Unique cellular protrusions mediate breast cancer cell migration by tethering to osteogenic cells

Aaron M Muscarella,Patrick G Mitchell,Fabio Stossi,Weijie Zhang,Wah Chiu,Michael A Mancini,Hai Wang,Wei Dai,Xiang H.-F Zhang,Luyu Jia

doi:10.1038/s41523-020-00183-8

Abstract

Migration and invasion are key properties of metastatic cancer cells. These properties can be acquired through intrinsic reprogramming processes such as epithelial-mesenchymal transition. In this study, we discovered an alternative “migration-by-tethering” mechanism through which cancer cells gain the momentum to migrate by adhering to mesenchymal stem cells or osteoblasts. This tethering is mediated by both heterotypic adherens junctions and gap junctions, and leads to a unique cellular protrusion supported by cofilin-coated actin filaments. Inhibition of gap junctions or depletion of cofilin reduces migration-by-tethering. We observed evidence of these protrusions in bone segments harboring experimental and spontaneous bone metastasis in animal models. These data exemplify how cancer cells may acquire migratory ability without intrinsic reprogramming. Furthermore, given the important roles of osteogenic cells in early-stage bone colonization, our observations raise the possibility that migration-by-tethering may drive the relocation of disseminated tumor cells between different niches in the bone microenvironment.

Highlights

Metastasis is the major challenge in research and treatment of cancers[1,2,3]
A recent study demonstrated that cancer-associated fibroblasts (CAFs) can lead collective migration through development of heterotypic adherens junctions constituted by N-cadherin of CAFs and E-cadherin of cancer cells[8]
We started with MCF-7 cells because these ER+ breast cancer cells can home to the osteogenic niche in vivo and form extensive cell-cell contact with osteogenic cells in 3D co-cultures as we showed in our previous works[12]

Summary

Introduction

Metastasis is the major challenge in research and treatment of cancers[1,2,3]. The metastasis cascade involves cellular migration. A basal-like reprogramming process has been observed to render cancer cells migratory without losing cell-cell adhesions, known as “collective migration”[5,6,7] Both EMT and collective migration can be induced by the microenvironment through paracrine or direct cell-cell contact. A recent study demonstrated that cancer-associated fibroblasts (CAFs) can lead collective migration through development of heterotypic adherens junctions constituted by N-cadherin of CAFs and E-cadherin of cancer cells[8]. These findings provide novel insights into the escape of tumor cells from primary tumors

Methods

Results

Conclusion