Biology subjects

Hassan, A. A.

Publications and source records attributed to Hassan, A. A..

3 recordsLinked to original sources

bioRxiv2025

Cancer-specific sialylation of insulin-like growth factor 1 receptor impairs therapeutic antibody binding and efficacy

Despite extensive efforts to develop insulin-like growth factor (IGF1R)-targeted therapies for various malignancies, none has received clinical approval in the past two decades. Here, we reveal that N-glycan sialylation significantly decreases recognition by the humanized monoclonal anti-IGF1R antibody ganitumab across various cancer types, reducing its efficacy both in vitro and in vivo. Sialoforms of IGF1R are virtually absent in normal cells, indicating that the modification is tumor-specific. Pharmacological inhibition of sialyltransferases significantly sensitizes metastatic tumors to ganitumab in a ganitumab-resistant ovarian cancer model. Enzymatic removal of sialic acids from tissue sections resulted in marked enhancement in antibody binding to ovarian cancer patient tumors, but not normal tissues. Upregulation of 2-6 sialyltransferase ST6GAL1 in tumor tissues was found to be responsible for sialylation of IGF1R. Consequently, ST6GAL1-high tumors were more likely to benefit from desialylation-mediated enhancement of ganitumab binding. Furthermore, through comprehensive glycoproteomics analysis, structural prediction, and molecular dynamics simulation, we identify Asn-607 (N607) as a crucial site harboring sialylated glycans. Mechanistically, N607 glycosylation destabilizes the IGF1R-ganitumab complex. Overexpression of IGF1R Asn-607-Gln (N607Q) mutant in IGF1R-knockout cancer cells increases ganitumab efficacy compared to wild-type IGF1R in vivo. Taken together, these findings highlight sialylation as a common barrier in IGF1R-targeted therapies and provide crucial insights for therapy enhancement in cancer and patient stratification for future clinical trials. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC="FIGDIR/small/682592v1_ufig1.gif" ALT="Figure 1"> View larger version (14K): org.highwire.dtl.DTLVardef@17c6d5corg.highwire.dtl.DTLVardef@1efe2f7org.highwire.dtl.DTLVardef@1dd05aorg.highwire.dtl.DTLVardef@159fb23_HPS_FORMAT_FIGEXP M_FIG C_FIG Synopsis2-6 sialylation of IGF1R Asn-607 by ST6GAL1 is prevalent in cancer. This modification disrupts the interaction of IGF1R with therapeutic mAb ganitumab. Removal of sialylation augments ganitumab efficacy.

cancer biology↗

bioRxiv2025

CD4+ T cells promote fibrosis during metabolic dysfunction-associated steatohepatitis

Unresolved inflammation and fibrosis are the two key features of metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of steatotic liver disease that can evolve into cirrhosis and liver cancer. Although innate immunity has been well studied in MASH, the role of CD4 T cells remains underexplored despite their potential to coordinate immune responses by providing help to other immune cells, promoting inflammation, or regulating immune activity through effector and regulatory subsets. To better understand the role of CD4+ T cells in the pathogenesis of MASH, we comprehensively characterized hepatic CD4+ T cells in murine and human MASH at a single-cell protein, transcriptional, and functional level. Mass cytometry and CITE-sequencing revealed a marked shift in intrahepatic CD4 T-cell composition in MASH, with enrichment of Th1, regulatory, and cytotoxic CD4 T cells. Similar phenotypic changes were mirrored in the peripheral blood and validated in human MASH samples. Functional assays demonstrated increased production of IFN{gamma} and TNF by hepatic CD4 T cells, highlighting their proinflammatory effector activity. Transcriptomic profiling identified Tnfrsf4 (OX40) upregulation in hepatic CD4 T cells during MASH. Therapeutic blockade of the OX40L-OX40 axis reversed hepatic fibrosis and improved histologic disease scores in mice with established MASH, and also decreased inflammatory markers in a human ex vivo liver model. Together, these studies provide a proteogenomic single-cell atlas for hepatic CD4 T cells and uncover a CD4 T cell-dependent immunopathogenic circuit as a promising immunotherapeutic target to alleviate MASH and liver fibrosis.

immunology↗

bioRxiv2024

In humans, insulo-striate structural connectivity is largely biased toward either striosome-like or matrix-like striatal compartments

The insula is an integral component of sensory, motor, limbic, and executive functions, and insular dysfunction is associated with numerous human neuropsychiatric disorders. Insular afferents project widely, but insulo-striate projections are especially numerous. The targets of these insulo-striate projections are organized into tissue compartments, the striosome and matrix. These striatal compartments have distinct embryologic origins, afferent and efferent connectivity, dopamine pharmacology, and susceptibility to injury. Striosome and matrix appear to occupy separate sets of cortico-striato-thalamo-cortical loops, so a bias in insulo-striate projections towards one compartment may also embed an insular subregion in distinct regulatory and functional networks. Compartment-specific mapping of insulo-striate structural connectivity is sparse; the insular subregions are largely unmapped for compartment-specific projections. In 100 healthy adults, we utilized probabilistic diffusion tractography to map and quantify structural connectivity between 19 structurally-defined insular subregions and each striatal compartment. Insulo-striate streamlines that reached striosome-like and matrix-like voxels were concentrated in distinct insular zones (striosome: rostro- and caudoventral; matrix: caudodorsal) and followed different paths to reach the striatum. Though tractography was generated independently in each hemisphere, the spatial distribution and relative bias of striosome-like and matrix-like streamlines were highly similar in the left and right insula. 16 insular subregions were significantly biased towards one compartment: seven toward striosome-like voxels and nine toward matrix-like voxels. Striosome-favoring bundles had significantly higher streamline density, especially from rostroventral insular subregions. The biases in insulo-striate structural connectivity we identified mirrored the compartment-specific biases identified in prior studies that utilized injected tract tracers, cytoarchitecture, or functional MRI. Segregating insulo-striate structural connectivity through either striosome or matrix may be an anatomic substrate for functional specialization among the insular subregions.

neuroscience↗