Mechanoresponsive stem cells to target cancer metastases through biophysical cues

Abstract

Despite decades of effort, little progress has been made to improve the treatment of cancer metastases. To leverage the central role of the mechanoenvironment in cancer metastasis, we present a mechanoresponsive cell system (MRCS) to selectively identify and treat cancer metastases by targeting the specific biophysical cues in the tumor niche in vivo. Our MRCS uses mechanosensitive promoter-driven mesenchymal stem cell (MSC)-based vectors, which selectively home to and target cancer metastases in response to specific mechanical cues to deliver therapeutics to effectively kill cancer cells, as demonstrated in a metastatic breast cancer mouse model. Our data suggest a strong correlation between collagen cross-linking and increased tissue stiffness at the metastatic sites, where our MRCS is specifically activated by the specific cancer-associated mechano-cues. MRCS has markedly reduced deleterious effects compared to MSCs constitutively expressing therapeutics. MRCS indicates that biophysical cues, specifically matrix stiffness, are appealing targets for cancer treatment due to their long persistence in the body (measured in years), making them refractory to the development of resistance to treatment. Our MRCS can serve as a platform for future diagnostics and therapies targeting aberrant tissue stiffness in conditions such as cancer and fibrotic diseases, and it should help to elucidate mechanobiology and reveal what cells “feel” in the microenvironment in vivo.

Stiffness heterogeneity-induced double-edged sword behaviors of carcinoma-associated fibroblasts in antitumor therapy

“…Stromal fibroblasts of pancreatic ductal adenocarcinoma tissues in mice promote the suppression of tumor growth upon ganciclovir administration [20,21]. Additionally, Liu et al [2] found that biophysical cues in vivo, specifically matrix stiffness, were potential targets of mesenchymal stem cell-based vectors for cancer treatment, whereas manipulating stroma stiffness may affect the outcomes of cancer treatment. Similarly, we found that when tumor cells were grown on soft PDMS substrates (5.3 kPa), PCM also prepared on the 5.3 kPa substrate led to inhibition of tumor cell survival in response to 5-FU, whereas PCM prepared on a stiffer substrate (46.7 kPa) had no obvious effect.…”

“…Tumor tissues exhibit increased stiffness compared with normal tissues. Recent evidence has demonstrated that stroma stiffness plays important roles in the resistance of tumors to chemotherapy [1,2]. Within stiff tissues, the distribution of stroma stiffness is often heterogeneous in different regions of the invasive tumor, in which geographically distinct regions display different constituents and architectures of the extracellular matrix [3,4].…”

The role of collagen in cancer: from bench to bedside

“…In esophageal SCC, increased collagen content was associated with chemotherapy resistance via the MAPK and PI3K/AKT pathways [179]. Even at metastatic sites, collagen crosslinking increases tissue stiffness to promote resistance to treatment [180]. Furthermore, increased collagen content was accompanied by increased hyaluronan accumulation, contributing to doxorubicin drug resistance in pancreatic cancer [181].…”

Lineage Commitment, Signaling Pathways, and the Cytoskeleton Systems in Mesenchymal Stem Cells

“…A growing body of evidence indicates that MSCs activate direct leukocyte-like homing mechanisms with positive tumor tropism in response to adhesion molecules and matrix stiffness. 181 Mechanoresponsive cell systems of the new generation with stiffness sensors can directly deliver antitumor agents to the tumor sites 182 at least in breast and lung cancer. Development of different mechanosensors for a variety of tissues will open a new era in the translational medicine of cancers.…”