Breast cancer-derived exosomal miR-105-5p facilitates the transformation of NFs into CAFs through LATS2-NF-κB signaling

Abstract

Studies of cell-to-cell activities in the tumor microenvironment (TME) have identified multiple potential targets for oncotherapy. The interplay between tumor cells and neighboring cancer-associated fibroblasts (CAFs) persists in all stages of tumor progression. In this study, we reveal that exosomes from breast cancer cells can be endocytosed into fibroblasts and transform normal fibroblasts (NFs) into CAFs and that the ability of exosomes from highly metastatic breast cancer cells is greater than that of those from poorly metastatic breast cancer cells. Further investigation reveals that exosomes from highly metastatic breast cancer cells contain much more miR-105-5p than those from poorly metastatic breast cells do and that exosomal miR-105-5p facilitates the transformation of NFs to CAFs. A detailed study reveals that RBMY1A1-dependent sorting of miR-105-5p into fibroblasts and subsequent internalization of miR-105-5p promote the transformation of NFs to CAFs by downregulating LATS2 expression and activating NF-κB signaling, which concurrently facilitates the EMT of breast cancer cells. Thus, our results indicate that exosomal miR-105-5p may be a potential target for novel therapeutic strategies to prevent the coevolution of breast cancer cells and CAFs.

1. Introduction

Breast cancer is the most commonly diagnosed malignancy among women [1] and has always been one of the leading causes of cancer-related death [2]. The primary and common cause of death is typically ascribed to the continuous advancement of the tumor or the unsuccessful outcome of the implemented treatment. Numerous studies have highlighted the roles of the tumor microenvironment (TME) in breast cancer progression and the prospects of TME-targeted therapy [3,4]. However, the current treatment of tumors typically merely focuses on tumor cells, and the TME is frequently overlooked or ignored in tumor therapy. This approach often leads to suboptimal treatment outcomes and potential recurrence of the tumor, as the complex interactions and influences within the TME are not taken into account. The disregard for the TME might also limit the development and efficacy of novel therapeutic modalities aimed at achieving more comprehensive and long-lasting tumor control.

The tumor microenvironment (TME) is constituted by numerous types of cells and extracellular matrix. As one of the most prevalent noncancerous cell types within the TME, cancer-associated fibroblasts (CAFs) have been thoroughly examined and are recognized to be implicated in a wide range of cellular processes, such as cell differentiation, proliferation, cell migration, and apoptosis. These processes play crucial roles in the development, progression, and metastasis of tumors, and the understanding of the functions and mechanisms of CAFs has become an important area of research in oncology [5]. The interaction between CAFs and other components of the TME also contributes to the complexity and heterogeneity of the tumor microenvironment, influencing the response to therapeutic interventions and prognosis of cancer patients. All of these can play critical roles in tumor biological behaviors, including tumorigenesis, tumor growth, angiogenesis, tumor progression, recurrence, and metastasis [5–7]. It has been reported that the various components in TME can promote the conversion of normal fibroblasts (NFs) to CAFs in multiple ways [5]. However, the underlying mechanism of the interaction between breast cancer cells and fibroblasts, especially how breast cancer cells promote the transformation of NFs into CAFs, has not been fully investigated.