Within the tumor microenvironment (TME), tumor cells are exposed to numerous mechanical forces, both internally and externally, which contribute to the metastatic cascade. From the initial growth of the tumor to traveling through the vasculature and to the eventual colonization of distant organs, tumor cells are continuously interacting with their surroundings through physical contact and mechanical force application. The mechanical forces found in the TME can be simplified into three main categories: (i) shear stress, (ii) tension and strain, and (iii) solid stress and compression. Each force type can independently impact tumor growth and progression. Here, we review recent bioengineering strategies, which have been employed to establish the connection between mechanical forces and tumor progression. While many cancers are explored in this review, we place great emphasis on cancers that are understudied in their response to mechanical forces, such as ovarian and colorectal cancers. We discuss the major steps of metastatic transformation and present novel, recent advances in model systems used to study how mechanical forces impact the study of the metastatic cascade. We end by summarizing systems that incorporate multiple forces to expand the complexity of our understanding of how tumor cells sense and respond to mechanical forces in their environment. Future studies would also benefit from the inclusion of time or the aspect of mechanical memory to further enhance this field. While the knowledge of mechanical forces and tumor metastasis grows, developing novel materials and in vitro systems are essential to providing new insight into predicting, treating, and preventing cancer progression and metastasis.

Growth factors (GF) are critical cytokines in wound healing. However, the direct delivery of these biochemical cues into a wound site significantly increases the cost of wound dressings and can lead to a strong immunological response due to the introduction of a foreign source of GFs. To overcome this challenge, we designed a poly(ethylene glycol) diacrylate (PEGDA) hydrogel with the potential capacity to sequester autologous GFs directly from the wound site. We demonstrated that synthetic peptide sequences covalently tethered to PEGDA hydrogels physically retained human transforming growth factor beta 1 (hTGFβ1) and human vascular endothelial growth factor (hVEGF) at 3.2 and 0.6 ng/mm², respectively. In addition, we demonstrated that retained hTGFβ1 and hVEGF enhanced human dermal fibroblasts (HDFa) average cell surface area and proliferation, respectively, and that exposure to both GFs resulted in up to 1.9-fold higher fraction of area covered relative to the control. After five days in culture, relative to the control surface, non-covalently bound hTGFβ1 significantly increased the expression of collagen type I and hTGFβ1 and downregulated vimentin and matrix metalloproteinase 1 expression. Cumulatively, the response of HDFa to hTGFβ1 aligns well with the expected response of fibroblasts during the early stages of wound healing.

Colorectal cancer tumors start as polyps on the inner lining of the colorectum, in which they are exposed to the mechanics of peristalsis. Our previous work leveraged a custom-built peristalsis bioreactor to demonstrate that colonic peristalsis led to cancer stem cell enrichment in colorectal cancer cells. However, this malignant mechanotransductive response was confined to select colorectal cancer lines that harbored an oncogenic mutation in the Kirsten rat sarcoma virus (KRAS) gene. In this study, we explored the involvement of activating KRAS mutations on peristalsis-associated mechanotransduction in colorectal cancer. Peristalsis enriched cancer stem cell marker Leucine-rich repeat–containing G protein–coupled receptor 5 (LGR5) in KRAS mutant lines in a Wnt ligand–independent manner. Conversely, LGR5 enrichment in wild-type KRAS lines exposed to peristalsis were minimal. LGR5 enrichment downstream of peristalsis translated to increased tumorigenicity in vivo. Differences in mechanotransduction were apparent via unbiased gene set enrichment analysis, in which many unique pathways were enriched in wild-type versus mutant lines. Peristalsis also triggered β-catenin nuclear localization independent of Wnt ligands, particularly in KRAS mutant lines. The involvement of KRAS was validated via gain and loss of function strategies. Peristalsis-induced β-catenin activation and LGR5 enrichment depended on the activation of the MEK/ERK cascade. Taken together, our results demonstrated that oncogenic KRAS mutations conferred a unique peristalsis-associated mechanotransduction response to colorectal cancer cells, resulting in cancer stem cell enrichment and increased tumorigenicity. These mechanosensory connections can be leveraged in improving the sensitivity of emerging therapies that target oncogenic KRAS. Implications: Oncogenic KRAS empowers colorectal cancer cells to harness the mechanics of colonic peristalsis for malignant gain independent of other cooperating signals.

Supplementary Figure 4 shows the gating strategy used for LGR5 analysis in Figure 6B.

Supplementary Figure 1 shows the gating strategy used for LGR5 analysis in Figures 1A, 1B, and 4B.