Claudio Ballabio

Abstract

Tumour intrinsic electrical activity drives small-cell lung cancer progression

Elevated or ectopic expression of neuronal receptors and ion channels promotes tumour progression in many cancer types, and neuroendocrine (NE) transformation of various adenocarcinomas has been associated with increased aggressiveness. Whether the prototypic neuronal feature, namely electrical excitability, exists in cancer cells and whether this impacts cancer progression remains mostly unexplored.

Small cell lung cancer (SCLC) is a poster child of highly aggressive NE cancers, comprised of two major distinct subtypes of cancer cells: NE cells and non-NE cells. We demonstrated that the NE cells are excitable, like neurons, while non-NE cells cannot fire action potentials, akin to astrocytes and other non-excitable cells.

Action potential firing in NE cells directly promotes SCLC malignancy; however, the high ATP demands of electrical activity also lead to unusual dependency on oxidative phosphorylation (OXPHOS) in NE cells, distinct from most cancer cells reported in the literature, which are non-excitable and heavily rely on aerobic glycolysis.

Notably, we found that non-NE cells metabolically support NE cells to sustain the ATP demand, promoting their excitability and malignancy. The drastic changes in the innervation landscape during SCLC progression might reflect a transition from the initial dependency of early-stage SCLC on external factors, namely cholinergic innervation in the tumour microenvironment, to a full-blown tumour autonomous vicious cycle, driven by cancer cell intrinsic electrical activity. This enables long-term tumorigenic capability and metastatic potential.