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 (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.

Correction: An activity-based fluorescent sensor with a penta-coordinate N-donor binding site detects Cu ions in living systems.

Correction for 'An activity-based fluorescent sensor with a penta-coordinate N-donor binding site detects Cu ions in living systems' by Kunika Gupta et al., Chem. Commun., 2023, 59, 8282-8285, https://doi.org/10.1039/D3CC02201C.

An activity-based fluorescent sensor with a penta-coordinate N-donor binding site detects Cu ions in living systems.

An activity-based sensor afforded a 63 times fluorescence-enhancement with Cu2+/Cu+ ions and could image Cu2+/Cu+ in living cells and in a multicellular organism. The sensor functioned only in the presence of ambient dioxygen and glutathione, and the characterization of intermediates and products hinted toward a sensing mechanism involving a CuII hydroperoxo species.