Biology subjects

Wang, J. M.

Publications and source records attributed to Wang, J. M..

5 recordsLinked to original sources

bioRxiv2024

Characterization of tumor heterogeneity through segmentation-free representation learning

The interaction between tumors and their microenvironment is complex and heterogeneous. Recent developments in high-dimensional multiplexed imaging have revealed the spatial organization of tumor tissues at the molecular level. However, the discovery and thorough characterization of the tumor microenvironment (TME) remains challenging due to the scale and complexity of the images. Here, we propose a self-supervised representation learning framework, CANVAS, that enables discovery of novel types of TMEs. CANVAS is a vision transformer that directly takes high-dimensional multiplexed images and is trained using self-supervised masked image modeling. In contrast to traditional spatial analysis approaches which rely on cell segmentations, CANVAS is segmentation-free, utilizes pixel-level information, and retains local morphology and biomarker distribution information. This approach allows the model to distinguish subtle morphological differences, leading to precise separation and characterization of distinct TME signatures. We applied CANVAS to a lung tumor dataset and identified and validated a monocytic signature that is associated with poor prognosis.

cancer biology↗

bioRxiv2022

Androgen-mediated TGFβ expression suppresses anti-tumor neutrophil response in bone metastatic prostate cancer

Prostate Cancer (PCa) bone metastases are associated with spinal cord compression, fracture, bone pain and death. Despite advances in the medical therapy for localized disease, metastatic disease is incurable and osseous progression is largely dictated by tumor-stromal interactions in the bone microenvironment. We showed previously that tumor bone neutrophils are tumoricidal to PCa but lose their cytotoxic potential as the tumor progresses. However, there have been no studies to date to clinically define and characterize neutrophils throughout the prostate cancer disease spectrum to determine their biomarker potential. Using patient peripheral blood polymorphonuclear neutrophils (PMNs), we identify that PCa progression dictates PMN properties, including viability, cell surface markers and gene expression. However, the majority of PMNs elicited an anti-tumor response ex vivo demonstrating that PMN cytotoxicity is cell autonomous and independent of PCa disease stage. In fact, we identify a novel role for androgen regulation, i.e., androgen deprivation therapy (ADT), in suppressing PMN cytotoxicity via altered transforming growth factor beta receptor I (T{beta}RI). Using preclinical models, we found that high dose testosterone/bipolar androgen therapy (BAT) and genetic or pharmacologic T{beta}RI inhibition combined with standard ADT rescued the androgen-associated suppression and restored PMN anti-tumor immune response. This combination provided a therapeutic strategy more impactful than ADT alone, in bone metastatic prostate cancer (BM-PCa). These studies: 1) highlight a necessity for both molecular and functional characterization of PMNs per cancer type and 2) reveals the ability to program PMN immune response for successful targeting of BM-PCa.

cancer biology↗

bioRxiv2021

Intra-species transcriptional profiling reveals key regulators of Candida albicans pathogenic traits

The human commensal and opportunistic fungal pathogen Candida albicans displays extensive genetic and phenotypic variation across clinical isolates. Here, we performed RNA sequencing on 21 well-characterized isolates to examine how genetic variation contributes to gene expression differences, and to link these differences to phenotypic traits. C. albicans adapts primarily through clonal evolution and yet hierarchical clustering of gene expression profiles in this set of isolates did not reproduce their phylogenetic relationship. Strikingly, strain-specific gene expression was prevalent in some strain backgrounds. Association of gene expression with phenotypic data by differential analysis, linear correlation, and assembly of gene networks connected both previously characterized and novel genes with 23 C. albicans traits. Construction of de novo gene modules produced a gene atlas incorporating 67% of C. albicans genes and revealed correlations between expression modules and important phenotypes such as systemic virulence. Furthermore, targeted investigation of two modules that have novel roles in growth and filamentation supported our bioinformatic predictions. Together, these studies reveal widespread transcriptional variation across C. albicans isolates and identify genetic and epigenetic links to phenotypic variation based on co-expression network analysis. ImportanceInfectious fungal species are often treated uniformly despite clear evidence of genotypic and phenotypic heterogeneity being widespread across strains. Identifying the genetic basis for this phenotypic diversity is extremely challenging because of the tens or hundreds of thousands of variants that may distinguish two strains. Here we use transcriptional profiling to determine differences in gene expression that can be linked to phenotypic variation among a set of 21 Candida albicans isolates. Analysis of this transcriptional dataset uncovered clear tends in gene expression characteristics for this species and new genes and pathways that associated with variation in pathogenic processes. Direct investigation confirmed functional predictions for a number of new regulators associated with growth and filamentation, demonstrating the utility of these approaches in linking genes to important phenotypes.

genomics↗

bioRxiv2018

The Genome of the Human Pathogen Candida albicans is Shaped by Mutation and Cryptic Sexual Recombination

The opportunistic fungal pathogen Candida albicans lacks a conventional sexual program and is thought to evolve, at least primarily, through the clonal acquisition of genetic changes. Here, we performed an analysis of heterozygous diploid genomes from 21 clinical isolates to determine the natural evolutionary processes acting on the C. albicans genome. Consistent with a model of inheritance by descent, most single nucleotide polymorphisms (SNPs) were shared between closely related strains. However, strain-specific SNPs and insertions/deletions (indels) were distributed non-randomly across the genome. For example, base substitution rates were higher in the immediate vicinity of indels, and heterozygous regions of the genome contained significantly more strain-specific polymorphisms than homozygous regions. Loss of heterozygosity (LOH) events also contributed substantially to genotypic variation, with most long-tract LOH events extending to the ends of the chromosomes suggestive of repair via break-induced replication. Importantly, some isolates contained highly mosaic genomes and failed to cluster closely with other isolates within their assigned clades. Mosaicism is consistent with strains having experienced inter-clade recombination during their evolutionary history and a detailed examination of nuclear and mitochondrial genomes revealed striking examples of recombination. Together, our analyses reveal that both (para)sexual recombination and mitotic mutational processes drive evolution of this important pathogen in nature. To further facilitate the study of genome differences we also introduce an online platform, SNPMap, to examine SNP patterns in sequenced C. albicans genomes.\n\nAUTHOR SUMMARYMutations introduce variation into the genome upon which selection can act. Defining the nature of these changes is critical for determining species evolution, as well as for understanding the genetic changes driving important cellular processes such as carcinogenesis. The fungus Candida albicans is a heterozygous diploid species that is both a frequent commensal organism and a prevalent opportunistic pathogen. Prevailing theory is that C. albicans evolves primarily through the gradual build-up of mutations, and a pressing question is whether sexual or parasexual processes also operate within natural populations. Here, we determine the evolutionary patterns of genetic change that have accompanied species evolution in nature by examining genomic differences between clinical isolates. We establish that the C. albicans genome evolves by a combination of base-substitution mutations, insertions/deletion events, and both short-tract and long-tract loss of heterozygosity (LOH) events. These mutations are unevenly distributed across the genome, and reveal that non-coding regions and heterozygous regions are evolving more quickly than coding regions and homozygous regions, respectively. Furthermore, we provide evidence that genetic exchange has occurred between isolates, establishing that sexual or parasexual processes have transpired in C. albicans populations and contribute to the diversity of both nuclear and mitochondrial genomes.

genomics↗

bioRxiv2017

Alpha-synuclein fibrils induce autophagy in microglial cells as a consequence of lysosomal damage.

Autophagy is a constitutive lysosomal catabolic pathway that degrades damaged organelles and protein aggregates. In Parkinsons disease, the synaptic protein alpha-synuclein (AS) accumulates in neuronal cell bodies and axons. Recent studies indicate that aggregation-prone proteins can spread to other brain cells - such as glia - contributing to progressive deterioration.\n\nAlthough autophagic dysfunction and protein aggregation have been linked to several neurodegenerative disorders, exact mechanisms are not clear and most work was done in neurons and not on microglial cells.\n\nHere we report that AS fibrils but not monomers induce lysosomal damage and autophagy in microglial cells and we extensively characterized the dynamics of this response by both live-cell imaging and correlative light-electron microscopy (CLEM). In addition, we found that autophagy inhibition in these cells impairs mitochondrial quality and leads to microglial cell death. We propose that AS accumulation in lysosomes leads to lysosomal damage, which in turn activates canonical autophagy as a rescue mechanism.\n\nOur results provide novel findings about the interaction between AS and the autophagy pathway in microglial cells, which may be important for targeting protein misfolding-associated neurodegenerative diseases.

cell biology↗