RESUMO
Neutrophil extracellular traps (NETs), which consist of chromatin DNA filaments coated with granule proteins, are released by neutrophils to trap microorganisms1-3. Recent studies have suggested that the DNA component of NETs (NET-DNA) is associated with cancer metastasis in mouse models4-6. However, the functional role and clinical importance of NET-DNA in metastasis in patients with cancer remain unclear. Here we show that NETs are abundant in the liver metastases of patients with breast and colon cancers, and that serum NETs can predict the occurrence of liver metastases in patients with early-stage breast cancer. NET-DNA acts as a chemotactic factor to attract cancer cells, rather than merely acting as a 'trap' for them; in several mouse models, NETs in the liver or lungs were found to attract cancer cells to form distant metastases. We identify the transmembrane protein CCDC25 as a NET-DNA receptor on cancer cells that senses extracellular DNA and subsequently activates the ILK-ß-parvin pathway to enhance cell motility. NET-mediated metastasis is abrogated in CCDC25-knockout cells. Clinically, we show that the expression of CCDC25 on primary cancer cells is closely associated with a poor prognosis for patients. Overall, we describe a transmembrane DNA receptor that mediates NET-dependent metastasis, and suggest that targeting CCDC25 could be an appealing therapeutic strategy for the prevention of cancer metastasis.
Assuntos
Neoplasias da Mama/patologia , DNA/metabolismo , Armadilhas Extracelulares/genética , Proteínas de Membrana/metabolismo , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Neutrófilos/metabolismo , Actinina/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Feminino , Humanos , Fígado/patologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Proteínas de Membrana/genética , Camundongos , Prognóstico , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de SinaisRESUMO
Bispecific antibodies (bsAbs) refer to a large family of molecules that recognize two different epitopes or antigens. Although a series of challenges, especially immunogenicity and chain mispairing issues, once hindered the development of bsAbs, they have been gradually overcome with the help of rapidly developing technologies in the past 5 decades. In the meantime, an increasing number of bsAb platforms have been designed to satisfy different clinical demands. Currently, numerous preclinical and clinical trials are underway, portraying a promising future for bsAb-based cancer treatment. Nevertheless, bsAb drugs still face enormous challenges in their application as cancer therapeutics, including tumor heterogeneity and mutational burden, intractable tumor microenvironment (TME), insufficient costimulatory signals to activate T cells, the necessity for continuous injection, fatal systemic side effects, and off-target toxicities to adjacent normal cells. Therefore, we provide several strategies as solutions to these issues, which comprise generating multispecific bsAbs, discovering neoantigens, combining bsAbs with other anticancer therapies, exploiting natural killer (NK)-cell-based bsAbs and producing bsAbs in situ. In this review, we mainly discuss previous and current challenges in bsAb development and underscore corresponding strategies, with a brief introduction of several typical bsAb formats.