Chromosomal 3q amplicon encodes essential regulators of secretory vesicles that drive secretory addiction in cancer

Cancer cells exhibit heightened secretory states that drive tumor progression. Here, we identify 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 (...

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Bibliographic Details
Published in:The Journal of clinical investigation 2024-04, Vol.134 (12)
Main Authors: Tan, Xiaochao, Wang, Shike, Xiao, Guan-Yu, Wu, Chao, Liu, Xin, Zhou, Biyao, Yu, Jiang, Duose, Dzifa Yawa, Xi, Yuanxin, Wang, Jing, Gupta, Kunika, Pataer, Apar, Roth, Jack A, Kim, Michael P, Chen, Fengju, Creighton, Chad J, Russell, William K, Kurie, Jonathan M
Format: Article
Language:English
Subjects:
Cancer
Cell organelles
Chromosomes
Development and progression
Gene amplification
Gene expression
Genetic aspects
Health aspects
Oncology, Experimental
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Summary:Cancer cells exhibit heightened secretory states that drive tumor progression. Here, we identify 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 Ca2+ Transporting 1 (ATP2C1). We show that GOLIM4 recruits ATP2C1 and Golgi phosphoprotein 3 (GOLPH3) to coordinate calcium-dependent cargo loading and Golgi membrane bending and vesicle scission. GOLIM4 depletion disrupts the protein complex, resulting in a secretory blockade that inhibits the progression of 3q-amplified malignancies. In addition to its role as a scaffold, GOLIM4 maintains intracellular manganese (Mn) homeostasis by binding excess Mn in the Golgi lumen, which initiates the routing of Mn-bound GOLIM4 to lysosomes for degradation. We show that Mn treatment inhibits the progression of multiple types of 3q-amplified malignancies by degrading GOLIM4, resulting in a secretory blockade that interrupts pro-survival autocrine loops and attenuates pro-metastatic processes in the tumor microenvironment. Potentially underlying the selective activity of Mn against 3q-amplified malignancies, ATP2C1 co-amplification increases Mn influx into the Golgi lumen, resulting in a more rapid degradation of GOLIM4. These findings show that functional cooperativity between co-amplified genes underlies heightened secretion and a targetable secretory addiction in 3q-amplified malignancies.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI176355