Abstract
Simple SummaryMetastasis of tumor cells is the leading cause of death in cancer patients. Concurrent therapy with surgical removal of primary and metastatic lesions is the main approach for cancer therapy. Currently, therapeutic resistant properties of cancer stem cells (CSCs) are known to drive malignant cancer progression, including metastasis. Our study aimed to identify molecular tools dedicated to the detection and treatment of CSCs. We confirmed that microRNA-210-3p (miR-210) was upregulated in colorectal stem-like cancer cells, which targeted stathmin1 (STMN1), to decrease cell elasticity for increasing mobility. We envision that strategies for softening cellular elasticity will reduce the onset of CSC-orientated metastasis.Cell migration is critical for regional dissemination and distal metastasis of cancer cells, which remain the major causes of poor prognosis and death in patients with colorectal cancer (CRC). Although cytoskeletal dynamics and cellular deformability contribute to the migration of cancer cells and metastasis, the mechanisms governing the migratory ability of cancer stem cells (CSCs), a nongenetic source of tumor heterogeneity, are unclear. Here, we expanded colorectal CSCs (CRCSCs) as colonospheres and showed that CRCSCs exhibited higher cell motility in transwell migration assays and 3D invasion assays and greater deformability in particle tracking microrheology than did their parental CRC cells. Mechanistically, in CRCSCs, microRNA-210-3p (miR-210) targeted stathmin1 (STMN1), which is known for inducing microtubule destabilization, to decrease cell elasticity in order to facilitate cell motility without affecting the epithelial–mesenchymal transition (EMT) status. Clinically, the miR-210-STMN1 axis was activated in CRC patients with liver metastasis and correlated with a worse clinical outcome. This study elucidates a miRNA-oriented mechanism regulating the deformability of CRCSCs beyond the EMT process.
Highlights
Cytoskeletal components, including microtubules, actins, and intermediate filaments, support the structure of eukaryotic cells with appropriate viscoelasticity to regulate physiological cell morphology [1], division [2–4], and movement [5,6]
In an attempt to discover mechanisms regulating the motility of cancer stem cells (CSCs), we initiated this study by expanding colorectal CSCs (CRCSCs) from two colorectal cancer (CRC) cell lines, HT29 and HCT15, using a serum-free cultivation platform, because stem-like cancer populations were enriched as cancer spheroids [32]
We found that the expanded HT29- and HCT15-CRCSCs grew as suspended colonospheres (Figure 1a) and showed increased expression of stemness genes, including NANOG, POU5F1, LGR5, CD44, and SNAI1 (Figure S1a)
Summary
Cytoskeletal components, including microtubules, actins, and intermediate filaments, support the structure of eukaryotic cells with appropriate viscoelasticity to regulate physiological cell morphology [1], division [2–4], and movement [5,6]. Intercellular communication and cell-extracellular matrix (ECM) interactions define the localized and premetastatic tumor microenvironment (TME) for stimulating cancer metastasis [7]. Cellular viscoelasticity has been studied using microrheology to determine the intracellular elastic and viscous moduli [8–10], little is known about the viscoelasticity of cancer cells during stepwise metastatic progression in distinct TMEs. Cancer stem cells (CSCs), a nongenetic source of phenotypic heterogeneity in bulky tumors, are responsible for tumor initiation, therapeutic resistance, and distal metastasis [11]. CD26(+) and Lgr5(+) CSCs are further suggested to contribute to the maintenance of distal metastasis [15,16]. CSC phenotypes can be induced by epithelialmesenchymal transition (EMT) inducers [17], maintained by inflammatory cytokines/ chemokines or defined by Wnt activity [18]. The mechanism by which CSCs modulate cellular viscoelasticity to promote local invasion and distal metastasis remains elusive
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