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Biology subjects

Samuel, D.

Publications and source records attributed to Samuel, D..

4 recordsLinked to original sources
bioRxiv2022

Spatial transcriptomics reveals distinct and conserved tumor core and edge architectures that predict survival and targeted therapy response

We performed the first integrative single-cell and spatial transcriptomic analysis on HPV-negative oral squamous cell carcinoma (OSCC) to comprehensively characterize tumor core (TC) and leading edge (LE) transcriptional architectures. We show that the TC and LE are characterized by unique transcriptional profiles, cellular compositions, and ligand-receptor interactions. We demonstrate that LE regions are conserved across multiple cancers while TC states are more tissue specific. Additionally, we found our LE gene signature is associated with worse clinical outcomes while the TC gene signature is associated with improved prognosis across multiple cancer types. Finally, using an in silico modeling approach, we describe spatially-regulated patterns of cell development in OSCC that are predictably associated with drug response. Our work provides pan-cancer insights into TC and LE biologies, a platform for data exploration (http://www.pboselab.ca/spatial_OSCC/) and is foundational for developing novel targeted therapies.

cancer biology↗
bioRxiv2019

Septin 9-containging filaments and Golgi assembly depend on two polybasic domains

Septins are GTP-binding proteins involved in several membrane remodeling mechanisms. They associate with membranes, presumably by using a polybasic domain (PB1) that interacts with phosphoinositides (PIs). Membrane-bound septins assemble into microscopic structures that regulate membrane shape. How septins exactly interact with PIs, assemble, and shape membranes is weakly understood. Here, we found that septin 9 has a second polybasic domain (PB2) conserved in the human septin family. Similarly to PB1, PB2 binds specifically to PIs, and both domains are critical for septin filament formation. However, septin 9 membrane association does not depend on these PB domains but on putative PB-adjacent amphipathic helices. The presence of the PB domains guarantees the protein enrichment to PI-contained membranes, which is critical for PI-enriched organelles. In particular, we found that septin 9 PB domains control the assembly and functionality of the Golgi apparatus. Our findings bring novel insights into the role of septins in organelle morphology. HighlightsO_LITwo polybasic domains mediate septin 9 interaction with PIs C_LIO_LIHuman septins have amphipathic helices suitable for binding membrane C_LIO_LISeptin 9 polybasic domains mediate septin high order structure formation C_LIO_LIMutation or depletion of septin polybasic domains induce Golgi fragmentation C_LI

cell biology↗
bioRxiv2018

Molecular basis for a novel systemic form of human hereditary apoA-I amyloidosis with vision loss

Hereditary apolipoprotein A-I (apoA-I) amyloidosis (AApoAI) is a life-threatening incurable genetic disorder whose molecular underpinnings and the full spectrum of afflicted organs are unclear. We report a new form of AApoAI with amyloid deposition in multiple organs, including an unprecedented retinal amyloidosis. Genetic and proteomic analyses identified Glu34Lys apoA-I as the fibrillar protein causing the clinical manifestations. A life-saving combined hepatorenal transplantation was performed for one Glu34Lys carrier. To elucidate structural underpinnings for amyloidogenic properties of Glu34Lys, we generated its recombinant globular domain and compared the conformation and dynamics of its lipid-free form with those of two other naturally occurring apoA-I variants, Phe71Tyr (amyloidogenic) and Leu159Arg (non-amyloidogenic). All variants showed reduced stability and altered aromatic residue packing. Molecular dynamics simulations revealed local helical unfolding and suggested that transient opening of Trp72 induced mutation-dependent structural perturbations in a sensitive region, including the major amyloid hotspot residues 14-22. We posit that a shift from the \"closed\" to an \"open\" orientation of Trp72 modulates structural protection of amyloid hotspots, suggesting a previously unknown early step in protein misfolding.

molecular biology↗