Biology subjects

Weiss, S. J.

Publications and source records attributed to Weiss, S. J..

3 recordsLinked to original sources

bioRxiv2025

Amoeboid-Mesenchymal Transition and the Proteolytic Control of Cancer Invasion Plasticity

Invasion plasticity allows malignant cells to toggle between collective, mesenchymal and amoeboid phenotypes while traversing extracellular matrix (ECM) barriers. Current dogma holds that collective and mesenchymal invasion programs trigger the mobilization of proteinases that digest structural barriers dominated by type I collagen, while amoeboid activity allows cancer cells to marshal mechanical forces to traverse tissues independently of ECM proteolysis. Here, we use cancer spheroid-3-dimensional matrix models, single-cell RNA sequencing, and human tissue explants to identify the mechanisms controlling mesenchymal versus amoeboid invasion. Unexpectedly, collective/mesenchymal- and amoeboid-type invasion programs - though distinct - are each characterized by active tunneling through ECM barriers, with expression of matrix-degradative metalloproteinases. CRISPR/Cas9-mediated targeting of a single membrane-anchored collagenase, MMP14/MT1-MMP, ablates tissue-invasive activity while co-regulating cancer cell transcriptional programs. Though changes in matrix architecture, nuclear rigidity, and metabolic stress as well as the presence of cancer-associated fibroblasts are proposed to support amoeboid activity, none of these changes restore invasive activity of MMP14-targeted cancer cells. While a requirement for MMP14 is bypassed in low-density collagen hydrogels, invasion by the proteinase-deleted cells is associated with nuclear envelope and DNA damage, highlighting a proteolytic requirement for maintaining nuclear integrity. Nevertheless, when cancer cells confront explants of live human breast tissue, MMP14 is again required to support invasive activity. Corroborating these results, spatial transcriptomic and immunohistological analyses of invasive human breast cancers identified clear expression of MMP14 in invasive cells that were further associated with degraded collagen, underlining the pathophysiologic importance of this proteinase in directing invasive activity in vivo.

cancer biology↗

bioRxiv2024

A multi-tissue de novo transcriptome assembly and relative gene expression of the vulnerable freshwater salmonid Thymallus ligericus

Freshwater ecosystems are among the most endangered worldwide. While numerous taxa are on the verge of extinction as a result of global changes and direct or indirect anthropogenic activity, genomic and transcriptomic resources are a key tool to comprehend species adaptability and serve as the foundation for conservation initiatives. The Loire grayling, Thymallus ligericus, is a freshwater European salmonid endemic to the upper Loire River basin. It comprises fragmented populations dispersed over a small area and has been identified as a vulnerable species. Here, we provide a multi-tissue de novo transcriptome assembly of T. ligericus. The final assembly, with a contig N50 of 1,221 and Benchmarking Universal Single-Copy Orthologs (BUSCO) scores above 94%, is made accessible, along with structural and functional annotations and relative gene expression of five tissues. This is the first transcriptomic resource for this species, and it will serve as the foundation for future research on a species that is increasingly exposed to environmental stressors.

genomics↗

bioRxiv2018

Macrophage-Dependent Trafficking and Remodeling of the Basement Membrane-Interstitial Matrix Interface

Macrophages infiltrate and remodel extracellular matrix barriers during development and disease. Bahr and Weiss demonstrate that human macrophages remodel native basement membrane barriers in an MT1-MMP-dependent fashion while retaining the ability to traverse tissue barriers by actomyosin-dependent forces alone.\n\nAbstractMacrophages dominate inflammatory environments where they modify the extracellular matrix by mobilizing complex repertoires of proteolytic enzymes. Nevertheless, the dominant proteinases used by macrophage as they confront physiologic tissue barriers remain undefined. Herein, we have characterized the molecular mechanisms that define human macrophage-extracellular matrix interactions ex vivo. Resting and immune-polarized macrophages are shown to proteolytically remodel basement membranes while infiltrating the underlying interstitial matrix. In an unbiased screen to identify key proteases, we find that the macrophage metalloproteinase, MT1-MMP, is the dominant effector of basement membrane degradation and invasion. Unexpectedly, macrophages can alternatively use actomyosin-dependent forces to transmigrate native basement membrane pores that provide cells with proteinase-independent access to the interstitial matrix. These studies not only identify MT1-MMP as a key proteolytic effector of extracellular matrix remodeling by human macrophages, but also define the invasive strategies used by macrophages to traverse physiologic tissue barriers.

immunology↗