Biology subjects

Quail, D.

Publications and source records attributed to Quail, D..

3 recordsLinked to original sources

bioRxiv2023

Tumour Extracellular Vesicles Induce Neutrophil Extracellular Traps To Promote Lymph Node Metastasis

Lymph nodes (LNs) are frequently the first sites of metastasis. Currently, the only prognostic LN assessment is determining metastasis status. However, there is evidence suggesting that LN metastasis is facilitated by a pre-metastatic niche induced by tumour derived extracellular vehicles (EVs). Therefore, it is important to detect and modify the LN environmental changes. We have previously reported that neutrophil extracellular traps (NETs) can sequester and promote distant metastasis. Here, we first confirmed that LN NETs are associated with reduced patient survival. Next, we demonstrated that NETs deposition precedes LN metastasis and NETs inhibition abolishes LN metastases in animal mode. Furthermore, we discovered that EVs are essential to the formation of LN NETs. Lymphatic endothelial cells secrete CXCL8/2 in response to EVs inducing NETs formation and the promotion of LN metastasis. Our findings are the first to reveal the role of EV induced NETs in LN metastasis and provide potential immunotherapeutic vulnerabilities. Graphic AbstractIllustrative demonstration of the LNs premetastatic niche formation induced by EVs and NETs. Primary tumour constantly secretes EVs, which were actively uptaken by LECs. LECs subsequently secretes CXCL8 or CXCL2 upon EV reception. CXCL8 and CXCL2 are both neutrophil chemoattractants and potent NETs inducers. The following neutrophil recruitment and NETs formation lead to increased LN metastasis burden. O_FIG O_LINKSMALLFIG WIDTH=173 HEIGHT=200 SRC="FIGDIR/small/532413v2_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@c0c371org.highwire.dtl.DTLVardef@15f6a92org.highwire.dtl.DTLVardef@14dbeedorg.highwire.dtl.DTLVardef@131d3eb_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Epigenetic plasticity cooperates with emergent cell-cell interactions to drive neoplastic tissue remodeling in the pancreas

The response to tumor-initiating inflammatory and genetic insults can vary amongst morphologically indistinguishable cells, suggesting yet uncharacterized roles for epigenetic plasticity during early neoplasia. To investigate the origins and impact of such plasticity, we perform single-cell analyses on normal, inflamed, pre-malignant and malignant tissues in autochthonous models of pancreatic cancer. We reproducibly identify heterogeneous cell-states that are primed for diverse late-emerging neoplastic fates and link these to chromatin remodeling at cell-cell communication loci. Using a new inference approach, we reveal signaling gene modules and tissue-level crosstalk, including a neoplasia-driving feedback loop between discrete epithelial and immune cell populations that we validate by genetic perturbation in mice. Our results uncover a neoplasia-specific tissue remodeling program that may be exploited for pancreas cancer interception. One-Sentence SummarySingle-cell analysis reveals that enhanced epigenetic plasticity drives pro-neoplastic crosstalk in early pancreatic cancer.

cancer biology↗

bioRxiv2020

The pleiotropic effects of the MNK1/2-eIF4E axis support immune suppression and metastasis in a model of postpartum breast cancer.

PurposeBreast cancer diagnosed within 10 years following childbirth is defined as postpartum breast cancer (PPBC) and is highly metastatic. Interactions between immune cells and other stromal cells within the involuting mammary gland are fundamental in facilitating an aggressive tumor phenotype. The MNK1/2-eIF4E axis promotes the translation of pro-metastatic mRNAs in tumor cells, but its role in modulating the function of non-tumor cells in the PPBC microenvironment, and in particular its activity in human PPBC, has not been explored. Experimental designWe used a combination of in vivo PPBC models and in vitro assays to study the effects of phospho-eIF4E deficiency on the pro-tumor function of select cells of the TME. Furthermore, we employed Imaging Mass Cytometry on PPBC and non-PPBC patient samples, to chart the expression of the MNK1/2-eIF4E axis components in the TME. ResultsHere, we show that phospho-eIF4E deficient (eIF4ES209A) PPBC mice are protected against lung metastasis and reveal differences in the lung immune microenvironment of the WT and eIF4ES209A mice. Moreover, we show that the expression of fibroblast-derived IL-33, an alarmin known to induce invasion, was repressed upon MNK1/2-eIF4E axis inhibition. Imaging Mass Cytometry results indicated that human PPBC contain phospho-eIF4E high-expressing tumor cells and CD8+ T cells displaying an activated dysfunctional phenotype. Finally, we block lung metastasis in PPBC mice, using combined MNK1/2 inhibition and anti-PD-1 therapy. ConclusionsThese findings implicate the involvement of the MNK1/2-eIF4E axis during PPBC metastasis and suggest a promising immunomodulatory route to enhance the efficacy of immunotherapy by blocking phospho-eIF4E. Translational relevancePostpartum breast cancer (PPBC) is highly aggressive. It is hypothesized that involution-induced changes in the postpartum breast microenvironment, which include an influx of inflammatory immune cells and activation of resident fibroblasts, facilitate the invasiveness of an existing neoplasm. We used imaging mass cytometry to do an in-depth profiling of the MNK1-eIF4E axis in the TME of a unique cohort of PPBC and non-PPBC patients. We observed patterns of phospho-eIF4E in non-tumor cells that were specific to the TME of PPBC. We also noted that the CD8+ T cells present in PPBC express an activated dysfunctional phenotype characterized by the co-expression of HLA-DR and PD-1. This study represents a first look at the expression of the MNK1-eIF4E axis in the stromal cells of metastatic breast cancer and has therapeutic implications as we show, in an animal model of PPBC, that MNK1/2 inhibition can be used to sensitize tumors to anti-PD1 immunotherapy.

cancer biology↗