Biology subjects

Spector, D.

Publications and source records attributed to Spector, D..

6 recordsLinked to original sources

bioRxiv2026

Probing the neural geometry of conscious object perception in time

Conscious object recognition is a critical brain function, key to making sense of the plethora of visual inputs and guiding adaptive behavior. Yet, the sequence of neural processing underlying conscious object recognition remains unclear. Existing proposals alternatively suggest that conscious object recognition proceeds in a "coarse-to-fine" sequence or a "fine-to-coarse" sequence. Here, we recorded high-density EEG while participants of both sexes performed a threshold-level object recognition task under different viewing conditions. Both superordinate and basic-level category information emerged early in neural activity, followed by a late superordinate category representation in an abstract format that is disentangled from low-level object features. Strikingly, in the early period, while basic-level category information positively correlated with perceptual awareness, superordinate category information negatively predicted perceptual awareness. By contrast, both superordinate and basic-level category information positively correlated with objective categorization accuracy in the early period. In the late period, both levels of category information positively correlated with awareness. These results suggest that neural processing underlying conscious object perception proceeds from the basic to the superordinate category level.

neuroscience↗

bioRxiv2023

A sub-set of guanine- and cytosine-rich genes are actively transcribed at the nuclear Lamin B1 region

Chromatin organization in the mammalian cell nucleus plays a vital role in the regulation of gene expression. The lamina-associated domain at the inner nuclear membrane has been shown to harbor heterochromatin, while the nuclear interior has been shown to contain most of the euchromatin. Here, we show that a sub-set of actively transcribing genes, marked by RNA Pol II pSer2, are associated with Lamin B1 at the inner nuclear envelope in mouse embryonic stem cells (mESCs) and the number of genes proportionally increases upon in vitro differentiation of mESC to olfactory precursor cells. These nuclear periphery-associated actively transcribing genes primarily represent housekeeping genes, and their gene bodies are significantly enriched with guanine and cytosine compared to genes actively transcribed at the nuclear interior. We found the promoters of these genes to also be significantly enriched with guanine and to be predominantly regulated by zinc finger protein transcription factors. We provide evidence supporting the emerging notion that the Lamin B1 region is not solely transcriptionally silent.

cell biology↗

bioRxiv2023

Identification of glioblastoma stem cell-associated lncRNAs using single-cell RNA-sequencing datasets

Glioblastoma multiforme (GBM) is an aggressive, heterogeneous grade IV brain tumor. Glioblastoma stem cells (GSCs) initiate the tumor and are known culprits of therapy resistance. Mounting evidence has demonstrated a regulatory role of long non-coding RNAs (lncRNAs) in various biological processes, including pluripotency, differentiation, and tumorigenesis. A few studies have suggested that aberrant expression of lncRNAs is associated with GSCs. However, a comprehensive single-cell analysis of the GSC-associated lncRNA transcriptome has not been carried out. Here, we analyzed recently published single-cell RNA-sequencing datasets of adult human GBM tumors, GBM organoids, GSC-enriched GBM tumors, and developing human brains to identify lncRNAs highly expressed in GBM. To categorize GSC populations in the GBM tumors, we used the GSC marker genes SOX2, PROM1, FUT4, and L1CAM. We found three major GSC population clusters: radial glia, oligodendrocyte progenitor cells, and neurons. We found 10-100 lncRNAs significantly enriched in different GSC populations. We also validated the level of expression and localization of several GSC-enriched lncRNAs using qRT-PCR, single-molecule RNA FISH, and sub-cellular fractionation. We found that the radial glia GSC-enriched lncRNA PANTR1 is highly expressed in GSC lines and is localized to both the cytoplasmic and nuclear fractions. In contrast, the neuronal GSC-enriched lncRNAs LINC01563 and MALAT1 are highly enriched in the nuclear fraction of GSCs. Together, this study identified a panel of uncharacterized GSC-specific lncRNAs. These findings set the stage for future in-depth studies to examine their role in GBM pathology and their potential as biomarkers and/or therapeutic targets in GBM.

cancer biology↗

bioRxiv2021

The long non-coding RNA MaTAR20 promotes mammary tumor growth by regulating angiogenesis pathways

Long non-coding RNAs (lncRNAs) are an emerging class of regulatory molecules that have been shown to play important roles in tumorigenesis and cancer progression. Here, we studied the recently identified lncRNA Mammary Tumor Associated RNA 20 (MaTAR20) in mammary cancer progression. A CRISPR/Cas9 knockout of MaTAR20 in the metastatic 4T1 cell line led to reduced cancer cell proliferation and increased cell surface adhesion compared to control cells. Consistent with these knockout results antisense oligonucleotide (ASO) mediated knockdown of MaTAR20 resulted in reduced growth and invasion in 4T1 cells, and in primary mammary tumor organoids derived from the MMTV-PyMT mouse model of breast cancer. Injection of MaTAR20-specific ASOs subcutaneously into tumor bearing MMTV-PyMT mice resulted in smaller and highly necrotic tumors in comparison to mice injected with a scrambled control ASO. To investigate the molecular mechanism by which MaTAR20 acts to advance mammary tumor progression, we applied a combination of RNA-sequencing and RNA-pulldown coupled to DNA-sequencing. These analyses demonstrated that the nuclear retained lncRNA is associated with several essential cancer signaling pathways such as VEGF signaling. In particular, MaTAR20 directly binds to and regulates the expression of Tnfsf15. Our results indicate that MaTAR20 is an important driver of mammary tumor progression and represents a promising new therapeutic target.

cancer biology↗

bioRxiv2021

Cancer phylogenetics using single-cell RNA-seq data

Phylogenetic methods are emerging as a useful tool to understand cancer evolutionary dynamics, including tumor structure, heterogeneity, and progression. Most currently used approaches utilize either bulk whole genome sequencing (WGS) or single-cell DNA sequencing (scDNA-seq) and are based on calling copy number alterations and single nucleotide variants (SNVs). scRNA-seq is commonly applied to explore differential gene expression of cancer cells throughout tumor progression. The method exacerbates the single-cell sequencing problem of low yield per cell with uneven expression levels. This accounts for low and uneven sequencing coverage and makes SNV detection and phylogenetic analysis challenging. In this paper, we demonstrate for the first time that scRNA-seq data contains sufficient evolutionary signal and can also be utilized in phylogenetic analyses. We explore and compare results of such analyses based on both expression levels and SNVs called from scRNA-seq data. Both techniques are shown to be useful for reconstructing phylogenetic relationships between cells, reflecting the clonal composition of a tumor. Both standardized expression values and SNVs appear to be equally capable of reconstructing a similar pattern of phylogenetic relationship. This pattern is stable even when phylogenetic uncertainty is taken in account. Our results open up a new direction of somatic phylogenetics based on scRNA-seq data. Further research is required to refine and improve these approaches to capture the full picture of somatic evolutionary dynamics in cancer.

cancer biology↗

bioRxiv2020

Activating a collaborative innate-adaptive immune response to control breast and ovarian cancer metastasis

Many cancers recruit monocytes/macrophages and polarize them into tumor-associated macrophages (TAMs). TAMs promote tumor growth and metastasis and inhibit cytotoxic T cells. Yet, macrophages can also kill cancer cells after polarization by e.g., lipopolysaccharide (LPS, a bacteria-derived toll-like receptor 4 [TLR4] agonist) and interferon gamma (IFN{gamma}). They do so via nitric oxide (NO), generated by inducible NO synthase (iNOS). Altering the polarization of macrophages could therefore be a strategy for controlling cancer. Here, we show that monophosphoryl lipid A (MPLA, a derivative of LPS) with IFN{gamma} activated macrophages isolated from metastatic pleural effusions of breast cancer patients to kill the corresponding patients cancer cells in vitro. Importantly, intratumoral injection of MPLA with IFN{gamma} not only controlled local tumor growth but also reduced metastasis in mouse models of luminal and triple negative breast cancers. Furthermore, intraperitoneal administration of MPLA with IFN{gamma} reprogrammed peritoneal macrophages, suppressed metastasis, and enhanced the response to chemotherapy in the ID8-p53-/- ovarian carcinoma mouse model. The combined MPLA+IFN{gamma} treatment reprogrammed the immunosuppressive microenvironment to be immunostimulatory by recruiting leukocytes, stimulating type I interferon signaling, decreasing tumor-associated (CD206+) macrophages, increasing tumoricidal (iNOS+) macrophages, and activating cytotoxic T cells through macrophage-secreted interleukin 12 (IL-12) and tumor necrosis factor (TNF). Both macrophages and T cells were critical for the anti-metastatic effects of MPLA+IFN{gamma}. MPLA and IFN{gamma} are already used individually in clinical practice, so our strategy to engage the anti-tumor immune response, which requires no knowledge of unique tumor antigens, may be ready for near-future clinical testing.

cancer biology↗