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

Authors

Xiaochao Tan, The University of Texas MD Anderson Cancer CenterFollow
Shike Wang, The University of Texas MD Anderson Cancer Center
Guan-Yu Xiao, The University of Texas MD Anderson Cancer Center
Chao Wu, The University of Texas MD Anderson Cancer Center
Xin Liu, The University of Texas MD Anderson Cancer Center
Biyao Zhou, The University of Texas MD Anderson Cancer Center
Yu Jiang, The University of Texas MD Anderson Cancer Center
Dzifa Y. Duose, The University of Texas MD Anderson Cancer Center
Yuanxin Xi, The University of Texas MD Anderson Cancer Center
Jing Wang, The University of Texas MD Anderson Cancer Center
Kunika Gupta, Tata Institute of Fundamental Research
Apar Pataer, The University of Texas MD Anderson Cancer Center
Jack A. Roth, The University of Texas MD Anderson Cancer Center
Michael P. Kim, The University of Texas MD Anderson Cancer Center
Fengju Chen, Baylor College of Medicine
Chad J. Creighton, Baylor College of Medicine
William K. Russell, The University of Texas Medical Branch
Jonathan M. Kurie, The University of Texas MD Anderson Cancer CenterFollow

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 Ca2+ transporting 1 (ATP2C1). We show that GOLIM4 recruited ATP2C1 and Golgi phosphoprotein 3 (GOLPH3) to coordinate Ca2+ -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.

Document Type

Article

Publication Date

4-12-2024

Notes/Citation Information

© 2024, Tan et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Digital Object Identifier (DOI)

https://doi.org/10.1172/JCI176355

Funding Information

This work was supported in part by grants from the NIH (R01CA236781 and R01CA255021-01, to JMK; P30CA125123, to CKO; U54CA224081, to JAR; and R03CA280382-01, to XT). The UTMB Mass Spectrometry Facility is supported in part by CPRIT grant RP190682 (to WKR). JMK holds the Gloria Lupton Tennison Distinguished Professorship in Lung Cancer. We thank Ankona Datta for sharing the Mn sensor M1.

Repository Citation

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., "Chromosomal 3q amplicon encodes essential regulators of secretory vesicles that drive secretory addiction in cancer" (2024). Markey Cancer Center Faculty Publications. 223.
https://uknowledge.uky.edu/markey_facpub/223