Lysosomal TMEM9‐LAMTOR4‐controlled mTOR signaling integrity is required for mammary tumorigenesis

Abstract

Lysosomes play vital roles in the degradation and recycling of various macromolecules, protein secretion, energy metabolism, and cell signaling. Increasing evidence suggests that deregulated lysosomes contribute to tumorigenesis. However, the underlying mechanisms of lysosomal deregulation in cancer remain elusive. We herein identified transmembrane protein 9 (TMEM9) as a crucial protein that modulates lysosomal metabolism and lysosome-associated signaling.The TMEM9 gene is markedly amplified in breast cancer, correlated with its transcriptional upregulation. TMEM9 depletion suppressed the proliferation of TMEM9 high breast cancer cells.Consistently, Tmem9 knockout inhibited mammary tumorigenesis in the genetically engineered mouse model. Conversely, the ectopic expression of TMEM9 in TMEM9 low breast cancer cells promoted cell proliferation. The lysosome purification and proteomics approach showed that TMEM9 physically and functionally interacts with LAMTOR4, a subunit of the Ragulator complex, to hyperactivate mTOR signaling in breast cancer. Moreover, the pharmacological blockade of the TMEM9-v-ATPase axis, combined with mTOR inhibitors, exhibited the synergistic growth inhibition of breast cancer cells. Our results reveal the mechanism of TMEM9-v-ATPase-activated mTOR signaling and further indicate that the TMEM9-v-ATPase axis is a therapeutic target for overcoming mTOR inhibitor resistance in breast cancer.

TMEM9 promotes lung adenocarcinoma progression via activating the MEK/ERK/STAT3 pathway to induce VEGF expression

“…It has been reported that TMEM9 promotes the proliferation of breast cancer and HCC cells [7,8]. In the study, we demonstrated that TMEM9 increased the proliferation and migration of LUAD.…”

“…In the study, we investigated the expression and function of TMEM9 in LUAD and demonstrated that TMEM9 promoted tumor cell proliferation, migration, and angiogenesis via increasing VEGF expression and secretion. Recently, several studies have reported that TMEM9 was overexpressed in multiple cancers and significantly correlated with poor prognosis [8][9][10]. Our results showed that TMEM9 mRNA and protein expression in LUAD tissues was higher than those in normal peritumorial tissues.…”

“…In addition, several studies showed that TMEM9 could facilitate the assembly of v-ATPase, which leads to vesicular acidification and lysosomal dysfunction that promotes tumor occurrence in hepatocellular carcinoma and colorectal cancer [7,9]. Zhang et al have recently established the significance of the lysosomal TMEM9-V-ATPase -regulator -Rag axis as a crucial regulator of mTOR signal integrity and proliferation of breast cancer cells [8]. This axis also influences the sensitivity of breast cancer cells to mTOR inhibitors, thereby presenting itself as a promising molecular target for breast cancer treatment and a therapeutic target for mTOR inhibitor-resistant patients.…”

“…Transmembrane protein 9 (TMEM9), a type I transmembrane protein situated in late endosomes and lysosomes, spans 183 amino acids and features a signal peptide and three glycosylation sites at the amino terminus [5]. TMEM9 has been implicated in various cellular mechanisms, including inflammation [6], tissue regeneration [7], cell differentiation, and tumorigenesis [8]. Many studies have demonstrated that TMEM9 is highly expressed in multiple human cancers, such as mammary tumors and hepatocellular and colorectal cancer [9].…”

Molecular subtype identification and prognosis stratification based on lysosome-related genes in breast cancer

“…Additionally, targeting HSPA8 by downregulating BCR-ABL can enhance the chemotherapy sensitivity of chronic myeloid leukemia cells [ 30 ]. The lysosomal TMEM9-LAMTOR axis has been found to play an important role in controlling mTOR signaling integrity in breast tumor development [ 31 ]. PSMD1 is a 26S proteasome subunit that regulates breast cancer cell growth by degrading p53 protein [ 32 ].…”