Collective cancer cell invasion induced by coordinated contractile stresses.

Angela M Jimenez Valencia,Josh Digiacomo,Pei-Hsun Wu,Inês Godet,Sean X Sun,Meng-Horng Lee,Pranay Rao,Daniele Gilkes,Lijuan He,Denis Wirtz,Osman N Yogurtcu

doi:10.18632/oncotarget.5874

Abstract

The physical underpinnings of fibrosarcoma cell dissemination from a tumor in a surrounding collagen-rich matrix are poorly understood. Here we show that a tumor spheroid embedded in a 3D collagen matrix exerts large contractile forces on the matrix before invasion. Cell invasion is accompanied by complex spatially and temporally dependent patterns of cell migration within and at the surface of the spheroids that are fundamentally different from migratory patterns of individual fibrosarcoma cells homogeneously distributed in the same type of matrix. Cells display a continuous transition from a round morphology at the spheroid core, to highly aligned elongated morphology at the spheroid periphery, which depends on both β1-integrin-based cell-matrix adhesion and myosin II/ROCK-based cell contractility. This isotropic-to-anisotropic transition corresponds to a shift in migration, from a slow and unpolarized movement at the core, to a fast, polarized and persistent one at the periphery. Our results also show that the ensuing collective invasion of fibrosarcoma cells is induced by anisotropic contractile stresses exerted on the surrounding matrix.

Highlights

40% of the 200,000 patients diagnosed with sarcoma worldwide will succumb from metastatic disease [1, 2]
The invasion distance of HT1080 tumor spheroids was determined by measuring the distance between spheroid-matrix interface and the spheroid initial radius (Δr = r(t)–r(0)), and showed a > 10 fold increase from its initial value over 6 days (Figure 1B)
This result suggested that cell spheroids were highly invasive and that this invasion process was fundamentally different from the case of homogeneously distributed cells embedded in 3D collagen gels at low density which undergo the socalled anisotropic random-walk migration [10] and from the case of cohesively growing spheroids which switch from exponential to linear growth beyond the crossover region (200 μm < r < 350 μm) [22, 23]

Summary

Introduction

40% of the 200,000 patients diagnosed with sarcoma worldwide will succumb from metastatic disease [1, 2]. Fibrosarcoma is a subtype of soft tissue sarcomas [3]. Metastasis remains the most common cause of fibrosarcoma-associated deaths [4]; the survival rate for high-grade tumors is only 30% [5]. Clinical characteristics of fibrosarcoma are poorly understood and described [4]. One of the major challenges in treating fibrosarcoma is the difficulty in determining the surgical resection area due to the infiltrative nature of the cells, which results in high (>50%) recurrence rate. Understanding the process of fibrosarcoma cell dissemination is critical to developing new strategies to treat this disease

Methods

Results

Conclusion