Neuronal mimicry generates an ecosystem critical for brain metastatic growth of SCLC

Abstract

Brain metastasis is a major cause of morbidity and mortality in cancer patients. Here we investigated mechanisms allowing small-cell lung cancer (SCLC) cells to grow in the brain. We show that SCLC cells undergo a cell state transition towards neuronal differentiation during tumor progression and metastasis, and that this neuronal mimicry is critical for SCLC growth in the brain. Mechanistically, SCLC cells re-activate astrocytes, which in turn promote SCLC growth by secreting neuronal pro-survival factors such as SERPINE1. We further identify Reelin, a molecule important in brain development, as a factor secreted by SCLC cells to recruit astrocytes to brain metastases in mice. This recruitment of astrocytes by SCLC was recapitulated in assembloids between SCLC aggregates and human cortical spheroids. Thus, SCLC brain metastases grow by co-opting mechanisms involved in reciprocal neuron-astrocyte interactions during development. Targeting such developmental programs activated in this cancer ecosystem may help treat brain metastases.

Neuronal-Activity Dependent Mechanisms of Small Cell Lung Cancer Progression

“…3b). When comparing murine SCLC cells transplanted to the flank or to the brain of mice 33 , we found a substantial number of SCLC genes upregulated in the context of the brain that overlapped with the genes found to be upregulated in the presence of neuronal co-cultures (Extended Data Fig. 3c).…”

“…Higher levels of these neuronal markers correlate with shorter survival and more metastatic disease [30][31][32] . Recently, studies have found that these neuronal gene expression programs in SCLC are implicated in driving metastatic progression by facilitating interactions with astrocytes in the brain microenvironment 33 . Yet, whether neuronal activity may be a regulator of progression and metastatic ability is not yet understood.…”

Lineage Plasticity in SCLC Generates Non-Neuroendocrine Cells Primed for Vasculogenic Mimicry

“…4H ). The VM-associated anticoagulant 42 and SCLC brain metastasis colonization factor 55 SERPINE1 , the angiogenesis-associated AXL receptor tyrosine kinase, 56 master-regulator of VM FOXC2 46 and endothelial-associated genes 57 were all significantly up-regulated in non-NE compared with NE cells ( Fig. 4H and I ).…”

Lineage plasticity in SCLC generates non-neuroendocrine cells primed for vasculogenic mimicry

“…The top 25 upregulated genes (>80 fold) in CDX non-NE cells included cell-cell adhesion receptor vascular cell adhesion molecule-1 ( VCAM1 ), cell-ECM adhesion receptor ITGA11 and multiple fibrillar and basement membrane collagen genes ( COL1A1, COL4A1, COL4A2, COL8A1, COL5A1 and COL12A1 ) (Figure 4H). The VM-associated anticoagulant 28 and SCLC brain metastasis colonization factor 40 SERPINE1 , the angiogenesis associated AXL receptor tyrosine kinase 41 , master-regulator of VM FOXC2 (Cannell et al ., under revision) and endothelial-associated genes 32 were all significantly upregulated in non-NE compared to NE cells (Figures 4H, 4I). Increased expression of COL1A1, ITGA11 and AXL proteins in non-NE CDX cells compared to their NE counterparts was confirmed in ex vivo cultures (Figure 4J).…”