Biology subjects

Bartos, L.

Publications and source records attributed to Bartos, L..

4 recordsLinked to original sources

bioRxiv2024

Limitations of the radiotheranostic concept in neuroendocrine tumors due to lineage-dependent somatostatin receptor expression on hematopoietic stem and progenitor cells

Radiopharmaceutical therapy (RPT) has become an effective treatment option for neuroendocrine tumors (NETs) and castration-resistant prostate cancer and is in clinical development for a growing number of indications. One of the major advantages of theranostic RPT is that the distribution of radiopharmaceuticals in the human body can be imaged, and radiation doses to the patients organs can be calculated. However, accurate dosimetry may be fundamentally limited by microscopic heterogeneity of radiopharmaceutical distribution. We developed fluorescent analogs of somatostatin-receptor-subtype 2 (SSTR2) targeting Lutetium-177 labelled radiopharmaceuticals that are clinically used in patients with neuroendocrine tumors (NETs) and studied their uptake by hematopoietic stem and progenitor cells (HSPC). Hematopoietic stem cells (HSCs) and multipotent progenitor cells (MPPs) showed high and specific SSTR2-ligand uptake, which was at similar levels as neuroendocrine tumor cells. Furthermore, they displayed a several-fold higher uptake of SSTR2-antagonists than of SSTR2-agonists. HSPC treatment with a 177Lu-labelled antagonist and agonist showed a stronger reduction of HSC proliferation by the antagonist. Due to the scarcity of HSCs and MPPs, their contribution to total bone marrow uptake of SSTR2-ligands is not detectable in imaging-based dosimetry studies. This likely explains why SSTR2-antagonists caused pancytopenia in clinical trials despite safe dosimetry estimates. In conclusion, target expression heterogeneity can lead to underestimation of radiopharmaceutical toxicity and should be considered when designing clinical trials for new radiopharmaceuticals. The implications of our findings go beyond somatostatin receptor-targeted radiopharmaceuticals and suggest more generally that first-in-human studies should not only be guided by radiation dosimetry from imaging studies but should also include careful escalation of the administered therapeutic activity. The MMC technology is modular and can be applied to other peptide or protein-based radiopharmaceuticals to study cellular distribution and potential bone marrow uptake prior to clinical testing.

cancer biology↗

bioRxiv2023

Enhanced Diffusion through Multivalency

In multivalent systems, multiple ligands from one entity simultaneously bind to multiple receptors on another entity. These interactions are of crucial significance in a wide range of biological and technological mechanisms, encompassing selectivity, host recognition, viral penetration, therapeutic delivery, as well as the adhesion phenomena found in cells, polymers, and nanoparticles. In this study, we used computer simulations to investigate 1D and 2D diffusion of adsorbed particles with varying valency but with the same overall affinity to the host. We demonstrate a remarkable diffusion acceleration for particles with increasing valency. Non-diffusing monovalent particle can attain almost unrestricted diffusion when becoming multivalent while retaining its affinity for the host tether or surface. Moreover, diffusion of multivalent particles with rigid ligand distribution can be controlled by patterned host receptors. Our results have practical implications for the design of fast-diffusing particles that maintain a strong affinity for target surfaces or molecules. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/558647v2_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@ef72d1org.highwire.dtl.DTLVardef@5b22e7org.highwire.dtl.DTLVardef@150868borg.highwire.dtl.DTLVardef@1b1364e_HPS_FORMAT_FIGEXP M_FIG C_FIG SignificanceWe investigated how the number of binding sites (referred to as valency) on particles or entities impacts their movement when attached to surfaces or filaments. Valency can be understood as how many "hands" a particle has to grip the surface. Surprisingly, particles with more "hands" move faster if they hold onto the surface with the same strength. Furthermore, the motion of these particles can be controlled by designing surfaces with specific patterns that the "hands" can grasp. This means that we can design particles that move rapidly while remaining attached to the desired locations. These findings hold promise for applications like drug delivery and materials technology, and for understanding biological processes.

biophysics↗

bioRxiv2023

Insertases Scramble Lipids: Molecular Simulations of MTCH2

Scramblases play a pivotal role in facilitating bidirectional lipid transport across cell membranes, thereby influencing lipid metabolism, membrane homeostasis, and cellular signaling. MTCH2, a mitochondrial outer membrane protein insertase, has a membrane-spanning hydrophilic groove resembling those that form the lipid transit pathway in known scramblases. Employing both coarse-grained and atomistic molecular dynamics simulations, we show that MTCH2 significantly reduces the free energy barrier for lipid movement along the groove and therefore can indeed function as a scramblase. Notably, the scrambling rate of MTCH2 in silico is similar to that of VDAC, a recently discovered scramblase of the outer mitochondrial membrane, suggesting a potential complementary physiological role for these mitochondrial proteins. Finally, our findings suggest that other insertases which possess a hydrophilic path across the membrane like MTCH2, can also function as scramblases. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=183 SRC="FIGDIR/small/553169v2_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@e78668org.highwire.dtl.DTLVardef@292ce0org.highwire.dtl.DTLVardef@1413077org.highwire.dtl.DTLVardef@d4e29b_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIScrambling activity of MTCH2 identified using computer simulations C_LIO_LIMTCH2 may act redundantly with VDAC as outer mitochondrial membrane scram-blase C_LIO_LIInsertases and scramblases may share a common functional mechanism C_LI

biophysics↗

bioRxiv2022

Mitochondrial phospholipid import mediated by VDAC, a dimeric beta barrel scramblase

Mitochondria are double-membrane-bounded organelles that depend critically on phospholipids supplied by the endoplasmic reticulum. These lipids must cross the outer membrane to support mitochondrial function, but how they do this is unclear. We identified the voltage-dependent ion channel (VDAC), an abundant outer membrane protein, as a scramblase-type lipid transporter that catalyzes lipid entry. On reconstitution into membrane vesicles, dimers of human VDAC1 and VDAC2 catalyze rapid transbilayer translocation of phospholipids by a mechanism that is unrelated to their channel activity. Coarse-grained molecular dynamics simulations of VDAC1 reveal that lipid scrambling occurs at a specific dimer interface where polar residues induce large water defects and bilayer thinning. The rate of phospholipid import into yeast mitochondria is an order of magnitude lower in the absence of VDAC homologs, indicating that VDACs provide the main pathway for lipid entry. Thus, VDAC isoforms, members of a superfamily of beta barrel proteins, moonlight as a new class of phospholipid scramblases - distinct from alpha-helical scramblase proteins - that act by an unprecedented mechanism to import lipids into mitochondria.

biochemistry↗