanosensing and mechanotransduction mechanisms in cells.

a, Cells have evolved to sense force either through protein-based mechanosensors or cytoskeletal and membrane-mediated molecular responses, in a process known as mechanosensing. Cells sense mechanical cues in multiple ways including; mechanosensitive ion channels, integrins in focal adhesions, cadherins in adheren junctions and nuclear membrane proteins in cytoskeletal interactions. b, Cells then translate these mechanical cues into biochemical signals that then elicit a biological response through a process termed mechanotransduction. In the case of focal adhesions, the initial activation and binding of integrins to the ECM can occur in the presence of low resisting forces (soft ECM), leading to the formation of a transient focal complex, where the integrin intracellular domain is weakly attached to F-actin. In the presence of high resisting forces (stiff ECM), the recruitment of adaptor proteins promotes integrin clustering, actin remodeling and myosin-mediated contraction to increase internal cellular tension. Force-bearing proteins such as talin undergo force-induced conformational changes, which promotes the local recruitment of other proteins to reinforce the linkage to actin, such as vinculin, to regulate local signaling to provide a positive feedback leading to further reinforcement and maturation of focal adhesions. Multiple mechanisms then contribute to regulate downstream signaling pathways mediating the biological responses to ECM mechanical cues. c, Examples of biological responses to ECM-derived mechanical cues occurring in different cell types. ECM cues influence cell-cell adhesions, regulates proliferation and apoptosis, directs cell migration and alters cell fate.

Figure 2.. Tissue forces in mammary gland development and function.

The mammary gland is subjected to a number of biophysical forces (red arrows) that facilitate its development and function. a, During puberty, branching is marked by the ductal outgrowth of the mammary epithelium into the adipocyte-rich (yellow) stroma of the fat pad by directing the collective migration of mammary epithelial cells (MEC) led by the terminal end bud (TEB). Branch orientation is regulated by the bundling of type I collagen fibers (grey) proximal to the TEB. b, The developed breast ducts comprise an inner layer of oriented luminal epithelial cells (green) and an outer layer of contractile myoepithelial cells (pink). c, During pregnancy, hormonal cues direct the expansion of alveolar cells that mature into milk-secreting cells. The alveoli expand out from the ducts filling the majority of the fat pad and the stroma is remodeled to accommodate the expanding epithelium. d, During lactation, the accumulation of milk and distension of ducts applies compressive stress on the surrounding cells and basement membrane. Upon suckling-mediated oxytocin stimulation, epithelial cells encounter inward tensile stress and the myoepithelium contracts to force milk out of the alveolar sacs. e, During involution, the mammary gland undergoes extensive remodeling of the cellular and extracellular stroma to the pre-pregnancy architecture. The remodeled stroma in these stages consequently alters the signals and forces encountered by MECs within the ducts and by doing so, sets the stage for subsequent cycles of proliferation, differentiation or involution.

Figure 3.. Disruption of tissue mechanics in breast cancer.

In the normal breast, forces between the epithelium and stroma maintain a state of tensional homeostasis. Normal ducts are surrounded by a compliant and soft ECM. In ductal carcinoma in situ (DCIS), epithelial cells proliferate within the lumen of the duct, exerting an outward projective compressive force on the adjacent myoepithelium and basement membrane (solid stress). These forces are countered by an inward projecting resistance force from the ECM. Accompanying DCIS progression is the remodeling, crosslinking and stiffening of the ECM by myofibroblasts and immune infiltrate. In parallel, interstitial pressure accumulates due to impaired lymphatic drainage and vessel compression. Together, these forces can generate regions of hypoxia within a tumor, which can induce epithelial-to-mesenchymal or stem-like transition in tumor cells. Neoplastic epithelial cells exhibit modified tensional homeostasis and respond to these accumulating forces. At some point, the myoepithelial-basement membrane barrier is breached, and linearized and stiffened ECM tracks surrounding ducts facilitate tumor cell invasion and metastasis.