Biology subjects

Syed, N.

Publications and source records attributed to Syed, N..

5 recordsLinked to original sources

bioRxiv2026

Integrated multi-omic analysis of pediatric metastatic osteosarcoma reveals endothelial cell plasticity and lineage infidelity.

While recent research has increasingly focused on the role of fibroblasts and macrophages in osteosarcoma, the tumor vasculature remains poorly understood, particularly in metastatic disease. To address this gap, we performed single-nuclei multi-ome (RNA+ATAC) sequencing on 24 human metastatic osteosarcoma specimens. We found that endothelial cells adopt a hybrid endothelial-mesenchymal state resembling endothelial-to-mesenchymal transition (EndMT) and that a subset of diploid endothelial cells expresses osteoblastic transcriptional profiles and gene regulatory networks (GRN). Joint copy-number analysis further identified osteosarcoma cells with endothelial transcriptional programs and GRNs, consistent with vascular mimicry. In vitro assays and syngeneic lineage-tracing experiments validated that tumor educated endothelial cells acquire osteoblast-like features. Together, these findings reveal substantial plasticity among endothelial and osteosarcoma cells in human and murine metastatic osteosarcoma, provide new insight into the how the metastatic microenvironment shapes the tumor vasculature, and challenge current models of osteosarcoma biology.

cancer biology↗

bioRxiv2025

Inflammasome Activation in Cutaneous Squamous Cell Carcinoma

Epithelia maintain their barrier function by exploiting the proliferative and plastic properties of stem cells to promote continual tissue regeneration. Consequently, however, these features make epithelia prone to tumorigenesis. Skin is the largest epithelial barrier and the source of cutaneous cancers, the deadliest of which are cutaneous squamous cell carcinomas (cSCCs). Despite the pervasiveness of these cancers, however, the molecular mechanisms employed by stem cells and their microenvironment to promote skin tumor development remain poorly defined. Our previous work revealed that genotoxic damage to normal skin activates inflammasome signaling crosstalk between epidermal epithelia and fibroblasts to promote epithelial stem cell hyperproliferation and fate misspecification. We hypothesized that these phenomena would also be featured during skin cancer development. Using mouse and human skin disease specimens, we determined that in vivo stem cell misspecification is a generalizable feature across diverse pathophysiological skin conditions, including cutaneous cancers, but is not present in normal high proliferative contexts. Strikingly, in vivo inflammasome activation was observed in both the epithelial and dermal compartments of cSCC tumors but was not evident in other skin pathologies. Probing further into the mechanism, we revealed that inflammasome pathway activation in cSCC is epithelial autonomous but non-cell autonomous. Furthermore, fibroblasts juxtaposed to the cSCC epithelial tumor interface exhibited population expansion as well as IL-1 signaling activation, which was absent in overlying epithelia. Based on these findings, we propose a model whereby epithelial-to-fibroblast inflammasome crosstalk initiates a fibroblast feed-forward IL-1 signaling loop that augments the tumor-promoting cSCC milieu.

cell biology↗

bioRxiv2020

NOVEL NUCLEAR ROLE OF HDAC6 IN PROGNOSIS AND THERAPEUTIC TARGET FOR COLORECTAL CANCER

Histone deacetylase 6 (HDAC6) inhibition is a potential treatment of a wide range of cancer types via the acetylation of diverse proteins in the cytoplasm. However, the regulation of histone acetylation and the maintenance of higher-order chromatin structure remains unidentified. Here, we investigated the effect of selective inhibition of HDAC6 by histone acetylation, chromatin relaxation assays, co-immunoprecipitation, acetylome peptide array and in vivo RNA microarray. Our data shows that nuclear HDAC6 physically interacts with the Histone 4 lysine 12 residue, and that HDAC6 inhibition increases acetylation specifically at this residue in several cancer types. Inhibition induces major chromatin structure modulation, but has no equivalent effect on knockout HDAC6-/- MEF cells. We identified several novel HDAC6-deacetylated substrates and high expression of HDAC6 in colorectal cancer (CRC) tissue association with reduced levels of H4K12ac and independent of the key CRC driver mutations, but positively associated with EGFR expression. Furthermore, in vivo HDAC6 inhibition induces significant tumor regression in a CRC xenograft mice model with significant changes in the expression of functional nuclear genes. We also demonstrated that a DNA damaging agent in combination with selective HDAC6 inhibition is effective and acts synergistically, inducing chromatin relaxation and increased cell death in CRC cells. CRC tissues (Normal versus tumor; n=58 matched pairs) together with TCGA data analysis of 467 CRC patients showed that high HDAC6 expression is associated with metastasis, overall and disease-free survival, and is an independent risk factor of CRC stage progression. Our findings designate a new role for nuclear HDAC6 both in cancer prognosis and as a new therapeutic target for CRC and other types of cancer. HighlightHistone deacetylases 6 activity; Chromatin relaxation; Histone modifications; Gene array; DOX: doxorubicin; OXA: oxaliplatin; 5-FU: fluorouracil; Ac: acetylation; MNase: Micrococal nuclease.

cancer biology↗

bioRxiv2020

A novel synthetic peptide provides neuroprotection and rescues rat cortical neurons from anesthetic-induced cell death and modulation of growth and synaptic assembly

Anesthetics, although necessary for many modern procedures, exert neurotoxic effects in various experimental models; the underlying mechanisms, however, remain unknown. In the absence of this information, any in vivo mitigation strategy would be challenging. To help address these gaps, we sought to determine whether preserving mitochondrial network integrity with a non-toxic, short-life synthetic peptide, P110, could protect cortical neurons against both inhalational and intravenous anesthetic-induced neurotoxicity. This study provides the first direct comparative account of three key general anesthetics (desflurane, propofol, and ketamine) under identical conditions and demonstrates their impact on cellular viability, neurite outgrowth, and synaptic network assembly on neonatal rat cortical neurons. Further, we discovered that the inhibition of Fis1 receptor-mediated fission reverses anesthetic-induced aberrations in an agent-specific manner. Our data thus underscore the importance of a reductionist approach, offering unique opportunities to explore non-toxic, mitochondria-based therapeutic tools for mitigating anesthetic-induced harm to the developing brain.

neuroscience↗

bioRxiv2020

Germline genetic contribution to the immune landscape of cancer

The role of germline genetics in shaping the tumor immune landscape is largely unknown. Using genotypes from >9,000 individuals in The Cancer Genome Atlas, we investigated the association of common and rare variants with 139 well-defined immune traits. Our analysis of common variants identified 10 immune traits with significant heritability estimates, and an additional 23 with suggestive heritability, including estimates of T-cell subset abundance and interferon signaling. We performed genome-wide association on the 33 heritable traits and identified 23 genome-wide significant loci associated with at least one immune trait, including SNPs in the IFIH1 locus previously associated with several autoimmune diseases. We also found significant associations between immune traits and pathogenic or likely-pathogenic rare variants in BRCA1 and in genes functionally linked to telomere stabilization, and Wnt/Beta-catenin signaling. We conclude that germline genetic variants significantly impact the composition and functional orientation of the tumor immune microenvironment.

immunology↗