Biology subjects

Kamm, R.

Publications and source records attributed to Kamm, R..

8 recordsLinked to original sources

bioRxiv2026

A mechanically actuated lung microvascular model reveals that breathing-like deformation enhances tumor cell extravasation

The lung is a common site of metastasis and is continuously deformed by breathing. Whether physiological breathing mechanics influence tumor cell extravasation is unknown. To address this, we developed a mechanically actuated microphysiological system combining perfusable lung-specific microvascular networks with breathing-like cyclic deformation. Under static conditions, lung-specific networks exhibited more lung-like vascular features and higher tumor cell extravasation rates than generic networks. The mechanically actuated device reproduced physiological tissue and vascular deformation, while 24 h of cyclic actuation did not alter vessel viability, permeability, or morphology compared with unactuated controls. Pre-actuation for 24 h, followed by tumor cell perfusion under static conditions, did not alter subsequent extravasation, whereas actuation initiated immediately after perfusion significantly increased extravasation compared with unactuated controls. This biomimetic platform enables direct investigation of how breathing-like vascular deformation influences metastasis and provides a versatile tool for studying vascular mechanobiology in the lung and other mechanically active organs.

bioengineering↗

bioRxiv2026

IntravChip: a vascularized and perfused microfluidic model of the primary tumor microenvironment to collect intravasated tumor cells

Hematogenous metastasis is initiated when tumor cells (TCs) intravasate into the vasculature, yet intravasation remains poorly understood because it is difficult to observe in vivo and intravasated TCs are challenging to isolate. To address these challenges, we developed IntravChip, a continuously perfused microfluidic platform containing a vascularized primary tumor microenvironment (TME) enabling the observation of TC intravasation, and a downstream chamber to collect intravasated TCs. The IntravChip can support a high TC concentration in the TME while maintaining complete vascular perfusion, which we found was necessary to collect intravasated cells. Using MDA-MB-231 breast TCs, we identified an optimal initial TC seeding density that, by day 9, yields a densely populated TME and 100-440 collected intravasated TCs. We validated the IntravChip across several TC types, showing that MDA-MB-231 and MV3 TCs have the highest intravasation rates while MCF-7 TCs have low intravasation efficiency. We also show that the IntravChip is compatible with super-resolution nano-imaging. Our devices enabled high-quality STORM imaging, which revealed that H3K9me3 nanodomains are significantly differentially distributed in intravasated MDA-MB-231 tumor cells compared to those residing in the TME. Finally, the IntravChip was validated as a platform to test the effects of anti-cancer drugs on tumor cells and on the vasculature. We showed that a 5 M concentration of sorafenib reduced intravasation events by 69% without impacting the morphology of the microvascular networks (MVNs), while a 10 M concentration led to a significant decrease in vessel diameter. This platform enables quantitative analysis of TC intravasation, collection of intravasated TCs for characterization, and screening of anti-metastatic therapies.

bioengineering↗

bioRxiv2025

Remodeling of self-assembled microvascular networks under long term flow

The incorporation of a functional perfusable microvascular network (MVN) is a common requirement for most organ on-chip-models. Long-term perfusion of MVNs is often required for the maturation of organ phenotypes and disease pathologies and to model the transport of cells and drugs entering organs. In our microphysiological system, we observe that flow can recover perfusion in regressed MVNs and maintain perfusable MVNs for at least 51 days. Throughout the 51 days, however, the MVNs are continuously remodeling to align with the direction of bulk flow and only appear to attain morphological homeostasis with the use of maintenance medium without growth factors. We observed that the flow resistance of the MVNs decreases over time, and using a computational model, we show that stable vessels have higher flow rates and velocities compared to regressing vessels. Cytokine analysis suggests that static conditions generate an inflammatory state, and that continuous flow reduces inflammation over an extended period. Finally, through bulk RNA sequencing we identify that both the endothelial and fibroblast cells are actively engaged in vascular and matrix remodeling due to flow and that these effects persist for at least 2 weeks. This MPS can be applied to study hemodynamically driven processes, such as metastatic dissemination or drug distribution, or to model long-term diseases previously not captured by MPS, such as chronic inflammation or aging-associated diseases.

biophysics↗

bioRxiv2025

A novel human blood-brain barrier model reveals pericytes as critical regulators of viral neuroinvasion

The blood-brain barrier (BBB) plays a vital role in regulating the passage of biomolecules between the bloodstream and the central nervous system (CNS) while also protecting the CNS from pathogens. Pericytes reside at the interface between the endothelial cells that form the vessel walls and the brain parenchyma. These cells are critical for maintaining BBB integrity and play key roles in regulating vessel permeability, blood flow, and immune cell migration. In this study, we developed a novel serum-free protocol to generate neural crest cell-derived pericytes (NCC-PCs) from human pluripotent stem cells (hPSCs). These NCC-PCs enhance BMEC barrier function and can be co-cultured with hPSC-derived brain microvascular endothelial cells (BMECs) in a contact co-culture BBB model that recapitulates the in vivo cellular interactions at the BBB. We used this model to evaluate the pathological consequences of BBB cell infection by highly neuroinvasive flaviviruses. Our results identify a previously undescribed role for NCC-PCs in maintaining BMEC barrier integrity during infection and reducing the spread of viral infection to the CNS.

microbiology↗

bioRxiv2024

Polyploidy of MDA-MB-231 cells drives increased extravasation with enhanced cell-matrix adhesion

Metastasis, the leading cause of cancer-related deaths, involves a complex cascade of events, including extravasation. Despite extensive research into metastasis, the mechanisms underlying extravasation remain unclear. Molecular targeted therapies have advanced cancer treatment, yet their efficacy is limited, prompting exploration into novel therapeutic targets. Here, we showed the association of polyploidy in MDA-MB-231 breast cancer cells and their extravasation, using microfluidic systems to reproduce the in vivo microvascular environment. We observed enhanced extravasation in polyploid cells alongside upregulated expression of genes involved in cell-substrate adhesion and cell mechanical dynamics. These findings offer insights into the relationship between polyploidy and extravasation, highlighting potential targets for cancer therapy.

bioengineering↗

bioRxiv2020

The effects of luminal and trans-endothelial fluid flows on the extravasation and tissue invasion of tumor cells in a 3D in vitro microvascular platform

Throughout the process of metastatic dissemination, tumor cells are continuously subjected to mechanical forces resulting from complex fluid flows due to changes in pressures in their local microenvironments. While these forces have been associated with invasive phenotypes in 3D matrices, their role in key steps of the metastatic cascade, namely extravasation and subsequent interstitial migration, remains poorly understood. In this study, an in vitro model of the human microvasculature was employed to subject tumor cells to physiological luminal, trans-endothelial, and interstitial flows to evaluate their effects on those key steps of metastasis. Luminal flow promoted the extravasation potential of tumor cells, possibly as a result of their increased intravascular migration speed. Trans-endothelial flow increased the speed with which tumor cells transmigrated across the endothelium as well as their migration speed in the matrix following extravasation. In addition, tumor cells possessed a greater propensity to migrate in close proximity to the endothelium when subjected to physiological flows, which may promote the successful formation of metastatic foci. These results show important roles of fluid flow during extravasation and invasion, which could determine the local metastatic potential of tumor cells.

cancer biology↗

bioRxiv2020

Glycocalyx-Mediated Vascular Dissemination of Circulating Tumor Cells

The glycocalyx on tumor cells has been recently identified as an important driver for cancer progression, possibly providing critical opportunities for treatment. Metastasis, in particular, is often the limiting step in the survival to cancer, yet our understanding of how tumor cells escape the vascular system to initiate metastatic sites remains limited. Using an in vitro model of the human microvasculature, we assess here the importance of the tumor and vascular glycocalyces during tumor cell extravasation. Through selective manipulation of individual components of the glycocalyx, we reveal a novel mechanism whereby tumor cells prepare an adhesive vascular niche by depositing components of the glycocalyx along the endothelium. Accumulated hyaluronic acid shed by tumor cells subsequently mediates adhesion to the endothelium via the glycoprotein CD44. Trans-endothelial migration and invasion into the stroma occurs through binding of the isoform CD44v to components of the sub-endothelial extra-cellular matrix. Targeting of the hyaluronic acid-CD44 glycocalyx complex results in significant reduction in the extravasation of tumor cells. These studies provide evidence of tumor cells repurposing the glycocalyx to promote adhesive interactions leading to cancer progression. Such glycocalyx-mediated mechanisms may be therapeutically targeted to hinder metastasis and improve patient survival.

cancer biology↗

bioRxiv2018

Balance of Mechanical Forces Drives Endothelial Gap Formation and May Facilitate Cancer and Immune-Cell Extravasation

The formation of gaps in the endothelium is a crucial process underlying both cancer and immune cell extravasation, contributing to the functioning of the immune system during infection, the unfavorable development of chronic inflammation and tumor metastasis. Here, we present a stochastic-mechanical multiscale model of an endothelial cell monolayer and show that the dynamic nature of the endothelium leads to spontaneous gap formation, even without intervention from the transmigrating cells. These gaps preferentially appear at the vertices between three endothelial cells, as opposed to the border between two cells. We quantify the frequency and lifetime of these gaps, and validate our predictions experimentally. Interestingly, we find experimentally that cancer cells also preferentially extravasate at vertices, even when they first arrest on borders. This suggests that extravasating cells, rather than initially signaling to the endothelium, might exploit the autonomously forming gaps in the endothelium to initiate transmigration.

bioengineering↗