bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2020.09.11.293837

Extracellular Vesicle-Mediated Purinergic Signaling Contributes to Host Microenvironment Plasticity and Metastasis in Triple Negative Breast Cancer

Duan, S.·Nordmeier, S.·Byrnes, A. E.·BUXTON, I. L. O.
View original source ↗Export metadata ↓

Abstract

Metastasis accounts for over 90% of cancer-related deaths. The mechanisms guiding this process remain unclear. Secreted nucleoside diphosphate kinase A and B (NDPK) support breast cancer metastasis. Proteomic evidence confirms their presence in breast cancer-derived extracellular vesicles (EVs). We investigated the role of EV-associated NDPK in modulating the host microenvironment in favor of pre-metastatic niche formation. We measured NDPK expression and activity in EVs isolated from triple-negative breast cancer (MDA-MB-231) and non-tumorigenic mammary epithelial (HME1) cells using flow cytometry, western blot, and ATP assay. We evaluated the effects of EV-associated NDPK on endothelial cell migration, vascular remodeling, and metastasis. We further assessed MDA-MB-231 EV induced-proteomic changes in support of pre-metastatic lung niche formation. NDPK-B expression and phosphotransferase activity were enriched in MDA-MB-231 EVs that promote vascular endothelial cell migration and disrupt monolayer integrity. MDA-MB-231 EV-treated mice demonstrate pulmonary vascular leakage and enhanced experimental lung metastasis, whereas treatment with an NDPK inhibitor or a P2Y1 purinoreceptor antagonist blunts these effects. We identified perturbations to the purinergic signaling pathway in experimental lungs, lending evidence to support a role for EV-associated NDPK-B in lung pre-metastatic niche formation and metastatic outgrowth.

Source connections

Explore related subjects

cancer biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Duan, S., Nordmeier, S., Byrnes, A. E., BUXTON, I. L. O.. 2020-09-11. Extracellular Vesicle-Mediated Purinergic Signaling Contributes to Host Microenvironment Plasticity and Metastasis in Triple Negative Breast Cancer. https://doi.org/10.1101/2020.09.11.293837

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Linking clinical border morphology to cell-scale growth mechanisms in melanoma: a segmentation-to-simulation alignment study

An irregular border is among the most informative visual cues for melanoma, yet the prevailing quantitative treatment of that irregularity, the box-counting fractal dimension, has rarely been connected to the cell-scale mechanism that produces it. We measured seven boundary descriptors on 1,581 lesions from the 2018 International Skin Imaging Collaboration archive segmented by an automatic thresholding route, retaining the expert ground-truth route as a sensitivity arm, and compared their medians across benign, in situ, and invasive grades. We then built a hybrid cellular automaton and swept four canonical cell-level mechanisms, scoring every simulated boundary with the same measurement code used on the patient images, before testing two mechanisms that lift the empty-neighbour division rule and aligning them to the observed malignant signature with a variance-based sensitivity analysis. The malignant signature is lobulation, not roughness: compactness rises from 1.351 to 1.810, solidity falls from 0.910 to 0.853, and convexity falls from 0.936 to 0.839 from benign to invasive lesions, with areas under the curve near 0.74, while the fractal dimension varies by only 0.024 across the three grades. All four canonical mechanisms, including loss of contact inhibition, converge on near-circular clusters at a distance of 1.147 to 1.166 from the malignant target. A long-range spatial heterogeneity in the growth rate, by contrast, reproduces the observed signature to a distance of 0.187, with the correlation length of the field, not its amplitude, the dominant parameter by total-effect index. A smooth, long-range growth-rate field is therefore sufficient to generate the lobular borders that characterise invasive melanoma, whereas the empty-neighbour assumption common to cellular automata is not. Because the winning field is imposed rather than emergent, the study resolves the alignment between border morphology and cell-scale mechanism while leaving open how such heterogeneity could arise from cell-autonomous dynamics.

cancer biology↗
bioRxiv2026

C19 trityl and silyl andrographolide analogs exhibit in vitro anticancer activity in murine cancer models

Andrographolide, a labdane diterpenoid isolated from A. paniculata has been investigated for activity in a broad panel of biological contexts, including its anti-inflammatory, antiviral, and anticancer properties. Previously, A-ring analogs of andrographolide bearing silyl and trityl ethers at C19 have demonstrated improved in vitro anticancer activity in human cancer cell lines, with putative activity through the Wnt1/{beta}-catenin signaling axis. In order to investigate the activity of this series of C19 andrographolide analogs, alongside a cyclic A-ring acetonide analog, as anticancer agents in murine cancer cell models, we evaluated antiproliferative activity of these compounds in B16F10 melanoma, CT26 colorectal adenocarcinoma, Neuro2a neuroblastoma, and 4T1 mammary ductal carcinoma cell lines, and found that most compounds exhibited potent micromolar level anticancer activity. Among these, all trityl ethers exhibited nearly indistinguishable IC50 values of 4-20 M, and generally exhibited greater potency compared to C19 silyl ether analogs. This anticancer activity was further validated through apoptosis flow cytometry, wherein we concluded that our compounds induced apoptosis to a greater extent than the parent compound, andrographolide. Further, we examine the role of modulation of canonical Wnt1/{beta}-catenin signaling in a series of co-delivery assays with CHIR-99021, a selective GSK-3{beta} kinase inhibitor, and MSAB, a selective {beta}-catenin degrader. Finally, we demonstrate that a selection of silyl ether analogs of andrographolide elicit cell cycle arrest by flow cytometry in a manner that is decoupled to in vitro potency trends. Altogether, we report the first in vitro evaluation of trityl and silyl ether analogs of andrographolide within murine adherent cancer cells.

cancer biology↗
bioRxiv2026

Aneuploidy profiling among different types of brain metastases reveals a colon cancer-specific chromosomal signature

Brain metastasis is a significant cause of patient morbidity and mortality. There is increasing evidence that genomic instability features such as aneuploidy are associated with metastases to the brain and other organs. We analyzed the genomic instability of brain metastases among different cancer types. This included brain metastases from non-small cell lung, breast, melanoma and colorectal cancer. Our study identified a significantly higher degree of genomic instability in colorectal brain metastases compared to the other types of brain metastases. Nex, we examined the brain metastases for the types of aneuploidy events, namely chromosomal arm imbalances that involved gains or losses. Colorectal cancer brain metastases had specific chromosomal arm imbalance profiles that included gains of 13q and 20q which were significantly more frequent compared to the other cancer types. We examined other colorectal cancer metastatic sites in the lung, liver, lymph nodes and the primary colon. Examining colorectal cancer metastases more closely, aneuploidy gains across either arms for chromosomes 7 and 16 were also higher among brain metastases compared to liver, lung and lymph node metastases. Overall, this study shows that colorectal cancer brain metastasis has specific aneuploidy profiles different than other cancer types as well as being different among other metastatic organ sites.

cancer biology↗