Biology subjects

Azar, F. N.

Publications and source records attributed to Azar, F. N..

3 recordsLinked to original sources

bioRxiv2025

Ovarian Cancer Drives TLR5-Dependent Expansion of Myeloid Progenitors Through Systemic Dissemination of Ligands

Ovarian cancer remains the most lethal gynecologic malignancy, due in part to the establishment of a profoundly immunosuppressive tumor microenvironment (TME). While TLR5 signaling has previously been implicated in promoting myeloid cell recruitment to the ovarian TME, the upstream source of ligand and its systemic effects on hematopoiesis remain poorly understood(1,2). Here, we show that ovarian cancer disrupts gut barrier integrity, leading to systemic translocation of TLR5 ligands into the peritoneum, blood, and bone marrow. This translocation correlates with enhanced expansion of myeloid progenitors in the bone marrow of wild-type (WT) but not TLR5-deficient (TLR5 KO) mice, leading to enhanced accumulation of monocytes into the tumor microenvironment. Pharmacologic blockade of TLR5 in tumor-bearing mice alters the composition of tumor-associated myeloid populations, increasing the frequency of monocytes and CCR2-expressing macrophages In the bone marrow of tumor-bearing WT mice. In the bone marrow, blockade of TLR5 signaling led to expansion of granulocyte-monocyte progenitors (GMPs), a phenotype recapitulated in a competitive chimera model. In vitro, stimulation of WT bone marrow cells with purified TLR5 ligands led to enhanced colony formation and skewed differentiation toward granulocyte-macrophage lineages. These data reveal that chronic TLR5 signaling, driven by tumor-induced gut leakage, promotes expansion of myeloid cells within the bone marrow and is a host-intrinsic mechanism driving accumulation of immature monocytes and macrophages into the tumor microenvironment.

immunology↗

bioRxiv2021

Reciprocal interactions between the gut microbiome and mammary tissue mast cells promote metastatic dissemination of HR+ breast tumors

Establishing commensal dysbiosis, defined as an inflammatory gut microbiome with low biodiversity, prior to breast tumor initiation, enhances early dissemination of hormone-receptor positive (HR+) mammary tumor cells. Here, we sought to define mammary tissue mediators of dysbiosis-induced tumor dissemination. We found that commensal dysbiosis increased both the frequency and profibrogenicity of mast cells in the mammary tissue, a phenotypic change that persisted after tumor implantation. Fibroblast activation and tissue remodeling associate with enhanced breast tumor metastasis. We employed pharmacological and adoptive transfer approaches to demonstrate that mammary tissue mast cells from dysbiotic animals enhances dissemination of HR+ tumor cells. Collagen levels in mammary tissues from HR+ breast cancer patients correlated with mast cell abundance, suggesting clinical relevance of mast cell-mediated fibroblast activation. Together, these data demonstrate that a gut-mast cell axis exists that induces fibroblast activation and orchestrates early dissemination of HR+ breast tumors. SignificanceOur study defines the mechanism by which an inflammatory gut microbiome facilitates HR+ breast tumor cell dissemination. We establish that gut commensal dysbiosis triggers mammary tissue mast cells to facilitate early metastatic dissemination. These findings highlight a novel gut microbiome-innate immune cell axis involved in negative breast cancer outcomes.

cancer biology↗

bioRxiv2019

Platinum chemotherapy induces lymphangiogenesis to prime tissues for tumor metastasis

Chemotherapy has been used to inhibit cancer growth for decades, but emerging evidence shows it can affect the tumor stroma unintentionally promoting cancer malignancy. After treatment of primary tumors, remaining drugs drain via lymphatics. Though all drugs interact with the lymphatics, we know little of their impact on them. Here, we show a previously unknown effect of platinums, a widely used class of chemotherapeutics, to directly induce systemic lymphangiogenesis and activation. These changes are dose-dependent, long-lasting, and occur in healthy and cancerous tissue in multiple mouse models of breast cancer. We saw similar effects in human ovarian and breast cancer patients whose treatment regimens included platinums. Carboplatin treatment of healthy mice prior to mammary tumor inoculation increases cancer metastasis as compared to no pre-treatment. These platinum-induced phenomena could be blocked by VEGFR3 inhibition. These findings have implications for cancer patients receiving platinums and may support the inclusion of anti-VEGFR3 therapy into treatment regimens or differential design of treatment regimens to alter these potential effects. SummaryPlatinum chemotherapy induces VEGFR3-dependent lymphangiogenesis, priming tissues for metastasis of breast cancer. Inhibition of VEGFR3 via antibody blockade can reverse these effects.

cancer biology↗