Biology subjects

Malin, J.

Publications and source records attributed to Malin, J..

7 recordsLinked to original sources

bioRxiv2024

Microenvironment Shapes Cell State, Plasticity, and Heterogeneity of Small Cell Lung Cancer

Small-cell lung cancer (SCLC) is the most fatal form of lung cancer. Intra-tumoral heterogeneity, marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states, defines SCLC, but the drivers of SCLC plasticity are poorly understood. To map the landscape of SCLC tumor microenvironment (TME), we apply spatially resolved transcriptomics and quantitative mass spectrometry-based proteomics to metastatic SCLC tumors obtained via rapid autopsy. The phenotype and overall composition of non-malignant cells in the tumor microenvironment (TME) exhibits substantial variability, closely mirroring the tumor phenotype, suggesting TME-driven reprogramming of NE cell states. We identify cancer-associated fibroblasts (CAF) as a crucial element of SCLC TME heterogeneity, contributing to immune exclusion, and predicting exceptionally poor prognosis. Together, our work provides a comprehensive map of SCLC tumor and TME ecosystems, emphasizing their pivotal role in SCLCs adaptable nature, opening possibilities for re-programming the intercellular communications that shape SCLC tumor states.

cancer biology↗

bioRxiv2024

High-throughput identification of the spatial origins of Drosophila optic lobe neurons using single-cell mRNA-sequencing

The medulla is the part of the Drosophila optic lobe with the greatest neuronal diversity, in which the identity of each neuronal type is specified in progenitors and newborn neurons via the integration of temporal, spatial, and Notch-driven patterning mechanisms. This identity is maintained in differentiating and adult neurons by the expression of neuronal type-specific combinations of terminal selectors, which are transcription factors expressed continuously during development and in the adult that are thought to control all neuronal type-specific gene expression. However, how the patterning mechanisms establish terminal selector expression is unknown. We have previously characterized the temporal and Notch origin of medulla neurons. Here we have used single-cell mRNA-sequencing to characterize their spatial origins and identified two new spatial subdomains. Together, this makes the medulla the first complex brain structure for which the patterning mechanisms specifying the identity of each neuronal type are known. This knowledge allowed us to identify correlations between patterning information, terminal selector expression and neuronal features. Our results suggest that different subsets of the patterning information accessible to a given neuronal type control the expression of each of its terminal selectors and of modules of terminal features, including neurotransmitter identity. Therefore, the evolution of new neuronal types could rely on the acquisition of modules of neuronal features pre-determined by their developmental origin.

developmental biology↗

bioRxiv2023

Spatial patterning regulates neuron numbers in the Drosophila visual system

Neurons must be made in the correct proportions to communicate with the appropriate synaptic partners and form functional circuits. In the Drosophila visual system, multiple subtypes of Distal medulla (Dm) inhibitory interneurons are made in distinct, reproducible numbers--from 5 to 800 per optic lobe. These neurons are born from a crescent-shaped neuroepithelium called the Outer Proliferation Center (OPC), which can be subdivided into specific domains based on transcription factor expression. We fate mapped Dm neurons and found that more abundant neural types are born from larger neuroepithelial subdomains, while less abundant subtypes are born from smaller ones. Additionally, morphogenetic Dpp/BMP signaling provides a second layer of patterning that subdivides the neuroepithelium into smaller domains to provide more granular control of cell proportions. Apoptosis appears to play a minor role in regulating Dm neuron abundance. This work describes an underappreciated mechanism for the regulation of neuronal stoichiometry.

developmental biology↗

bioRxiv2023

Coordinated Rho1-dependent mechanical cell-to-cell interactions and medioapical contractile pulsing regulate morphogenesis in the Drosophila retina

Lattice cells (LCs) in the developing Drosophila retina constantly move and change shape before attaining final forms. Previously we showed that repeated contraction and expansion of apical cell contacts affect these dynamics. Here we describe a second contributing factor, the assembly of a medioapical actomyosin ring composed of nodes linked by filaments that attract each other, fuse, and contract the LCs apical area. This medioapical actomyosin network is dependent on Rho1 and its known effectors. Apical cell area contraction alternates with relaxation, generating pulsatile changes in apical cell area. Strikingly, cycles of contraction and relaxation of cell area are reciprocally synchronized between adjacent LCs. Further, in a genetic screen, we identified RhoGEF2 as an activator of these Rho1 functions and RhoGAP71E/C-GAP as an inhibitor. Thus, Rho1 signaling regulates pulsatile medioapical actomyosin contraction exerting force on neighboring cells, coordinating cell behavior across the epithelium. This ultimately serves to control cell shape and maintain tissue integrity during epithelial morphogenesis of the retina. Short summaryRosa et. al. describe a Rho1-dependent pulsatile medioapical actomyosin network that couples neighboring retina lattice cells biomechanically, creating an adaptive supracellular actomyosin network that coordinates the mechanical behavior of neighboring cells and regulates cell shape and tissue integrity.

developmental biology↗

bioRxiv2023

Pten, Pi3K and PtdIns(3,4,5)P3 dynamics modulate pulsatile actin branching in Drosophila retina morphogenesis

Epithelial remodeling of the Drosophila retina depends on the pulsatile contraction and expansion of apical contacts between the cells that form its hexagonal lattice. Phosphoinositide PI(3,4,5)P3 (PIP3) accumulates around tricellular adherens junctions (tAJs) during contact expansion and dissipates during contraction, but with unknown function. Here we found that manipulations of Pten or Pi3K that either decreased or increased PIP3 resulted in shortened contacts and a disordered lattice, indicating a requirement for PIP3 dynamics and turnover. These phenotypes are caused by a loss of protrusive branched actin, resulting from impaired activity of the Rac1 Rho GTPase and the WAVE regulatory complex (WRC). We additionally found that during contact expansion, Pi3K moves into tAJs to promote the cyclical increase of PIP3 in a spatially and temporally precise manner. Thus, dynamic regulation of PIP3 by Pten and Pi3K controls the protrusive phase of junctional remodeling, which is essential for planar epithelial morphogenesis. Graphical Abstract: Control of contact length by Pi3K, Pten and PIP3. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=149 SRC="FIGDIR/small/533017v2_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@bef175org.highwire.dtl.DTLVardef@1de40e9org.highwire.dtl.DTLVardef@77b645org.highwire.dtl.DTLVardef@15f84df_HPS_FORMAT_FIGEXP M_FIG C_FIG Pi3K regulates the transition from contraction to expansion through its tension-dependent localization to tAJs and modulation of its lipid phosphatase activity. Pten localizes uniformly to regulate PIP3 turnover and attenuate PIP3 production. (A) Tension shortens contacts, concentrates Pi3K at four spots at a distance from tAJs, and inhibits Pi3Ks lipid phosphatase function. (B) High tension ultimately disassembles contractile networks allowing Pi3K to flow toward tAJs, produce PIP3 and activate the WRC to promote actin branching and contact expansion. (C) High protrusion in expanded contacts disperses the WRC and disassembles the branched actin network. (D) Branched actin disassembly allows the assembly and contraction of an actomyosin network, which increases tension and contracts the contact leading to the flow of Pi3K away from tAJs and inhibition of its lipid phosphatase function, thus completing the cycle.

developmental biology↗

bioRxiv2020

A transcription-centric model of SNP-Age interaction

Complex age-associated phenotypes are caused, in part, by an interaction between an individuals genotype and age. The mechanisms governing such interactions are however not entirely understood. Here, we provide a novel transcriptional mechanism-based framework - SNiPage, to investigate such interactions, whereby a transcription factor (TF) whose expression changes with age (age-associated TF), binds to a polymorphic regulatory element in an allele-dependent fashion, rendering the target genes expression dependent on both, the age and the genotype. Applying SNiPage to GTEx, we detected ~637 interacting TF-SNP-Gene triplets on average across 25 tissues, where the TF binds to a regulatory SNP in the genes promoter or putative enhancer and potentially regulates its expression in an age- and allele-dependent fashion. The detected SNPs are enriched for epigenomic marks indicative of regulatory activity, exhibit allele-specific chromatin accessibility, and spatial proximity to their putative gene targets. Furthermore, the TF-SNP interaction-dependent target genes have established links to aging and to age-associated diseases. In six hypertension-implicated tissues, detected interactions significantly inform hypertension state of an individual. Lastly, the age-interacting SNPs exhibit a greater proximity to the reported phenotype/diseases-associated SNPs than eSNPs identified in an interaction-independent fashion. Overall, we present a novel mechanism-based model, and a novel framework SNiPage, to identify functionally relevant SNP-age interactions in transcriptional control and illustrate their potential utility in understanding complex age-associated phenotypes.

genetics↗

bioRxiv2018

CyanoGate: A Golden Gate modular cloning suite for engineering cyanobacteria based on the plant MoClo syntax

Recent advances in synthetic biology research have been underpinned by an exponential increase in available genomic information and a proliferation of advanced DNA assembly tools. The adoption of plasmid vector assembly standards and parts libraries has greatly enhanced the reproducibility of research and exchange of parts between different labs and biological systems. However, a standardised Modular Cloning (MoClo) system is not yet available for cyanobacteria, which lag behind other prokaryotes in synthetic biology despite their huge potential in biotechnological applications. By building on the assembly library and syntax of the Plant Golden Gate MoClo kit, we have developed a versatile system called CyanoGate that unites cyanobacteria with plant and algal systems. We have generated a suite of parts and acceptor vectors for making i) marked/unmarked knock-outs or integrations using an integrative acceptor vector, and ii) transient multigene expression and repression systems using known and novel replicative vectors. We have tested and compared the CyanoGate system in the established model cyanobacterium Synechocystis sp. PCC 6803 and the more recently described fast-growing strain Synechococcus elongatus UTEX 2973. The system is publicly available and can be readily expanded to accommodate other standardised MoClo parts.

synthetic biology↗