RESUMO
Albeit genetically highly heterogeneous, muscular dystrophies (MDs) share a convergent pathology leading to muscle wasting accompanied by proliferation of fibrous and fatty tissue, suggesting a common MD-pathomechanism. Here we show that mutations in muscular dystrophy genes (Dmd, Dysf, Capn3, Large) lead to the spontaneous formation of skeletal muscle-derived malignant tumors in mice, presenting as mixed rhabdomyo-, fibro-, and liposarcomas. Primary MD-gene defects and strain background strongly influence sarcoma incidence, latency, localization, and gender prevalence. Combined loss of dystrophin and dysferlin, as well as dystrophin and calpain-3, leads to accelerated tumor formation. Irrespective of the primary gene defects, all MD sarcomas share non-random genomic alterations including frequent losses of tumor suppressors (Cdkn2a, Nf1), amplification of oncogenes (Met, Jun), recurrent duplications of whole chromosomes 8 and 15, and DNA damage. Remarkably, these sarcoma-specific genetic lesions are already regularly present in skeletal muscles in aged MD mice even prior to sarcoma development. Accordingly, we show also that skeletal muscle from human muscular dystrophy patients is affected by gross genomic instability, represented by DNA double-strand breaks and age-related accumulation of aneusomies. These novel aspects of molecular pathologies common to muscular dystrophies and tumor biology will potentially influence the strategies to combat these diseases.
Assuntos
Aneuploidia , Dano ao DNA , Músculo Esquelético/patologia , Distrofias Musculares/genética , Sarcoma/genética , Animais , Calpaína/genética , Calpaína/metabolismo , Células Cultivadas , Hibridização Genômica Comparativa , Modelos Animais de Doenças , Disferlina , Distrofina/deficiência , Distrofina/genética , Distrofina/metabolismo , Feminino , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Distrofias Musculares/diagnóstico , Distrofias Musculares/metabolismo , Mutação , N-Acetilglucosaminiltransferases/genética , N-Acetilglucosaminiltransferases/metabolismoRESUMO
Exportin 1 (XPO1), also known as chromosome region maintenance protein 1, plays a crucial role in maintaining cellular homeostasis via the regulated export of a range of cargoes, including proteins and several classes of RNAs, from the nucleus to the cytoplasm. Dysregulation of this protein plays a pivotal role in the development of various solid and haematological malignancies. Furthermore, XPO1 is associated with resistance to several standard-of-care therapies, including chemotherapies and targeted therapies, making it an attractive target of novel cancer therapies. Over the years, a number of selective inhibitors of nuclear export have been developed. However, only selinexor has been clinically validated. The novel mechanism of action of XPO1 inhibitors implies a different toxicity profile to that of other agents and has proved challenging in certain settings. Nonetheless, data from clinical trials have led to the approval of the XPO1 inhibitor selinexor (plus dexamethasone) as a fifth-line therapy for patients with multiple myeloma and as a monotherapy for patients with relapsed and/or refractory diffuse large B cell lymphoma. In this Review, we summarize the progress and challenges in the development of nuclear export inhibitors and discuss the potential of emerging combination therapies and biomarkers of response.