The Role of Extracellular Vesicles in Cancer

Intercellular communication is a key feature of cancer progression and metastasis. Extracellular vesicles (EVs) are generated by all cells, including cancer cells, and recent studies have identified EVs as key mediators of cell-cell communication via packaging and transfer of bioactive constituents to impact the biology and function of cancer cells and cells of the tumor microenvironment. Here, we review recent advances in understanding the functional contribution of EVs to cancer progression and metastasis, as cancer biomarkers, and the development of cancer therapeutics

Exosomes modified with anti-MEK1 siRNA lead to an effective silencing of triple negative breast cancer cells

Available online 28 September 2023Triple negative breast cancer (TNBC) is a highly heterogenous disease not sensitive to endocrine or HER2 therapy and standardized treatment regimens are still missing. Therefore, development of novel TNBC treatment approaches is of utmost relevance. Herein, the potential of MAPK/ERK downregulation by RNAi-based therapeutics in a panel of mesenchymal stem-like TNBC cell lines was uncovered. Our data revealed that suppression of one of the central nodes of this signaling pathway, MEK1, affects proliferation, migration, and invasion of TNBC cells, that may be explained by the reversion of the epithelial-mesenchymal transition phenotype, which is facilitated by the MMP-2/MMP-9 downregulation. Moreover, an exosome-based system was successfully generated for the siRNA loading (iExoMEK1). Our data suggested absence of modification of the physical properties and general integrity of the iExoMEK1 comparatively to the unmodified counterparts. Such exosome-mediated downregulation of MEK1 led to a tumor regression accompanied by a decrease of angiogenesis using the chick chorioallantoic-membrane model. Our results highlight the potential of the targeting of MAPK/ERK cascade as a promising therapeutic approach against TNBC.This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/ BIO/04469/2020 unit. CAM and immunohistochemistry experiments have been funded by ICVS Scientific Microscopy Platform, member of the national infrastructure PPBI - Portuguese Platform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122); by National funds, through the Foundation for Science and Technology (FCT) - project UIDB/50026/ 2020 and UIDP/50026/2020 and by the project NORTE-01-0145- FEDER-000039, supported by Norte Portugal Regional Operational Program (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). Débora Ferreira is recipient of a fellowship supported by a doctoral advanced training (call NORTE-69-2015-15) funded by the European Social Fund under the scope of Norte2020 - Programa Operacional Regional do Norte. Débora Ferreira also acknowledges “Liga Portuguesa contra o cancro - Núcleo Regional do Norte (LPCC-NRN)” for her fellowship. The authors thank Diana Vilas Boas (CEB/University of Minho) for confocal microscopy technical support. Cátia Santos-Pereira acknowledges the PhD fellowship PD/BD/128032/2016 funded by FCT under the scope of the doctoral program in Applied and Environmental Microbiology (DP_AEM). Julieta Afonso acknowledges the Postdoctoral fellowship SFRH/BPD/116784/2016 funded by FCT. The work performed in the Kalluri Laboratory was supported by funds from UT MD Anderson Cancer Center and the Sid Richardson Foundation.info:eu-repo/semantics/publishedVersio

Engineered Exosomes Targeting Myc Reverse the Proneural-Mesenchymal Transition and Extend Survival of Glioblastoma

Dysregulated Myc signaling is a key oncogenic pathway in glioblastoma multiforme (GBM). Yet, effective therapeutic targeting of Myc continues to be challenging. Here, we demonstrate that exosomes generated from human bone marrow mesenchymal stem cells (MSCs) engineered to encapsulate siRNAs targeting Myc (iExo-Myc) localize to orthotopic GBM tumors in mice. Treatment of late stage GBM tumors with iExo-Myc inhibits proliferation and angiogenesis, suppresses tumor growth, and extends survival. Transcriptional profiling of tumors reveals that the mesenchymal transition and estrogen receptor signaling pathways are impacted by Myc inhibition. Single nuclei RNA sequencing (snRNA-seq) shows that iExo-Myc treatment induces transcriptional repression of multiple growth factor and interleukin signaling pathways, triggering a mesenchymal to proneural transition and shifting the cellular landscape of the tumor. These data confirm that Myc is an effective anti-glioma target and that iExo-Myc offers a feasible, readily translational strategy to inhibit challenging oncogene targets for the treatment of brain tumors

Dry Climate Disconnected the Laurentian Great Lakes

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94725/1/eost16649.pd

Molecular and mechanical regulators of mesenchymal stem cell microenvironments

Mesenchymal stem cells (MSCs) are multipotent cells that are recruited to sites of inflammation, where they interact with the microenvironment to induce tissue regeneration. As a result, MSCs have shown promise clinically as candidates for tissue engineering and therapeutic targets; however, implementation in the clinic has been limited by an incomplete understanding of how mechanical and chemical cues provided by the microenvironment influence MSC behavior. We first show how molecular cues change the intracellular mechanical properties of differentiating MSCs. We then developed 3D gelatin scaffolds for the expansion and differentiation of MSCs. We found that the composition of the scaffold dictated whether the mechanical or architectural properties directed MSC differentiation. In addition to aiding in tissue regeneration, MSCs are also recruited to tumors, where they interact with the tumor microenvironment to promote metastasis. We sought to elucidate if MSCs are differentially adherent, and potentially recruited more frequently, to metastatic versus nonmetastatic tumors. We found that MSCs are more adherent to metastatic cancer cells and this response can be reversed by blocking the adhesion molecule cadherin 11. Finally, we utilized a 3D coculture model to determine how interactions between metastatic cancer cells and MSCs influence cancer cell invasion. Coculture with MSCs induced directional migration in cancer cells that was dependent on transforming growth factor β (TGF-β) and downstream mechanosensitive pathways. These studies elucidate how MSCs interact with their environment and may have important implications in biomaterial design and the development of cancer therapeutics.Ph.D

Mechanisms associated with biogenesis of exosomes in cancer

Abstract Intercellular communication between cellular compartments within the tumor and at distant sites is critical for the development and progression of cancer. Exosomes have emerged as potential regulators of intracellular communication in cancer. Exosomes are nanovesicles released by cells that contain biomolecules and are exchanged between cells. Exchange of exosomes between cells has been implicated in a number of processes critical for tumor progression and consequently altering exosome release is an attractive therapeutic target. Here, we review current understanding as well as gaps in knowledge regarding regulators of exosome release in cancer

Enacting national social distancing policies corresponds with dramatic reduction in COVID19 infection rates

The outbreak the SARS-CoV-2 (CoV-2) virus has resulted in over 6.5 million cases of COVID19, greatly stressing global healthcare infrastructure. Lacking medical prophylactic measures to combat disease spread, many nations have adopted social distancing policies in order to mitigate transmission of CoV-2. While mathematical models have suggested the efficacy of social distancing to curb the spread of CoV-2, there is a lack of systematic studies to quantify the real-world efficacy of these approaches. Here, we first demonstrate that implementation of social distancing policies in US states corresponded with a reduction in COVID19 spread rates, and that the reduction in spread rate is proportional to the average change in mobility. We validate this observation on a worldwide scale by analyzing COVID19 spread rate in 134 nations with varying social distancing policies. Globally, we find that social distancing policies significantly reduced the COVID19 spread rate, with resulting in an estimated 65% reduction (95% CI = 39–80%) in new COVID19 cases over a two week time period. These data suggest that social distancing policies may be a powerful tool to prevent spread of COVID19 in real-world scenarios

Protection against SARS-CoV-2 by BCG vaccination is not supported by epidemiological analyses

The Bacillus Calmette–Guerin (BCG) vaccine provides protection against tuberculosis (TB), and is thought to provide protection against non-TB infectious diseases. BCG vaccination has recently been proposed as a strategy to prevent infection with SARS-CoV-2 (CoV-2) to combat the COVID-19 outbreak, supported by its potential to boost innate immunity and initial epidemiological analyses which observed reduced severity of COVID-19 in countries with universal BCG vaccination policies. Seventeen clinical trials are currently registered to inform on the benefits of BCG vaccinations upon exposure to CoV-2. Numerous epidemiological analyses showed a correlation between incidence of COVID-19 and BCG vaccination policies. These studies were not systematically corrected for confounding variables. We observed that after correction for confounding variables, most notably testing rates, there was no association between BCG vaccination policy and COVD-19 spread rate or percent mortality. Moreover, we found variables describing co-morbidities, including cardiovascular death rate and smoking prevalence, were significantly associated COVID-19 spread rate and percent mortality, respectively. While reporting biases may confound our observations, our epidemiological findings do not provide evidence to correlate overall BCG vaccination policy with the spread of CoV-2 and its associated mortality

Enhanced Adhesion of Stromal Cells to Invasive Cancer Cells Regulated by Cadherin 11

Cancer-associated fibroblasts (CAFs) are known to promote tumor growth and metastasis; however their differential accumulation in invasive and noninvasive tumors is not fully understood. We hypothesized that differences in cell adhesion may contribute to this phenomenon. To test this, we analyzed the adhesion of CAF-precursor fibroblasts and mesenchymal stem cells to invasive and noninvasive cancers originating from the the breast, ovaries, and prostate. In all cases, stromal cells preferentially adhered to more invasive cancer cells. Modulating integrin and cadherin binding affinities with calcium chelation revealed that adhesion was independent of integrin activity but required cadherin function. Invasive cancer cells had increased expression of mesenchymal markers cadherin 2 and 11 that localized with stromal cell cadherin 11, suggesting that these molecules are involved in stromal cell engraftment. Blockade of cadherin 11 on stromal cells inhibited adhesion and may serve as a target for metastatic disease