RESUMO
Transforming growth factor-beta (TGFß) is a multifunctional cytokine with a well-established role in mammary gland development and both oncogenic and tumor-suppressive functions. The extracellular matrix (ECM) indirectly regulates TGFß activity by acting as a storage compartment of latent-TGFß, but how TGFß is released from the ECM via proteolytic mechanisms remains largely unknown. In this study, we demonstrate that hepsin, a type II transmembrane protease overexpressed in 70% of breast tumors, promotes canonical TGFß signaling through the release of latent-TGFß from the ECM storage compartment. Mammary glands in hepsin CRISPR knockout mice showed reduced TGFß signaling and increased epithelial branching, accompanied by increased levels of fibronectin and latent-TGFß1, while overexpression of hepsin in mammary tumors increased TGFß signaling. Cell-free and cell-based experiments showed that hepsin is capable of direct proteolytic cleavage of fibronectin but not latent-TGFß and, importantly, that the ability of hepsin to activate TGFß signaling is dependent on fibronectin. Altogether, this study demonstrates a role for hepsin as a regulator of the TGFß pathway in the mammary gland via a novel mechanism involving proteolytic downmodulation of fibronectin.
Assuntos
Fibronectinas , Fator de Crescimento Transformador beta , Animais , Fibronectinas/metabolismo , Camundongos , Proteólise , Serina Endopeptidases/genética , Fator de Crescimento Transformador beta/metabolismoRESUMO
Elevated MYC expression sensitizes tumor cells to apoptosis but the therapeutic potential of this mechanism remains unclear. We find, in a model of MYC-driven breast cancer, that pharmacological activation of AMPK strongly synergizes with BCL-2/BCL-XL inhibitors to activate apoptosis. We demonstrate the translational potential of an AMPK and BCL-2/BCL-XL co-targeting strategy in ex vivo and in vivo models of MYC-high breast cancer. Metformin combined with navitoclax or venetoclax efficiently inhibited tumor growth, conferred survival benefits and induced tumor infiltration by immune cells. However, withdrawal of the drugs allowed tumor re-growth with presentation of PD-1+/CD8+ T cell infiltrates, suggesting immune escape. A two-step treatment regimen, beginning with neoadjuvant metformin+venetoclax to induce apoptosis and followed by adjuvant metformin+venetoclax+anti-PD-1 treatment to overcome immune escape, led to durable antitumor responses even after drug withdrawal. We demonstrate that pharmacological reactivation of MYC-dependent apoptosis is a powerful antitumor strategy involving both tumor cell depletion and immunosurveillance.
Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Genes myc/efeitos dos fármacos , Imunoterapia , Compostos de Anilina/farmacologia , Animais , Anticorpos Monoclonais Humanizados , Apoptose/imunologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linfócitos T CD8-Positivos , Linhagem Celular Tumoral/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Combinação de Medicamentos , Feminino , Células HEK293 , Xenoenxertos , Humanos , Metformina/farmacologia , Camundongos , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-bcl-2 , Sulfonamidas/farmacologia , Proteína bcl-XRESUMO
The original version of this Article contained an error in Fig. 7. In panel b, the survival curves were shifted relative to the y axis. This error has been corrected in both the PDF and HTML versions of the Article.