Lysosomal transmembrane protein TMEM106B alters TFEB signaling and the tumor immune microenvironment

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NOVEL REGULATORS OF CELLULAR SECRETION ALTER THE TUMOR MICROENVIRONMENT TO DRIVE METASTASIS

Lung cancer is a highly aggressive disease responsible for ~25% of all cancer-related deaths, due in part to its proclivity to metastasize. Treating metastasis holds potential for improving patient survival but requires a deeper investigation into the underlying mechanisms. Some of these processes that can regulate metastasis are: (1) Oncogenic targets of epithelial micro-RNAs (miRNAs) are epigenetically de-repressed upon loss of the miRNAs during epithelial-to-mesenchymal transition (EMT) and in cancer. EMT confers plasticity and fitness to cancer cells promoting their survival through the metastatic cascade. This cascade and EMT are initiated by loss of the miRNA200 family (miR-200) and the miRNA-96 cluster (miR~96), which allows its targets to be de-repressed in mesenchymal cells. Targets that are upregulated by the loss of miR-200 and miR~96 are Zeb1 and Foxf2, which associate with metastasis and poor patient prognosis. (2) Altered Golgi morphology and enhanced Golgi exocytosis during EMT promotes lung cancer metastasis. Zeb1-mediated EMT regulates Golgi dynamics and integrity, thereby enhancing and polarizing Golgi exocytosis to the invasive front of the tumors to promote metastasis. Altered Golgi functions promote secretion of extracellular components like MMPs, collagens, glycosaminoglycans, cytokines, etc., thus priming the tumor microenvironment for malignancy. However, the drivers that orchestrate these changes in the Golgi remain undefined. Additionally, inhibiting Golgi secretion has been unsuccessful for treating metastatic lung cancer in the clinic. Thus, improving our understanding of regulators of Golgi integrity and exocytosis will aid in impeding this dynamic process to treat metastasis. In this dissertation, using a high-throughput invasion screen, I established Impad1 and Kdelr2 as robust, independent drivers of lung cancer invasion and metastasis. I further elucidated that Impad1 is a novel target of the epithelial miRNAs, miR-200 and miR~96, and is de-repressed during EMT. Impad1 modulates Golgi morphology, and vesicular trafficking through its interaction with a trafficking protein, Syt11. These changes in the Golgi dynamics alter the extracellular matrix and the immune landscape to promote invasion and metastasis. Inhibiting Impad1 disrupted the cancer cell secretome, reversed the invasive phenotype, and enhanced anti-tumor immune surveillance. I identified Impad1 as a novel functional link that connects EMT- and Golgi secretome-mediated changes to lung cancer metastasis. Additionally, I demonstrated that Kdelr2 also enhances Golgi-mediated exocytosis of MMPs to drive invasion and metastasis; however, it works independent of EMT. Hence, the data highlights that EMT is sufficient but not necessary to modulate Golgi dynamics and secretion during cancer malignancy. Collectively, this work signifies the importance of the Golgi and cellular secretion in lung cancer progression. Moreover, it also establishes novel drivers that can be targeted to control Golgi-mediated exocytosis, thereby impeding metastatic disease

Dance of The Golgi: Understanding Golgi Dynamics in Cancer Metastasis

The Golgi apparatus is at the center of protein processing and trafficking in normal cells. Under pathological conditions, such as in cancer, aberrant Golgi dynamics alter the tumor microenvironment and the immune landscape, which enhances the invasive and metastatic potential of cancer cells. Among these changes in the Golgi in cancer include altered Golgi orientation and morphology that contribute to atypical Golgi function in protein trafficking, post-translational modification, and exocytosis. Golgi-associated gene mutations are ubiquitous across most cancers and are responsible for modifying Golgi function to become pro-metastatic. The pharmacological targeting of the Golgi or its associated genes has been difficult in the clinic; thus, studying the Golgi and its role in cancer is critical to developing novel therapeutic agents that limit cancer progression and metastasis. In this review, we aim to discuss how disrupted Golgi function in cancer cells promotes invasion and metastasis