Biology subjects

Vusich, J.

Publications and source records attributed to Vusich, J..

3 recordsLinked to original sources

bioRxiv2026

Tumor-derived FXII engages the intrinsic coagulation cascade to support breast cancer liver metastasis.

Metastasis is the leading cause of death in breast cancer, yet the mechanisms controlling organotropism are not well defined. Coagulation has emerged as a biologically relevant contributor to metastatic progression, but mechanisms linking pro-thrombotic phenotypes to organ-specific metastasis remain unresolved, significantly hindering the development of novel treatments. Here, a serial transplantation approach was used to enrich for liver organotropism from a spontaneous mouse mammary tumor model with occasional liver and lymph node metastasis. Comparative transcriptomics between the enriched liver and lymph node metastases revealed strong upregulation of coagulation in liver metastases, due in part to loss of repression of FXII with knockout of the E2F5 transcription factor. In vitro clotting assays demonstrated that tumor-derived FXII was sufficient to induce fibrin(ogen) clot formation. Moreover, liver metastatic cells exhibit elevated lipid peroxide levels and impaired lipid droplet formation associated with a pro-coagulant phenotype. Inhibition of coagulation with low molecular weight heparin reduced the presence of circulating tumor cells and suppressed liver metastasis in the mouse model. Human electronic health record data supported the translational relevance of these findings. Together, these data reveal a new mouse model where loss of E2F5 has resulted in tumors with elevated expression of FXII that have a propensity for liver metastasis and illustrates that anti-coagulation dramatically reduces the liver-specific metastasis in breast cancer. HighlightsE2F5 conditional knockout model develops breast tumors with liver tropism Liver metastasis hijacks the intrinsic coagulation cascade mediated by tumor-derived FXII Liver metastatic cells displayed lipid metabolic alterations that contributed to a pro-coagulant phenotype Low molecular weight heparin blocks liver metastasis and significantly reduces circulating tumor cells

cancer biology↗

bioRxiv2024

Transcriptional Regulation of Mammary Alveolar Proliferation and Differentiation during Early Pregnancy

The E2F transcription factors are well-established cell cycle regulators, but their roles in coordinating proliferation and differentiation remain poorly understood. Here, we investigated the function of E2F5 during mammary gland development using a mammary epithelial-specific conditional knockout model. We found that E2F5 expression and chromatin binding increase during early pregnancy, coinciding with the critical window of alveolar development. Loss of E2F5 resulted in delayed alveolar expansion during early pregnancy, characterized by reduced side branching and smaller alveolar structures during early pregnancy. Mechanistically, E2F5 deletion led to reduced expression of canonical E2F target genes involved in cell cycle progression. Surprisingly, E2F5 loss also caused enrichment of luminal progenitor populations at the expense of differentiated alveolar cells, with chromatin profiling revealing substantial depletion of the repressive H3K27me3 mark at luminal progenitor-associated genes. These findings suggest that E2F5 promotes differentiation of luminal progenitors into proliferative alveolar precursors during early pregnancy. We propose that E2F5 coordinates both proliferation and differentiation by driving progenitor cells to differentiate into mature luminal cells. The dual function of E2F5 in mammary development distinguishes it from classical cell cycle regulators and positions it as a critical coordinator of the developmental transitions required for lactation.

developmental biology↗

bioRxiv2024

Atypical Cell Cycle Regulation Promotes Mammary Stem Cell Expansion and Therapeutic Resistance

BackgroundThe cell cycle of mammary stem cells must be tightly regulated to ensure normal homeostasis of the mammary gland to prevent abnormal proliferation and susceptibility to tumorigenesis. The atypical cell cycle regulator, Spy1 can override cell cycle checkpoints, including those activated by the tumour suppressor p53 which mediates mammary stem cell homeostasis. Spy1 has also been shown to promote expansion of select stem cell populations in other developmental systems. Spy1 protein is elevated during proliferative stages of mammary gland development, is found at higher levels in human breast cancers, and promotes susceptibility to mammary tumourigenesis when combined with loss of p53. We hypothesized that Spy1 cooperates with loss of p53 to increase susceptibility to tumour initiation due to changes in susceptible mammary stem cell populations during development and drives the formation of more aggressive stem like tumours. MethodsUsing a transgenic mouse model driving expression of Spy1 within the mammary gland, mammary development and stemness were assessed. These mice were intercrossed with p53 null mice to study the tumourigenic properties of Spy1 driven p53 null tumours, as well as global changes in signaling via RNA sequencing analysis. ResultsWe show that elevated levels of Spy1 leads to expansion of mammary stem cells, even in the presence of p53, and an increase in mammary tumour formation. Spy1-driven tumours have an increased cancer stem cell population, decreased checkpoint signaling, and demonstrate an increase in therapy resistance. Loss of Spy1 decreases tumor onset and reduces the cancer stem cell population. ConclusionsThis data demonstrates the potential of Spy1 to expand mammary stem cell populations and contribute to the initiation and progression of aggressive, drug resistant breast cancers with increased cancer stem cell populations.

cancer biology↗