Fingleton, B. | Search bioRxiv

bioRxiv2026

Regulation of tumor proliferation by unlocking silent synapses on metastatic cancer cells

Several studies have revealed deleterious synapse formation onto cancer cells within the brain tumor microenvironment, yet these synapses are [~]100-fold weaker in presynaptic release rates and postsynaptic strength relative to bona fide synapses formed between neurons. Here, we find that most of the functional synapses on tumor cells are kept dormant and can be unlocked by overcoming GABAB receptor-mediated metabotropic signaling in neurons. Scavenging G{beta}{gamma} signaling in neurons increased presynaptic release probability on tumor cells and augmented cancer cell proliferation. Optical analysis of the tumor microenvironment revealed regulated secretion of neurotransmitters from tumor cells in response to GABAB receptor inhibition or electrical stimulation. These results reveal how cancer cells with a high propensity for brain metastasis leverage precise moments of aberrant excitation between neurons to engage reciprocal interactions that ultimately fuel cancer proliferation.

neuroscience↗

bioRxiv2024

Trem2 deficiency attenuates breast cancer tumor growth in lean, but not obese or weight loss, mice and is associated with alterations of clonal T cell populations

AbstractObesity is an established risk factor for breast cancer development and worsened prognosis; however, the mechanisms for this association - and the potential benefits of weight loss - have not been fully explored. The adipose environment surrounding breast tumors, which is inflamed in obesity, has been implicated in tumor progression. An emerging therapeutic target for cancer is TREM2, a transmembrane receptor of the immunoglobulin superfamily that is expressed on macrophages in adipose tissue and tumors. We utilized genetic loss of function (Trem2+/+ and Trem2-/-) models and dietary (lean, obese, and weight loss) intervention approaches to examine impacts on postmenopausal breast cancer. Remarkably, Trem2 deficiency ameliorated tumor growth in lean, but not obese or weight loss mice. Single-cell RNA sequencing, in conjunction with VDJ sequencing of tumor and tumor-adjacent mammary adipose tissue (mATTum-adj) immune cells, revealed that tumors of lean Trem2-/- mice exhibited a shift in clonal CD8+ T cells from an exhausted to an effector memory state, accompanied with increased clonality of CD4+ Th1 cells, that was not observed in any other diet-genotype group. Notably, identical T cell clonotypes were identified in the tumor and mATTum-adj of the same mouse. Finally, an immune checkpoint study demonstrated that PD-1 therapy restricted tumor growth in lean and weight loss, but not obese mice. We conclude that weight history is relevant when considering potential efficacy of TREM2 inhibition in postmenopausal breast cancer. This work reveals immunological interactions between tumors and surrounding adipose tissue, highlighting significant differences under obese and weight loss conditions.

cancer biology↗