2. Academic Validation
  3. Chromosomal 3q amplicon encodes essential regulators of secretory vesicles that drive secretory addiction in cancer

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

  • J Clin Invest. 2024 Apr 25:e176355. doi: 10.1172/JCI176355.
Xiaochao Tan 1,  Shike Wang 1,  Guan-Yu Xiao 1,  Chao Wu 1,  Xin Liu 1,  Biyao Zhou 1,  Jiang Yu 1,  Dzifa Yawa Duose 2,  Yuanxin Xi 3,  Jing Wang 3,  Kunika Gupta 4,  Apar Pataer 5,  Jack A Roth 5,  Michael P Kim 6,  Fengju Chen 7,  Chad J Creighton 7,  William K Russell 8,  Jonathan M Kurie 1
Affiliations

Affiliations

  • 1 Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, United States of America.
  • 2 Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, United States of America.
  • 3 Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, United States of America.
  • 4 Department of Chemical Sciences, Tata Institute of Fundamental Research, Mumbai, India.
  • 5 Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, United States of America.
  • 6 Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, United States of America.
  • 7 Department of Medicine and Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, United States of America.
  • 8 Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, United States of America.
PMID: 38662435 DOI: 10.1172/JCI176355
Abstract

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.

Keywords

Cancer gene therapy; Cell biology; Lung cancer; Oncology; Protein traffic.

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