Colonization of distant organs by tumor cells generating circulating homotypic clusters adaptive to fluid shear stress

Abstract

Once disseminated tumor cells (DTCs) arrive at a metastatic organ, they remain there, latent, and become seeds of metastasis. However, the clonal composition of DTCs in a latent state remains unclear. Here, we applied high-resolution DNA barcode tracking to a mouse model that recapitulated the metastatic dormancy of head and neck squamous cell carcinoma (HNSCC). We found that clones abundantly circulated peripheral blood dominated DTCs. Through analyses of multiple barcoded clonal lines, we identified specific subclonal population that preferentially generated homotypic circulating tumor cell (CTC) clusters and dominated DTCs. Despite no notable features under static conditions, this population significantly generated stable cell aggregates that were resistant to anoikis under fluid shear stress (FSS) conditions in an E-cadherin-dependent manner. Our data from various cancer cell lines indicated that the ability of aggregate-constituting cells to regulate cortical actin-myosin dynamics governed the aggregates’ stability in FSS. The CTC cluster-originating cells were characterized by the expression of a subset of E-cadherin binding factors enriched with actin cytoskeleton regulators. Furthermore, this expression signature was associated with locoregional and metastatic recurrence in HNSCC patients. These results reveal a biological selection of tumor cells capable of generating FSS-adaptive CTC clusters, which leads to distant colonization.

Circulating tumor cells: Towards mechanical phenotyping of metastasis

“…Both P2Y2 receptors ablation and ATP release blockade strongly reduce metastasis (Schumacher et al, 2013). Another known interaction occurs between a6b1-integrin on platelets and ADAM9 on CTCs (Mammadova-Bach et al, 2016). A different advantage of CTCs binding platelets is the activation of YAP1 signaling reducing anoikis (Haemmerle et al, 2017).…”

“…Similarly, CTC clusters under FSS develop their own survival strategies like the generation of stable cell aggregates resistant to anoikis in an E-cadherin-dependent manner. Interestingly, CTCs clusters are also able to regulate their cortical actin-myosin dynamic achieving higher stability under FSS (Maeshiro et al, 2021). Hetero-cluster formed between CTCs and CAFs enhance FSS resistance via intercellular contact and soluble derived factors.…”

Biophysics involved in the process of tumor immune escape

“…This form of deformation of the member is known as shear, and its cross section is the shear surface. The magnitude of the shear force per unit area of the cross section is called shear stress Blood flow and peripheral cells ( Maeshiro et al., 2021 ; Pomianek et al., 1996 ) Strain ∖ Describes the deformation of an object relative to its original length, measured as a percentage Solid tumor; intravascular wall ( Cardillo et al., 2006 ) Stiffness ∖ Describes the elasticity of a material or the recovery of its original shape after deformation Solid tumors; fibroblasts; extracellular matrix ( Seewaldt 2014 ; Fenner et al., 2014 ; McLane and Ligon 2015 ) Flexibility ∖ Describes the ability of an object to recover its original shape after the removal of an external force. Solid tumors; intravascular walls; extracellular matrix ( Szabo and Merks 2013 ) Viscoelasticity ∖ Objects exhibit both elastic and viscous properties when they deformed.…”

Phenotypic Plasticity during the Dissemination of Circulating Tumour Cell Clusters: A Model Involving TGFβ1-Mediated Cluster Dissociation, Adherence and Single-Cell Extravasation

“…Their presence is generally associated with bad prognosis [4] and several factors are thought to contribute to the increased metastatic potential of CTC clusters compared to single CTCs. For instance, while in circulation, CTC clusters might have increased resistance to shear stress [16], programmed cell death, anoikis [17], immune attacks [18] and drug therapies [19]. Furthermore, it has been shown that CTC clusters feature DNA methylation patterns that promote the expression of stem-cell related genes [20], and that the formation of clusters promotes a metabolic switch that increases the efficiency of metastasis [21].…”