Necroptosis triggers inflammatory interferon signatures in patient-derived metastatic breast cancer organoids

Resistance to chemotherapy and programmed cell death (PCD), including apoptosis, strongly affects BC therapy success and remains a major challenge. Although necroptosis, a lytic, and via damage-associated molecular patterns (DAMP) release, highly immunogenic mode of PCD, might overcome apoptosis resistance, there is an urgent need for physiological and translational human models to model necroptosis and PCD resistance in BC.

Here, we apply 3D patient-derived, metastatic human mammary organoids (hMOs) to model apoptosis resistance, necroptosis and inflammatory signaling using single-cell CITE-sequencing, time-lapse live cell brightfield and immunofluorescent confocal microscopy as well as biochemical approaches. Smac mimetic-triggered apoptosis triggered could be confirmed in a panel of BC hMOs. Upon inducing apoptosis resistance with caspase inhibition, BC hMOs rapidly undergo necroptosis with profound MLKL phosphorylation.