1. Chromosomal 3q amplicon encodes essential regulators of secretory vesicles that drive secretory addiction in cancer
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Tan, Xiaochao, Wang, Shike, Xiao, Guan-Yu, Wu, Chao, Liu, Xin, Zhou, Biyao, Jiang, Yu, Duose, Dzifa Y., Xi, Yuanxin, Wang, Jing, Gupta, Kunika, Pataer, Apar, Roth, Jack A., Kim, Michael P., Chen, Fengju, Creighton, Chad J., Russell, William K., and Kurie, Jonathan M.
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Oncology, Experimental ,Gene expression -- Research ,Cell organelles -- Health aspects -- Genetic aspects ,Gene amplification -- Research ,Cancer -- Genetic aspects -- Development and progression -- Research ,Chromosomes -- Health aspects ,Health care industry - Abstract
Cancer cells exhibit heightened secretory states that drive tumor progression. Here, we identified a chromosome 3q amplicon that serves as a platform for secretory regulation in cancer. The 3q amplicon encodes multiple Golgi-resident proteins, including the scaffold Golgi integral membrane protein 4 (GOLIM4) and the ion channel ATPase secretory pathway [Ca.sup.2+] transporting 1 (ATP2C1). We show that GOLIM4 recruited ATP2C1 and Golgi phosphoprotein 3 (GOLPH3) to coordinate [Ca.sup.2+]-dependent cargo loading, Golgi membrane bending, and vesicle scission. GOLIM4 depletion disrupted the protein complex, resulting in a secretory blockade that inhibited the progression of 3q-amplified malignancies. In addition to its role as a scaffold, GOLIM4 maintained intracellular manganese (Mn) homeostasis by binding excess Mn in the Golgi lumen, which initiated the routing of Mn-bound GOLIM4 to lysosomes for degradation. We show that Mn treatment inhibited the progression of multiple types of 3q-amplified malignancies by degrading GOLIM4, resulting in a secretory blockade that interrupted prosurvival autocrine loops and attenuated prometastatic processes in the tumor microenvironment. As it potentially underlies the selective activity of Mn against 3q-amplified malignancies, ATP2C1 coamplification increased Mn influx into the Golgi lumen, resulting in a more rapid degradation of GOLIM4. These findings show that functional cooperativity between coamplified genes underlies heightened secretion and a targetable secretory addiction in 3q-amplified malignancies., Introduction In one working hypothesis, cancer cells are the primary architects of the tumor microenvironment (1). Despite a large body of preclinical evidence supporting their antitumor activities (1), strategies to [...]
- Published
- 2024
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