Tissue mechanics in tumor heterogeneity and aggression

Abstract

Tumorigenesis ensues within a heterogeneous tissue microenvironment that promotes malignant transformation, metastasis and treatment resistance. A major feature of the tumor microenvironment is the heterogeneous population of cancer-associated fibroblasts and myeloid cells that stiffen the extracellular matrix. The heterogeneously stiffened extracellular matrix in turn activates cellular mechanotransduction and creates a hypoxic and metabolically hostile microenvironment. The stiffened extracellular matrix and elevated mechanosignaling also drive tumor aggression by fostering tumor cell growth, survival, and invasion, compromising antitumor immunity, expanding cancer stem cell frequency, and increasing mutational burden, which promote intratumor heterogeneity. Delineating the molecular mechanisms whereby tissue mechanics regulate these phenotypes should help to clarify the basis for tumor heterogeneity and cancer aggression and identify novel therapeutic targets that could improve patient outcome. Here, we discuss the role of the extracellular matrix in driving cancer aggression through its impact on tumor heterogeneity.

Keywords: cancer stem cell; extracellular matrix; mechanobiology; metastasis; stiffness; therapeutic resistance; tumor heterogeneity.

Figure 1.. Extracellular matrix (ECM) stiffness as a central hub in tumor heterogeneity and progression.

Cartoon depicting how a remodeled, crosslinked, and stiffened tumor stroma impacts diverse cancer hallmarks that drive tumor heterogeneity and promote cancer aggression.

Figure 2.. Mechanisms underlying fibrotic extracellular matrix (ECM)-dependent tumor progression.

Cartoon illustrating the way in which a fibrotic stroma and a stiffened ECM drive tumor progression and aggression. (A) Cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and activated fibroblasts deposit, remodel, and crosslink the tumor ECM to promote tumor cell growth, survival, and an epithelial-to-mesenchymal transition (EMT) that expands cancer stem cell frequency. (B) A fibrotic, stiffened tumor stroma induces hypoxia to promote cancer cell stress adaptation and metabolic rewiring that enhances their growth and survival and treatment resistance. (C) A stiffened ECM enhances the recruitment of protumoral myeloid and lymphoid cells and drives immune reprogramming to facilitate tumor escape from antitumoral immunity. (D) The cancer cells and the cells from the tumor microenvironment, including infiltrating immune cells, secrete soluble factors (cytokines, growth factors, exosomes, metabolites) that stimulate stromal fibroblasts and mesenchymal cells to synthesize, secrete, remodel, and crosslink ECM that drives tumor heterogeneity and fosters tumor progression and aggression. Abbreviations: CCL2, C-C motif chemokine ligand 2; FGF, fibroblast growth factor; IL-6, interleukin-6; TGF-β, transforming growth factor beta; VEGF, vascular endothelial growth factor.

Figure 3.. Extracellular matrix (ECM) and microenvironment-focused cancer therapies: targets and strategies.

(A) Schematic depicting therapeutic opportunities targeting the ECM in cancer, including inhibition of ECM deposition, disruption of ECM crosslinking, and modulation of mechanosignaling induced by tumor forces. The inserted table summarizes known inhibitors, their targets, and mechanisms of action. (B) Schematic illustrating therapeutic strategies targeting the tumor microenvironment, including immunotherapies and anti-angiogenic therapies. The inserted table lists known tumor microenvironment therapies, their targets, and mechanisms of action. Abbreviations: HA, hyaluronic acid; LOX, lysyl oxidase; MMP, metalloproteinase; PD1, programmed cell death; TAMS, tumor-associated macrophages; VEGF, vascular endothelial growth factor.