p62/sequestosome-1 (SQSTM1) is a multifunctional adaptor protein and autophagic substrate which accumulates in cells with hyperactive mTORC1, such as kidney cells with mutations in the tumor suppressor genes TSC1 or TSC2. Here we report that p62 is a critical mediator of TSC2-driven tumorigenesis, as Tsc2+/− and Tsc2f/f Ksp-CreERT2+ mice crossed to p62−/− mice were protected from renal tumor development. Metabolic profiling revealed that depletion of p62 in Tsc2-null cells decreased intracellular glutamine, glutamate, and glutathione (GSH). p62 positively regulated the glutamine transporter Slc1a5 and increased glutamine uptake in Tsc2-null cells. We also observed p62-dependent changes in Gcl, Gsr, Nqo1 and Srxn1 which were decreased by p62 attenuation and implicated in GSH production and utilization. p62 attenuation altered mitochondrial morphology, reduced mitochondrial membrane polarization and maximal respiration, and increased mitochondrial ROS and mitophagy marker PINK1. These mitochondrial phenotypes were rescued by addition of exogenous GSH and overexpression of Sod2, which suppressed indices of mitochondrial damage and promoted growth of Tsc2-null cells. Finally, p62 depletion sensitized Tsc2-null cells to both oxidative stress and direct inhibition of glutathione biosynthesis by buthionine sulfoximine (BSO). Our findings show how p62 helps maintain intracellular pools of glutathione needed to limit mitochondrial dysfunction in tumor cells with elevated mTORC1, highlighting p62 and redox homeostasis as nodal vulnerabilities for therapeutic targeting in these tumors.

Bone metastasis is present in a high percentage of breast cancer (BCa) patients with distant disease, especially in those with the estrogen receptor‐positive (ER+) subtype. Most cells that escape primary tumors are unable to establish metastatic lesions, which suggests that target organ microenvironments are hostile for tumor cells. This implies that BCa cells must achieve a process of speciation to adapt to the new conditions imposed in the new organ. Bone has unique characteristics that can be exploited by cancer cells: it undergoes constant remodeling and comprises diverse environments (including osteogenic, perivascular, and hematopoietic stem cell niches). This allows colonizing cells to take advantage of numerous adhesion molecules, matrix proteins, and soluble factors that facilitate homing, survival, and, eventually, metastatic outgrowth. However, in most cases, metastatic lesions enter into a latency state that can last months, years, or even decades, before forming a clinically detectable macrometastasis. This dormant state challenges the effectiveness of adjuvant chemotherapy. Detecting which tumors are more prone to metastasize to bone and developing new specific therapies that target bone metastasis represent urgent clinical needs. Here, we review the biological mechanisms of BCa bone metastasis and provide the latest options of treatments and predictive markers that are currently in clinical use or are being tested in clinical assays. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Inhibitors of the mechanistic target of rapamycin (mTOR) are currently used to treat advanced metastatic breast cancer. However, whether an aggressive phenotype is sustained through adaptation or resistance to mTOR inhibition remains unknown. Here, complementary studies in human tumors, cancer models and cell lines reveal transcriptional reprogramming that supports metastasis in response to mTOR inhibition. This cancer feature is driven by EVI1 and SOX9. EVI1 functionally cooperates with and positively regulates SOX9, and promotes the transcriptional upregulation of key mTOR pathway components (REHB and RAPTOR) and of lung metastasis mediators (FSCN1 and SPARC). The expression of EVI1 and SOX9 is associated with stem cell-like and metastasis signatures, and their depletion impairs the metastatic potential of breast cancer cells. These results establish the mechanistic link between resistance to mTOR inhibition and cancer metastatic potential, thus enhancing our understanding of mTOR targeting failure.