Biology subjects

Millman, M.

Publications and source records attributed to Millman, M..

3 recordsLinked to original sources

bioRxiv2025

Engineered Extracellular Vesicles Enriched with miR-214 Enhance the Efficacy of Chemotherapy for Ovarian Cancer

Recurrent ovarian cancer (OC) remains a major cause of mortality due to chemoresistance and metastasis. Epigenetic dysfunction, particularly through altered microRNA (miRNA) expression, contributes to disease progression. Targeting these molecular aberrations is critical to prevent recurrence, limit metastasis and improve patient outcomes. Here, we identify the miR-214-3p/miR-199a-5p cluster as a stage-associated, tumor-suppressive network that is lost in recurrent and chemoresistant OC, but can be restored using engineered small extracellular vesicles enriched with this cluster (m214-sEVs). Using a clinically relevant mouse model that mimics spontaneous OC relapse following first-line platinum-based chemotherapy, we showed that m214-sEVs were internalized by OC cells and the OC niche fibroblasts via clathrin-mediated endocytosis, resulting in the elevation of miR-214-3p/miR-199a-5p and the downregulation of chemoresistance-associated genes, including toll-like receptor 4 (TLR4), {beta}-catenin, and the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein YKT6. Moreover, secondary tumor-derived sEVs (t-sEVs) released by OC and niche cells that internalized m214-sEVs reduced pro-metastatic proteins, such as integrin {beta}1 and matrix metalloproteinase 9 (MMP9), in their cargo and limited their capacity to promote invasion and resistance. In vitro, YKT6 overexpression in ovarian cancer stem cells (OCSCs) attenuated the effect of m214-sEVs on sensitizing carboplatin to block OCSC migration. These findings demonstrate that engineered m214-sEVs designed to restore clinically lost tumor-suppressive miRNAs can concurrently reverse chemoresistance and reprogram tumor-derived EV communication by targeting oncogenic networks. Statement of SignificanceEngineered small extracellular vesicles delivering miR-214-3p/miR-199a-5p overcome chemoresistance and inhibit recurrence in ovarian cancer by targeting oncogenic networks and reprogramming tumor-derived extracellular vesicle communication within the tumor microenvironment.

cancer biology↗

bioRxiv2023

Adipose-derived exosomal miR-421 targets CBX7 and promotes metastatic potential in ovarian cancer cells

BackgroundChromobox protein homolog 7 (CBX7), a member of the Polycomb repressor complex, is a potent epigenetic regulator and gene silencer. Our group has previously reported that CBX7 functions as a tumor suppressor in ovarian cancer cells and its loss accelerated formation of carcinomatosis and drove tumor progression in an ovarian cancer mouse model. The goal of this study is to identify specific signaling pathways in the ovarian tumor microenvironment that down-regulate CBX7. Given that adipocytes are an integral component of the peritoneal cavity and the ovarian tumor microenvironment, we hypothesize that the adipose microenvironment is an important regulator of CBX7 expression. ResultsUsing conditioned media from human omental explants, we found that adipose-derived exosomes mediate CBX7 downregulation and enhance migratory potential of human ovarian cancer cells. Further, we identified adipose-derived exosomal miR-421 as a novel regulator of CBX7 expression and the main effector that downregulates CBX7. ConclusionIn this study, we identified miR-421 as a specific signaling pathway in the ovarian tumor microenvironment that can downregulate CBX7 to induce epigenetic change in OC cells, which can drive disease progression. These findings suggest that targeting exosomal miR-421 may curtail ovarian cancer progression.

cancer biology↗

bioRxiv2019

Microbial biogeography and ecology of the mouth and implications for periodontal diseases

Human-associated microbial communities differ in composition among body sites and between habitats within a site. Patterns of variation in the distribution of organisms across time and space is referred to as biogeography. The human oral cavity is a critical observatory for exploring microbial biogeography because it is spatially structured, easily accessible, and its microbiota has been linked to the promotion of both health and disease. The biogeographic features of microbial communities residing in spatially distinct but ecologically similar environments on the human body, including the subgingival crevice, have not yet been adequately explored. The purpose of this paper is twofold. First, we seek to provide the dental community with a primer on biogeographic theory, highlighting its relevance to the study of the human oral cavity. For this reason, we summarize what is known about the biogeographic variation of dental caries and periodontitis and postulate as to how this may be driven by spatial patterning in oral microbial community composition and structure. Second, we present a number of methods that investigators can use to test specific hypotheses using biogeographic theory. To anchor our discussion, we apply each method to a case study and examine the spatial variation of the human subgingival microbiota of 2 individuals. Our case study suggests that subgingival communities in the aggregate may conform to an anterior-to-posterior gradient in community composition. The gradient appears to be structured both by deterministic and non-deterministic processes, though additional work is needed to test and confirm specific hypotheses. A better understanding of biogeographic patterns and processes will advance our understanding of ways to optimize the efficacy of dental interventions targeting the oral microbiota.

ecology↗