Roberts-Thomson, S. J. | Search bioRxiv

bioRxiv2025

Simultaneous single cell imaging of calcium signal dynamics in breast cancer and neural cells reveals communication in a model of brain metastasis

The brain provides a unique metastatic microenvironment for breast cancer cells, where calcium signaling dynamics play critical roles in both cancer cell behavior and normal brain function. Calcium signal-mediated communication between breast cancer and neural cells has not yet been demonstrated through selective activation of breast cancer cells at the single cell level. To address this, we combined neural matrices of differentiated human neural progenitor cells with breast cancer cells expressing spectrally distinct genetically encoded calcium indicators. Specific activation of breast cancer cells increased calcium signaling activity in neural matrices with distinct temporal and spatial characteristics. Neural matrices also remodeled the expression of calcium-sensitive transcription factor SOX2 in a manner dependent on proximity to breast cancer cells. This work is the first simultaneous single-cell assessment of calcium signaling dynamics between breast cancer cells and neural cells modelling interactions within the brain metastatic niche.

cancer biology↗

bioRxiv2023

Spatial architecture of high-grade glioma reveals tumor heterogeneity within distinct domains

High-grade gliomas are aggressive primary brain cancers with poor response to standard regimens, driven by immense heterogeneity. In isocitrate dehydrogenase (IDH) wild-type high-grade glioma (glioblastoma, GBM), increased intra-tumoral heterogeneity is associated with more aggressive disease. Recently, spatial technologies have emerged to dissect this complex heterogeneity within the tumor ecosystem by preserving cellular organization in situ. Here, we construct a high-resolution molecular landscape of GBM and IDH-mutant high-grade glioma patient samples to investigate the cellular subtypes and spatial communities that compose high-grade glioma using digital spatial profiling and spatial molecular imaging. This uncovered striking diversity of the tumor and immune microenvironment, that is embodied by the heterogeneity of the inferred copy-number alterations in the tumor. Reconstructing the tumor architecture revealed two distinct niches, one composed of tumor cell states that most closely resemble normal glial cells, associated with microglia; and the other niche populated by monocytes and mesenchymal tumor cells. We further reveal that communication between tumor and immune cells is underpinned by tumor-specific ligands, such as TGF{beta} signaling in astrocyte-like tumor cells. This primary study reveals high levels of intra-tumoral heterogeneity in high-grade gliomas, associated with a diverse immune landscape within spatially localized regions.

cancer biology↗