Simultaneously targeting extracellular vesicle trafficking and TGF-β receptor kinase activity blocks signaling hyperactivation and metastasis

Abstract

Metastasis is the leading cause of cancer-related deaths. Transforming growth factor beta (TGF-β) signaling drives metastasis and is strongly enhanced during cancer progression. Yet, the use of on-target TGF-β signaling inhibitors in the treatment of cancer patients remains unsuccessful, highlighting a gap in the understanding of TGF-β biology that limits the establishment of efficient anti-metastatic therapies. Here, we show that TGF-β signaling hyperactivation in breast cancer cells is required for metastasis and relies on increased small extracellular vesicle (sEV) secretion. Demonstrating sEV’s unique role, TGF-β signaling levels induced by sEVs exceed the activity of matching concentrations of soluble ligand TGF-β. Further, genetic disruption of sEV secretion in highly-metastatic breast cancer cells impairs cancer cell aggressiveness by reducing TGF-β signaling to nearly-normal levels. Otherwise, TGF-β signaling activity in non-invasive breast cancer cells is inherently low, but can be amplified by sEVs, enabling invasion and metastasis of poorly-metastatic breast cancer cells. Underscoring the translational potential of inhibiting sEV trafficking in advanced breast cancers, treatment with dimethyl amiloride (DMA) decreases sEV secretion, TGF-β signaling activity, and breast cancer progression in vivo. Targeting both the sEV trafficking and TGF-β signaling by combining DMA and SB431542 at suboptimal doses potentiated this effect, normalizing the TGF-β signaling in primary tumors to potently reduce circulating tumor cells, metastasis, and tumor self-seeding. Collectively, this study establishes sEVs as critical elements in TGF-β biology, demonstrating the feasibility of inhibiting sEV trafficking as a new therapeutic approach to impair metastasis by normalizing TGF-β signaling levels in breast cancer cells.

A New Systemic Disease Mouse Model for Glioblastoma Capable of Single-Tumour-Cell Detection

“…The mice were monitored for recovery, and 4 days later, a non-labelled contralateral tumour was implanted using the same procedure. This model mimicked several other contralateral models we and others have used to investigate tumour cell infiltration/invasion or therapeutic interventions [35][36][37]. Following the experimental end-point (based on daily monitoring and the condition of the mice and ranging from 13-39 days after implantation of the cells), the mice were euthanised, and blood samples were collected and their organs were snap-frozen.…”

Exosome-Mediated Antigen Delivery: Unveiling Novel Strategies in Viral Infection Control and Vaccine Design

“…The dual function of exosomes in the tumor context, with their strong capacity to ensure communication but with adverse pro-tumor effects, has led to the development of two main types of exosome-based anti-cancer strategies. One is based on the inhibition of EV trafficking to improve new therapeutic combinations [ 113 ]. Another is based on the engineering of exosomes to use them as nano-vectors for therapies [ 114 ].…”

Exosome-mediated Antigen Delivery: Unveiling Novel Strategies in Viral Infection Control

“…Thus, in the context of cancer, exosomes would play determinant roles in the migration and proliferation capacities of tumor cells, in angiogenesis and in the remodeling of the tumor's immune microenvironment [100,101]. In this way, given the duality of EVs in terms of their pro-tumor effects, but also their strong ability to mediate communication in a microenvironment, the strategies for dealing with EVs in cancer are based, on the one hand, on inhibiting EV trafficking as a new method to improve new therapeutic combinations [102] and, on the other hand, on engineering EVs to use them as vectors for therapies [103].…”