Lack of caspase 8 directs neuronal progenitor-like reprogramming and small cell lung cancer progression
Abstract
Abstract Most neuroendocrine cancers lack caspase 8 protein expression. While this feature was thought to facilitate escape from extrinsic apoptosis, its cancer-regulatory function has remained unexplored. Here, we devise a mouse model of small cell lung cancer (SCLC) recapitulating the lack of expression of caspase 8 seen in humans and uncover an unexpected role for necroptosis-fueled pre-tumoral inflammation resulting in reprogramming towards a neuronal progenitor cell-like state and increased metastatic disease. Notably, transcriptional signatures of this cellular state are enriched in relapsed and metastatic human SCLC. Mechanistically, caspase 8 loss within the pre-tumoral niche promotes inflammation marked by increased recruitment of regulatory T cells (Tregs) which are responsible for the promotion of metastatic disease. Importantly, inactivation of the necroptosis executioner MLKL reverses pre-tumoral inflammation, decreases metastasis as well as neuronal-like reprogramming. Taken together, our findings suggest that pre-tumoral inflammatory cell death contributes to neuronal progenitor mimicry, immunosuppression and increased metastasis in SCLC.
Article Details
Authors (33)
Ariadne Androulidaki
Fanyu Liu
Christina M. Bebber
Ilmars Kisis
Vignesh Sakthivelu
Pascal Hunold
Lioba Koerner
Alina Dahlhaus
Fatma Isil Yapici
Christina Grimm
Alicja Pacholewska
Sofya Tishina
Franka Doskotz
Lucia A. Torres Fernández
Jenny Stroh
Ali T. Abdallah
Julia Beck
Lejla Mulalic
Anna Schmitt
Holger Grüll
Thorsten Persigehl
Alexander Quaas
Martin Peifer
Johannes Brägelmann
H. Christian Reinhardt
Pascal Nieper
Robert Hänsel-Hertsch
Roman K. Thomas
Julie George
Michal R. Schweiger
Manolis Pasparakis
Filippo Beleggia
Silvia von Karstedt