Abstract
Tumor microtubes (TM) enable astrocytoma invasion, network communication, and radioresistance.
Major finding: Tumor microtubes (TM) enable astrocytoma invasion, network communication, and radioresistance.
Mechanism: GAP43 induces the formation of a network of TMs connected by GJA1 to maintain calcium homeostasis.
Impact: Pharmacologic targeting of TMs in radioresistant brain tumors may improve patient survival.
The most common glial brain tumors are astrocytomas (including glioblastomas) and oligodendrogliomas, both of which frequently harbor mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes. However, astrocytomas are highly invasive and have poorer prognosis compared with oligodendrogliomas, which exhibit codeleted chromosomes 1p/19q and are more responsive to therapy. To investigate the underlying mechanisms of this differential radiosensitivity, Osswald and colleagues performed a longitudinal study of orthotopic fluorescently labeled patient-derived glioblastomas. In vivo microscopy revealed the formation of brain parenchyma–infiltrating membrane tubes by tumor cells as a new mechanism of brain invasion. These membrane tubes, termed tumor microtubes (TM), followed axons and formed a multicellular network of ultra-long, long-lived TMs. IDH1 mutant–specific immunostaining revealed that TMs were abundant in patient astrocytomas with intact 1p/19q but were almost nonexistent in oligodendrogliomas harboring codeletion of 1p/19q. Intercellular calcium waves (ICW), which were reduced after treatment with a gap junction blocker, were propagated along astrocytoma TMs in both directions. Furthermore, astrocytoma TMs increased in number and calcium communication in response to cytotoxic radiation. Analysis of The Cancer Genome Atlas dataset revealed that gap junction protein α1 (GJA1, also known as connexin 43) was upregulated in human gliomas harboring intact 1p/19q, and GJA1 immunopositivity was observed at the gap junctions between TMs. Consistent with these findings, GJA1 knockdown resulted in loss of ICW synchronicity and a decrease in TMs, and reduced tumor growth and the radioprotective effect of TMs. Pathway analysis and knockdown experiments identified growth-associated protein 43 (GAP43) as a driver of TM formation, and expression of GAP43 in oligodendrogliomas with codeleted 1p/19q induced TM formation, invasion, and increased radioresistance. Together, these results show how 1p/19q codeletion makes brain tumors more therapeutically sensitive, elucidate the TM-mediated process of glioma invasion, and suggest that the TM network, which drives radioresistance by maintaining cellular homeostasis in gliomas, may be therapeutically targeted.
