Abstract
Metastatic lung cancer is the leading cause of cancer-associated mortality worldwide, therefore necessitating novel approaches to identify specific genetic drivers for lung cancer progression and metastasis. We recently performed an in vivo gain-of-function genetic screen to identify driver genes of lung cancer metastasis. In the study reported here, we identify TMEM106B as a primary robust driver of lung cancer metastasis. Ectopic expression of TMEM106B could significantly promote the synthesis of enlarged vesicular lysosomes that are laden with elevated levels of active cathepsins. In a TFEB-dependent manner, TMEM106B could modulate the expression of lysosomal genes of the coordinated lysosomal expression and regulation (CLEAR) pathway in lung cancer cells and patient samples. We also demonstrate that TMEM106B-induced lysosomes undergo calcium-dependent exocytosis, thereby releasing active lysosomal cathepsins necessary for TMEM106B-mediated cancer cell invasion and metastasis in vivo, which could be therapeutically prevented by pharmacological inhibition of cathepsins. Further, in TCGA LUAD data sets, 19% of patients show elevated expression of TMEM106B, which predicts for poor disease-free and overall-survival.
Highlights
Metastatic lung cancer is the leading cause of cancer-associated mortality worldwide, necessitating novel approaches to identify specific genetic drivers for lung cancer progression and metastasis
Out of the 217 genes screened, we identified 28 potent drivers of lung cancer metastasis (~12% of the screened genes) based on positive enrichment of their associated barcodes in lung metastases
We determined that TMEM106B expression resulted in upregulation of almost all of the coordinated lysosomal expression and regulation (CLEAR) lysosomal genes we examined through RT-qPCR analysis of 393P and 344SQ cells (Fig. 4c and Supplementary Figure 5E), whereas these genes were repressed upon shRNA-mediated TMEM106B knockdown in metastatic lung cancer cells (Fig. 5d and Supplementary Figure 1A)
Summary
Metastatic lung cancer is the leading cause of cancer-associated mortality worldwide, necessitating novel approaches to identify specific genetic drivers for lung cancer progression and metastasis. We recently performed an in vivo gain-of-function genetic screen to identify driver genes of lung cancer metastasis. In the study reported here, we identify TMEM106B as a primary robust driver of lung cancer metastasis. It was reported that overexpression of TMEM106B in neuronal cells resulted in the activation of the lysosomal stress signaling by translocating the transcription factor TFEB, a member of the MiTF family, into the nucleus and up-regulating the coordinated lysosomal expression and regulation (CLEAR) network genes[14]. TMEM106B deregulates lysosome function by affecting lysosomal synthesis and exocytosis in lung cancer cells, resulting in increased release of lysosomal cathepsins into the extracellular matrix, leading to cellular invasion and metastasis. Therapeutic intervention of TMEM106B activity by inhibiting cathepsins in vivo in a metastatic syngeneic mice model with aloxistatin treatment successfully blocks TMEM106B-mediated metastasis
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