Biology subjects

Al-Hilal, T.

Publications and source records attributed to Al-Hilal, T..

4 recordsLinked to original sources

bioRxiv2026

Stress-Survival Pathway Profiling Reveals MCM10 as a Candidate Biomarker of Hispanic Colorectal Cancer Disparities

BackgroundColorectal cancer (CRC) remains the second leading cause of cancer mortality in the U.S., with significant racial and ethnic disparities in incidence, survival, and mortality rates. The rising incidence of early-onset CRC and the frequent presentation at advanced stages of CRC among the Hispanics makes this an important ethnic group to study. A deeper understanding of the complex interplay between molecular, genetic, and environmental factors is critical for developing targeted therapies to reduce the prevalence in specific racial and ethnic groups, such as Hispanics. This study explores the role of stress-survival pathway (SSP) genes in early-onset and late-stage CRC, primarily focusing on disparities between Hispanics and Non-Hispanic Whites (NHWs). Additionally, this study investigates the role of MCM10, in contributing to CRC disparities among the Hispanic populations with an emphasis of early-onset and late-stage CRC Hispanics. MethodsOne of our previous studies had identified some SSP protein coding genes associated with CRC. The transcript and protein level expressions of these genes were validated in CRC cell lines, cDNA arrays, and tissue microarrays, using qRT-PCR and immunohistochemistry, respectively. The transcript level expressions of differentially expressed SSP genes were further evaluated in Hispanic and NHWs tumor tissues, including early onset and late-stage cohorts. Additionally, we performed cellular, physiological, and functional assays to explore the role of MCM10 in tumor progression, before and after siRNA mediated knockdown of MCM10. High-throughput transcriptomic and proteomic analyses were performed to reveal the underlying molecular mechanism. ResultsWe observed the differential expressions of twelve SSP genes in CRC cell lines, at the transcript level; that of ten genes in early and late stages using cDNA arrays, and nine genes at the protein levels using tissue microarrays and immunohistochemistry. Hispanic CRC samples showed differential expression of all nine SSP genes compared to NHWs, in early-onset, and late-stage CRC, with all genes being upregulated other than CDK4 and PRDX4 in late-stage CRC and CDK4 in early-onset CRC. Our functional study demonstrated that MCM10 knockdown in CRC cell lines significantly reduced cell proliferation, growth, invasion, and migration by inducing cell cycle arrest, apoptosis, and reactive oxygen species pathways. The integrative RNA-sequencing and proteomics study identified that PPFIA1 could be associated with MCM10 mediated cancer progression. The role of MCM10 and PPFIA1 in cancer progression has also been validated by CRISPR-Cas9 mediated MCM10 knock out, using a Hispanic CRC patient derived organoid. ConclusionThe differential expression of SSP genes suggest a potential molecular contribution to CRC disparities in the Hispanic population. The essential oncogenic role of MCM10 and its axis with PPFIA1 was identified; this could lead to a new avenue for therapeutics targeting the MCM10-PPFIA1 axis, thereby, combating early-onset and advanced-stage CRC in this high-risk ethnic group. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=177 HEIGHT=200 SRC="FIGDIR/small/698057v2_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@11528c8org.highwire.dtl.DTLVardef@288d15org.highwire.dtl.DTLVardef@466703org.highwire.dtl.DTLVardef@150890_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

FOLR1-targeted Actinium-225-based Alpha-particle Therapy Eliminates Ovarian Cancer

Despite the advancement in therapies, ovarian cancer treatment is challenging due to poor prognosis and high relapse associated with acquired resistance. Targeting overexpression of FOLR1 in ovarian cancers has proven to be an attractive strategy. The recent FDA approval of FOLR1 targeted antibody drug conjugate has shown promising results albeit resistance with repeated use appears inevitable. Emerging targeted alpha-particle therapies, particularly Actinium-225 (225Ac), for treating refractory cancers have opened avenues for improved therapeutic options. The success of alpha-particle therapy relies on tumor specific delivery of the alpha emitters. Herein we describe the first example of FOLR1-targeted 225Ac alpha-particle therapy for treatment of ovarian cancer. Longitudinal PET imaging demonstrated high tumor-specific uptake of FOLR1 in SKOV3 xenografts. FOLR1-targeted 225Ac demonstrated high therapeutic efficacy achieving marked tumor regression, 80% survival and 40% complete response. The therapy resulted in tumor specific double stranded DNA damage, and no obvious toxicity was observed in normal tissues. Estimated human dosimetry showed high absorbed dose for tumor and minimal absorbed dose for healthy tissues establishing its safety. In totality, FOLR1-targeted 225Ac alpha-particle therapy is an efficacious and safe treatment with high feasibility for clinical translation to fight against ovarian cancer.

bioengineering↗

bioRxiv2025

αTAT1 defines a microtubule mechanosensing axis that drives fibroblast durotaxis and fibrosis across organs

Durotaxis, the directed migration of cells along gradients of extracellular stiffness, drives tissue fibrosis by recruiting fibroblasts to stiffened injury sites where hey differentiate into myofibroblasts and deposit scar tissue. While actin cytoskeletal tension and focal adhesion dynamics have been implicated in this process, the contribution of microtubules to cellular mechanosensing and durotaxis has remained undefined. Here, we uncover TAT1-mediated microtubule acetylation as a master regulator of fibroblast mechanosensing and stiffness-directed durotaxis. By catalyzing -tubulin K40 acetylation, TAT1 confers the structural flexibility required for directional microtubule alignment and persistent polarity along stiffness gradients, enabling fibroblasts to sense mechanical cues and initiate profibrotic programs. Loss of TAT1 abolishes K40 acetylation, disrupts focal adhesion FAK signaling, and suppresses YAP nuclear localization, thereby uncoupling extracellular matrix stiffness from downstream mechanotransduction. Global or fibroblast-specific deletion of TAT1 markedly reduces fibroblast durotaxis and myofibroblast accumulation, and protects mice from lung, dermal, and kidney fibrosis in experimental models, without affecting inflammation or vascular integrity. Together, our findings define TAT1-dependent microtubule mechanosensing as a central cytoskeletal pathway coupling fibroblast mechanobiology to organ fibrosis in vivo, positioning the TAT1 catalytic domain as a novel mechano-therapeutic target in fibrotic disease.

cell biology↗

bioRxiv2024

The prion-like protein Doppel: A soluble biomarker steering ovarian cancers peritoneal to circulatory dissemination

Detecting ovarian cancer (OC) early using existing biomarkers, e.g., cancer antigen 125 (CA125), is challenging due to its ubiquitous expression in many tissues. Doppel, a prion-like protein, expresses in male reproductive organ but absent in female reproductive systems and healthy tissues, but plays an important role in neoangiogenesis. Here, we have shown two platforms, soluble Doppel in sera/ascites and Doppel expressed circulating tumor cells (Dpl+CTC) in the whole blood, to detect subsets of epithelial OC (EOC). Increased level of Doppel in the sera of OC patients, in three different cohorts, confirm Doppel as OC specific biomarker. Serum Doppel level distinguishes EOC subtypes and early stages HGSOCs from non-cancerous conditions with high sensitivity and specificity. Stratifying the EOCs based on Doppel level, we categorized them into Doppel-high (Dplhi) and Doppel-low (Dpllow) groups. Using ascites-derived organoids and single cell sequencing of whole ascites of Dplhi and Dpllow patients, we identify that Doppel induces epithelial-mesenchymal transition (EMT) and creates an immunosuppressive microenvironment, respectively. Doppel levels in the sera/ascites correlate with the changes of Dpl+CTC number in whole blood, highlighting the association of Doppel-induced EMT with CTC dissemination in circulation. Thus, Doppel-based detection of EOC subtypes could be a promising platform as clinical biomarker and link Doppel-axis with OC dissemination.

cancer biology↗