Tissue Force Programs Cell Fate and Tumor Aggression

Abstract

Biomechanical and biochemical cues within a tissue collaborate across length scales to direct cell fate during development and are critical for the maintenance of tissue homeostasis. Loss of tensional homeostasis in a tissue not only accompanies malignancy but may also contribute to oncogenic transformation. High mechanical stress in solid tumors can impede drug delivery and may additionally drive tumor progression and promote metastasis. Mechanistically, biomechanical forces can drive tumor aggression by inducing a mesenchymal-like switch in transformed cells so that they attain tumor-initiating or stem-like cell properties. Given that cancer stem cells have been linked to metastasis and treatment resistance, this raises the intriguing possibility that the elevated tissue mechanics in tumors could promote their aggression by programming their phenotype toward that exhibited by a stem-like cell.Significance: Recent findings argue that mechanical stress and elevated mechanosignaling foster malignant transformation and metastasis. Prolonged corruption of tissue tension may drive tumor aggression by altering cell fate specification. Thus, strategies that could reduce tumor mechanics might comprise effective approaches to prevent the emergence of treatment-resilient metastatic cancers. Cancer Discov; 7(11); 1224-37. ©2017 AACR.

Figure 1. Corrupted tensional homeostasis accompanies tumor progression

The tensional balance required for the proper organization and function of adult tissues can be perturbed by oncogenic mutations that modify mechanosensitive signaling in cells (path going left). Alternatively, oncogenic mutations may be preceded by an increase in tissue mechanics that results from chronic fibrosis or injury (path going right). Cells are in a dynamic mechanoreciprocity with their environment such that newly transformed cells can remodel the extracellular matrix which will feed back and further stimulate mechanosignaling in the tumor cells and surrounding stromal cells. This vicious feedforward mechanism feeds into and promotes tumor evolution until a new tensional homeostasis is established in the tumor. This process may favor the growth, survival and expansion or transdifferentiation of stem-like tumor cells that are typically more aggressive given that they frequently display an enhanced survival phenotype and a predisposition to disseminate.

Figure 2. Mechanical forces can promote tumor aggression

An expanding tumor mass results in increased solid stress. Solid stress refers to the force exerted by the solid structural components of a tissue experiencing growth. This stress, together with the mechanical resistance produced by the extracellular matrix (ECM) and stromal cells, promotes an increase in interstitial pressure. Interstitial pressure relates to the interstitial fluid occupying the space between cells and containing water-soluble components of biological tissues. High hydrostatic pressure will force plasma to exit blood and lymphatic capillaries to enter the interstitial space. Conversely, when hydrostatic pressure in capillaries is decreased, interstitial fluid can enter these vessels. Thus, high solid stress and interstitial pressure can impair lymphatic drainage and drug delivery, and in severe cases can precipitate vessel compression and collapse. Insufficient blood supply generates regions of hypoxia within a tumor, a condition which can induce an epithelial-to-mesenchymal or stem-like transition and treatment resistant qualities in tumor cells. To counter these mechanical stresses, tumors often develop a desmoplastic response characterized by the recruitment of fibroblasts and immune cells with increased deposition of ECM proteins including collagen, fibronectin and Tenascin C. Fibroblasts can stimulate tumor cell growth through paracrine factors and together with tumor cells, remodel the ECM through cell generated tension and elevated production of ECM molecules and crosslinking enzymes. A linearized and stiffened ECM provides tracks for immune infiltration and may facilitate tumor cell invasion and metastasis.

Figure 3. Biomechanical force may promote tumor progression by establishing an aggressive tumor cell hierarchy

In a hierarchical model of tumorigenesis, transformation may originate from among any of the different lineages that form a tissue including stem cells, progenitor cells, or their differentiated progeny. Normal stem and progenitor cells are intrinsically programmed for self-renewal and survival; therefore, their dysregulation could generate cancer stem cells (CSCs) or tumor initiating cells (TICs) with similar capacities for self-renewal and the propagation of differentiated tumor cells. Alternatively, CSCs may be derived from oncogenic events occurring in mature somatic cells that enable the acquisition of CSC properties. Alterations to biomechanical forces through a transformed physical and genetic landscape may contribute to CSC formation by favoring the proliferative expansion of a specific stem/progenitor population, or by inducing an epithelial-to-mesenchymal transition (EMT) and the dedifferentiation of more differentiated transformed cells. An expanded progenitor population represents an attractive long-lived target for the accumulation of oncogenic mutation and tumor initiation. A stochastic model of tumor progression suggests the stepwise acquisition of sporadic mutations and clonal evolution through competitive selection. In all likelihood, tumors develop through mechanisms that include both hierarchical and stochastic models and force induced tissue remodeling and programming of tumor cells may play a significant role in regulating tumor heterogeneity and tumor cell plasticity.

Figure 4. Mechanical control of tumor cell fate

This illustration summarizes some of the mechanisms by which a stiff ECM or augmented cellular tension may alter tumor cell fate. A stiffened matrix strengthens cell-ECM interactions in tumor cells and prompts the disruption of E-cadherin mediated cell-cell junctions, thereby freeing β-catenin to relocate to the nucleus (β). Similarly, mechanical stress may cause the mislocalization of cell polarity proteins. Breast cancer cells cultured on a stiff matrix exhibit SCRIB mislocalization, leading to nuclear translocation of the Hippo signaling pathway transcriptional coactivator TAZ, to induce stem-like programming of tumor cells. Integrin receptor clustering and adhesion plaque formation through the recruitment of Vinculin, Talin, and other focal adhesion components is another consequence of tumor cell interaction with a stiff matrix. Focal adhesion maturation may then stimulate Rho/ROCK mediated actomyosin contractility and intracellular signaling through FAK, ERK and PI3K to enhance cell growth and survival. Integrin clustering may be further modified by a bulky glycocalyx, which creates a membrane kinetic trap for integrin complex assembly. Mechanical stress on tumor cells also activates the cellular production and secretion of WNTs, which may drive stem-like phenotypes in tumor cells through β-catenin activity. Moreover, the mechanical action of integrin adhesion and cell-generated tension releases latent-TGFβ from the ECM, allowing it to potentially stimulate tumor cell Epithelial-to-mesenchymal transition (EMT), invasion and metastasis. High cell tension might also alter the activity of the transcription factor, HIF-1α, in addition to YAP/TAZ and β-catenin, to promote gene expression patterns associated with an EMT and the acquisition of stem-like properties.