Schnepp, P. M. | Search bioRxiv

bioRxiv2021

Macrophages induce inflammation by efferocytosis of apoptotic prostate cancer cells via HIF-1α stabilization

Clearance of apoptotic cancer cells by macrophages, known as efferocytosis, fuels the bone-metastatic growth of prostate cancer cells via pro-inflammatory and immunosuppressive processes. However, the exact molecular mechanisms remain unclear. In this study, single-cell transcriptomics of bone marrow macrophages undergoing efferocytosis of apoptotic prostate cancer cells revealed a significant enrichment of a cellular response to hypoxia. Here we show that efferocytic macrophages promote HIF-1 stabilization under normoxic conditions through interaction with phosphorylated STAT3. Inflammatory cytokine gene expression analysis of efferocytic HIF-1-mutant macrophages revealed a reduced expression of the pro-tumorigenic Mif. Furthermore, stabilization of HIF-1 using the HIF-prolyl-hydroxylase inhibitor, Roxadustat, enhanced MIF expression in macrophages. Finally, macrophages treated with recombinant MIF protein activated NF-{kappa}B (p65) signaling and increased the expression of pro-inflammatory cytokines. Altogether, these findings suggest that the clearance of apoptotic cancer cells by tumor-associated macrophages triggers p-STAT3/HIF-1/MIF signaling to enhance tumor-promoting inflammation in bone, suggesting this axis as a target for metastatic prostate cancer.

cancer biology↗

bioRxiv2019

Rab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth

GRAPHICAL ABSTRACT\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC=\"FIGDIR/small/666750v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (68K):\norg.highwire.dtl.DTLVardef@16dc0c4org.highwire.dtl.DTLVardef@8ab7e2org.highwire.dtl.DTLVardef@12e5acforg.highwire.dtl.DTLVardef@4bf298_HPS_FORMAT_FIGEXP M_FIG C_FIG SUMMARYBreast cancer brain metastases (BCBM) have a 5-20 year latency and account for up to 30% of mortality. Developing new therapeutics requires a molecular understanding of adaptation to the brain microenvironment. Here, we combined RNA-sequencing of BCBM development with a reverse genetic screen in Drosophila melanogaster and identified Rab11b, an endosomal recycling protein, as a mediator of metastatic adaptation. We show that disseminated cells up-regulate Rab11b early after arrival in the brain, allowing control of the cell surface proteome through recycling of proteins required for successful interaction with the microenvironment, including integrin {beta}1. Rab11b-mediated control of integrin {beta}1 surface expression allows ligation to the brain ECM, activating mechanotransduction signaling to allow survival and proliferation. We propose a model in which up-regulation of Rab11b allows disseminated cells to recycle needed proteins during metastatic adaptation, without strictly requiring transcription and translation, to allow for metastatic outgrowth.\n\nManuscript SummaryRab11b up-regulation in the brain microenvironment promotes recycling of cargo proteins required for breast cancer brain metastasis, including increased surface expression of integrin {beta}1, which allows brain extracellular matrix attachment and mechanotransduction. Inhibition of the mevalonate pathway with statins prevents geranylgeranylation of Rab11b, decreasing cargo recycling, and inhibiting brain metastasis.

cancer biology↗