Mechanisms of regulation of metastasis by cancer extracellular vesicle-activated pathway

The National Cancer Institute awarded a Cooperative Agreement worth $667,575 to Case Western Reserve University on July 8, 2026, under the Cancer Biology Research program (CFDA 93.396) to investigate mechanisms by which cancer extracellular vesicles drive breast cancer metastasis and to evaluate therapeutic interventions targeting this pathway.

The research will examine the role of kindlin-2 (K2), an oncogenic protein enriched in small extracellular vesicles (SEVs) secreted by breast cancer cells, in tumor progression and metastatic spread. The work uses a multi-method approach including two-dimensional cell cultures, patient-derived three-dimensional organoids, and breast cancer mouse models with primary tumor resection to isolate the effects of SEVs on metastasis. The study will evaluate the impact of blocking nuclear transport of tumor extracellular vesicle cargo, including the use of PRR851, a nuclear transport inhibitor, on K2-driven metastasis. The research will characterize crosstalk between SEVs and the metastatic microenvironment using multi-omics to identify molecular and immune signatures modulated by SEV cargo, with and without K2 expression.

Case Western Reserve University's Office of Research Administration, performing in affiliation with University Hospitals of Cleveland, is the recipient. The period of performance runs from the award date through June 30, 2031, with work performed in Cleveland, Ohio. The Cancer Biology Research program funds fundamental research on cancer cause and nature with the expectation of improving prevention, detection, diagnosis, and treatment of neoplastic diseases.

Abstract

An incomplete understanding of breast cancer (BC) metastasis, the second leading cause of cancer-related death in women, has hindered effective therapeutic development. BC metastases are partly driven by systemic effects, notably through small extracellular vesicles (SEVS) secreted by BC cells, which carry cancer-specific cargo that modulates metastasis in distant microenvironments. The sossey-alaoui lab recently identified the oncogenic axis kindlin-2 (K2) as a key driver of BC metastasis and, with DR. Languino lab showing its enrichment in prostate and BC cell-derived SEVS. K2 is also found in the nucleus, where IT influences cancer cell senescence. The lorico lab discovered a novel nuclear transport (NT) pathway enabling EV- derived cargo to localize to specific sub-nuclear regions, potentially promoting metastasis by concentrating pro-metastatic proteins and rnas. We hypothesize that K2⁺ SEVS play a central role in initiating metastasis, and that depleting K2 or blocking its nuclear entry can hinder metastatic progression by reshaping the metastatic microenvironment (MME). Based on this, our study aims to: (I) investigate the role of K2⁺ SEVS in tumor progression and metastasis using 2D cultures, patient-derived 3D organoids, and BC mouse models with primary tumor resection to isolate the effects of SEVS on metastasis. (II) evaluate the impact of inhibiting NT of tumor EV cargo, including using PRR851, a specific NT inhibitor developed by the lorico lab, on K2- driven metastasis. (II) characterize the crosstalk between SEVS and the metastasis microenvironment (MME) using multi-omics to identify molecular and immune signatures modulated by SEV cargo, with and without K2 expression. This research will define how K2⁺- SEVS and their nuclear entry influence metastasis and MME remodeling. Our systems-level approach aligns with and enhances ongoing projects within the metnet consortium. All data will be shared via an established data-sharing framework, supporting broader collaborative efforts in BC metastasis research. Notably, our proposal is the first within metnet to focus on the systemic role of SEVS in metastatic progression.