Biology subjects

Gray, G. K.

Publications and source records attributed to Gray, G. K..

4 recordsLinked to original sources

bioRxiv2026

Circadian misalignment underlies immune escape in breast cancer

Circadian regulation shapes tissue physiology, yet how it organizes cellular and molecular dynamics within the tumor microenvironment (TME) and influences tumor immunity remains unclear. Using temporal single-nucleus multiomic profiling of mouse breast tumors, we uncovered extensive circadian programs that are both cell-type-specific and shared across the TME, governing proliferation and immune responses. Notably, cancer epithelial cells exhibited global acrophase misalignment relative to immune populations. This intercellular desynchrony manifests as temporal decoupling between tumor proliferation and immune activation, discordant antigen presentation and T cell recognition with intrinsic activation-exhaustion overlap in T cells, and asynchronous PD-1/PD-L1 oscillations that sustain checkpoint-mediated suppression. Similar patterns were observed in human triple-negative breast cancer (TNBC). Together, these findings establish intercellular circadian misalignment as a mechanism of tumor immune evasion and position the circadian architecture of the tumor-immune ecosystem as a previously underappreciated determinant of tumor development and therapeutic response. HIGHLIGHTSO_LISingle-cell multiomics maps circadian regulation of tumor-immune programs. C_LIO_LICircadian regulation in cancer epithelial cells is misaligned with immune cell populations. C_LIO_LITumor-immune temporal misalignment undermines antitumor immunity. C_LIO_LICircadian misalignment in human TNBC suggests relevance for immunotherapy timing. C_LI

cancer biology↗

bioRxiv2023

Glutathione supports lipid abundance in vivo

Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are reported to be highest in liver tissue, which is also a hub for lipid production. While the loss of GSH did not cause liver failure, it decreased lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we found that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the livers balance of redox buffering and triglyceride production.

biochemistry↗

bioRxiv2022

A transcriptional response to replication stress selectively expands a subset of BRCA2-mutant mammary epithelial cells

BRCA2 mutation carriers preferentially develop luminal-like breast cancers, but it remains unclear how BRCA2 mutations affect mammary epithelial subpopulations. Here, we report that Brca2mut/WT mammary organoids subjected to replication stress activated a transcriptional response that selectively expands Brca2mut/WT luminal cells lacking hormone receptor expression (HR-). While CyTOF analyses revealed comparable epithelial compositions among wildtype and Brca2mut/WT mammary glands, Brca2mut/WT HR- luminal cells exhibited greater organoid formation and preferentially survived and expanded under replication stress. ScRNA-seq analysis corroborated the expansion of HR- luminal cells which express elevated levels of Tetraspanin-8 (Tspan8) and Thrsp mRNA, and pathways implicated in replication stress survival including Type I interferon responses. Notably, CRISPR/Cas9-mediated deletion of Tspan8 or Thrsp prevented Brca2mut/WT HR- luminal cell expansion. Our findings indicate that Brca2mut/WT cells have an activate a transcriptional response after replication stress that preferentially favours outgrowth of HR- luminal cells through the expression of interferon-responsive and mammary alveolar genes.

cancer biology↗

bioRxiv2019

Aging-associated alterations in the mammary gland revealed by single-cell RNA sequencing

Aging of the mammary gland is closely associated with increased susceptibility to diseases such as cancer, but there have been limited systematic studies of aging-induced alterations within this organ. We performed high-throughput single-cell RNA-sequencing (scRNA-seq) profiling of mammary tissues from young and old nulliparous mice, including both epithelial and stromal cell types. Our analysis identified altered proportions and distinct gene expression patterns in numerous cell populations as a consequence of the aging process, independent of parity and lactation. In addition, we detected a subset of luminal cells that express both hormone-sensing and alveolar markers and decrease in relative abundance with age. These data provide a high-resolution landscape of aging mammary tissues, with potential implications for normal tissue functions and cancer predisposition.

cell biology↗