cell adhesion
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Weak Cell Adhesion is a Prognostic Signature of Invasive Cancer
Project Summary Despite early detection, low-grade and localized breast cancers such as ductal carcinoma in situ (DCIS) can relapse in up to 20% of cases despite standard of care. For DCIS, relapse affects over 12,000 U.S. women annually and has increased 60% in the last 40 years. Current diagnostic assessments including histopathological markers often miss early disseminating cells, lack specificity, or cannot distinguish cancer from non-cancer cells in the stroma. Hence there is an unmet need for cancer diagnostic technologies that employ radically different characterization methods. For example, significant physical differences exist between metastasizing and benign breast cancer cells, owing to metastasizing cells detaching from the primary tumor, migrating through the surrounding stroma, intravasating and extravasating, and ultimately engrafting in distant tissues. We recently demonstrated that cancer cells with weaker adhesion migrate faster and metastasize more frequently in murine breast cancer models than strongly adherent cells. In a small pilot study of human breast tumors, we also observed that the abundance of weakly adherent (WA) cells scales with disease severity; subpopulations from invasive carcinomas were the least adherent. However, a subset of DCIS cases displayed much less adhesion, suggesting that these patients may have a tumor subpopulation that progresses to metastatic disease despite standard-of-care treatment. Weak adhesion is a defining physical characteristic of tumors, but to establish their role in initiation, metastasis, and patient outcomes, we will leverage model systems and our newly patented adhesion technology to answer these fundamental questions of cancer biology and clinical translation. To understand the impact of adhesion on cancer progression, we will evaluate the tumor-initiating potential of WA versus strongly adherent (SA) tumor cells in a murine breast cancer model before confirming how weak adhesion advantages cells to cause secondary disease using bioengineered in vitro models. In dissecting the stages of metastasis where WA cells exhibit advantages, e.g., recapitulating stromal niche, transendothelial migration, and tissue-specific colonization, we will identify mechanisms that enable WA cells to thrive and evaluate therapeutic targets that disrupt these pathways. Finally, we will analyze the adhesion profiles of resected tumors and stroma from 80 breast cancer patients with DCIS or invasive disease. Adhesion data will be correlated with conventional assessment methods and ultimately with patient outcomes, e.g., disease-free and progression-free intervals. We anticipate that the DCIS subpopulation that aligns with the adhesion signature of invasive carcinomas will have shorter intervals and survival time. This integrated study design bridges mouse models, mechanistic bioengineering assays, and human samples to clarify the metastatic potential and prognostic value of WA breast cancer cells. Our use of mouse models in this grant is required to study the interactions among tumor cells, immune cells, vasculature, and stromal tissues that drive tumor formation in vivo. Bioengineered in vitro systems lack the complexity to ask such questions and using injected tumor cells is not possible in humans.
Identifying host-interacting proteins of Sneathia vaginalis
PROJECT SUMMARY AND ABSTRACT Sneathia vaginalis is a member of the human normal flora of the vagina. It is also a human pathogen that is associated with preterm birth and amniotic fluid infections as well as the most common bacterial species associated with HPV infection and cervical cancer. The identification of S. vaginalis as a human pathogen is recent and little is known about how this bacterium interacts with the host in either its commensal or pathogenic lifestyles. With the exception of a single toxin, no additional virulence factors have been identified. Our preliminary data demonstrates that S. vaginalis grows to high cell density in rich media; however, it fails to grow planktonically in other media unless host cells are present indicating that S. vaginalis relies on host cells for nutrients. This is consistent with its reduced genome. In addition, bacterial proliferation requires close proximity with the host cells and previous studies demonstrate that S. vaginalis can bind a variety of host cells. The proteins that mediate contact are unknown. We hypothesize that proteins on the surface of S. vaginalis are critical for host cell adhesion. We will use two Aims to examine this. Aim 1 will use mass spectrometry to identify S. vaginalis surface proteins. Aim 2 generates deletion strains of potential adhesins identified in Aim 1 as well as predicted host-interacting proteins that have already been identified bioinformatically based on those in other bacteria. The mutant bacteria are then tested in host-cell adhesion assays. Together, these aims will identify for the first time the proteins found on the surface of S. vaginalis while identifying proteins that interact with host cells that would be expected to contribute to either its commensal or pathogenic lifestyles or both. Moreover, these studies would be used to inform clinical lab practice as surface-expressed proteins could be used to identify identifying markers of S. vaginalis detection.
Cellular Crosstalk in Brain Development, Evolution and Disease
Cellular crosstalk is an essential process during brain development and is influenced by numerous factors, including cell morphology, adhesion, the local extracellular matrix and secreted vesicles. Inspired by mutations associated with neurodevelopmental disorders, we focus on understanding the role of extracellular mechanisms essential for the proper development of the human brain. Therefore, we combine 2D and 3D in vitro human models to better understand the molecular and cellular mechanisms involved in progenitor proliferation and fate, migration and maturation of excitatory and inhibitory neurons during human brain development and tackle the causes of neurodevelopmental disorders.
Cell-type specific genomics and transcriptomics of HIV in the brain
Exploration of genome organization and function in the HIV infected brain is critical to aid in the understanding and development of treatments for HIV-associated neurocognitive disorder (HAND). Here, we applied a multiomic approach, including single nuclei transcriptomics, cell-type specific Hi-C 3D genome mapping, and viral integration site sequencing (IS-seq) to frontal lobe tissue from HIV-infected individuals with encephalitis (HIVE) and without encephalitis (HIV+). We observed reorganization of open/repressive (A/B) compartment structures in HIVE microglia encompassing 6.4% of the genome with enrichment for regions containing interferon (IFN) pathway genes. 3D genome remodeling was associated with transcriptomic reprogramming, including down-regulation of cell adhesion and synapse-related functions and robust activation of IFN signaling and cell migratory pathways, and was recapitulated by IFN-g stimulation of cultured microglial cells. Microglia from HIV+ brains showed, to a lesser extent, similar transcriptional alterations. IS-seq recovered 1,221 integration sites in the brain that were enriched for chromosomal domains newly mobilized into a permissive chromatin environment in HIVE microglia. Viral transcription, which was detected in 0.003% of all nuclei in HIVE brain, occurred in a subset of highly activated microglia that drove differential expression in HIVE. Thus, we observed a dynamic interrelationship of interferon-associated 3D genome and transcriptome remodeling with HIV integration and transcription in the brain.
Defining the synapse-specific landscape of cell adhesion molecules in the fly visual system
FENS Forum 2024
Neuroanatomical characterisation of the cell adhesion molecule IgSF9b reveals heterogeneous synaptic localization across different regions of the mouse brain
FENS Forum 2024
cell adhesion coverage
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