Biology subjects

Rehemtulla, A.

Publications and source records attributed to Rehemtulla, A..

4 recordsLinked to original sources

bioRxiv2024

A molecularly engineered lectin destroys EGFR and inhibits the growth of non-small cell lung cancer

Survival rates for non-small cell lung cancer (NSCLC) remain low despite the advent of novel therapeutics. Tyrosine kinase inhibitors (TKIs) targeting mutant epidermal growth factor receptor (EGFR) in NSCLC have significantly improved mortality but are plagued with challenges--they can only be used in the small fraction of patients who have susceptible driver mutations, and resistance inevitably develops. Aberrant glycosylation on the surface of cancer cells is an attractive therapeutic target as these abnormal glycosylation patterns are typically specific to cancer cells and are not present on healthy cells. H84T BanLec (H84T), a lectin previously engineered by our group to separate its antiviral activity from its mitogenicity, exhibits precision binding of high mannose, an abnormal glycan present on the surface of many cancer cells, including NSCLC. Here, we show that H84T binds to and inhibits the growth of diverse NSCLC cell lines by inducing lysosomal degradation of EGFR and leading to cancer cell death through autophagy. This is a mechanism distinct from EGFR TKIs and is independent of EGFR mutation status; H84T inhibited proliferation of both cell lines expressing wild type EGFR and those expressing mutant EGFR that is resistant to all TKIs. Further, H84T binds strongly to multiple and diverse clinical samples of both pulmonary adenocarcinoma and squamous cell carcinoma. H84T is thus a promising potential therapeutic in NSCLC, with the ability to circumvent the challenges currently faced by EGFR TKIs.

cancer biology↗

bioRxiv2021

Subclonal evolution and expansion of THY1-positive cells is associated with recurrence in glioblastoma

PurposeGlioblastoma (GBM) is a lethal disease characterized by inevitable recurrence. Here we investigate the molecular pathways mediating resistance, with the goal of identifying therapeutic opportunities to target this tumor. Experimental DesignWe developed a longitudinal in vivo recurrence model utilizing patient-derived explants to produce paired specimens (pre- and post-recurrence) following temozolomide(TMZ) and radiation(IR). These specimens were evaluated for treatment response and to identify gene expression pathways driving treatment resistance. Findings were clinically validated using spatial transcriptomics of human GBMs. ResultsThese studies reveal in replicate cohorts, a gene expression profile characterized by upregulation of mesenchymal and stem-like genes at recurrence. Analyses of clinical databases revealed increased expression of this transcriptional profile to be significantly associated with worse median overall survival (248 days vs 430 days, p=0.0004), and upregulation of this profile at recurrence. Most notably, we identified upregulation of TGF{beta} signaling, and more than one-hundred-fold increase in THY1 levels at recurrence. Utilizing cell sorting, we observed that THY1-positive cells represented <10% of cells in the treatment-naive tumors and 75-96% in the recurrent tumors. We then isolated THY1-positive cells from treatment-naive patient samples and determined that they were inherently resistant to chemoradiation in orthotopic models. Additionally, using image-guided biopsies from treatment-naive human GBM, we conducted spatial transcriptomic analyses. This revealed rare THY1+ regions characterized by mesenchymal/stem-like gene expression, analogous to our recurrent mouse model samples, which co-localized with macrophages within the perivascular niche. Since TGF{beta} signaling contributes to a mesenchymal/stem-like phenotype, we inhibited TGF{beta}RI activity in vivo which resulted in decreased mesenchymal/stem-like protein levels, including THY1, and restored sensitivity to TMZ/IR in recurrent tumors. ConclusionsThese findings reveal that GBM recurrence may result from tumor repopulation by pre-existing, therapy-resistant, THY1-positive, mesenchymal/stem-like cells within the perivascular niche. Furthermore, our data demonstrate the promise of targeting upregulated pathways in resistant subclones as a novel mechanism to achieve therapeutic response, and specifically that THY1 expression may represent a biomarker of response to TGF{beta} inhibition.

cancer biology↗

bioRxiv2020

Genome architecture and transcription data reveal allelic bias during the cell cycle

Every human somatic cell inherits a maternal and a paternal genome, which work together to give rise to cellular phenotypes. However, the allele-specific relationship between gene expression and genome structure through the cell cycle is largely unknown. By integrating haplotype-resolved genome-wide chromosome conformation capture, mature and nascent mRNA, and protein binding data, we investigate this relationship both globally and locally. We introduce the maternal and paternal 4D Nucleome, enabling detailed analysis of the mechanisms and dynamics of genome structure and gene function for diploid organisms. Our analyses find significant coordination between allelic expression biases and local genome conformation, and notably absent expression bias in universally essential cell cycle and glycolysis genes. We propose a model in which coordinated biallelic expression reflects prioritized preservation of essential gene sets.

bioinformatics↗

bioRxiv2020

Mitochondrial Complex II In Intestinal Epithelial Cells Regulates T-cell Mediated Immunopathology

Intestinal epithelial cell (IEC) damage by T cells contributes to alloimmune, autoimmune and iatrogenic diseases such as graft-versus-host disease (GVHD), inflammatory bowel disease (IBD) and immune checkpoint blockade (ICB) mediated colitis, respectively. Despite significant advances in understanding the aberrant biology of T cells in these diseases, little is known about how the fundamental biological processes of the target IECs influence the disease severity. Here, through analyses of metabolic pathways of IECs, we identified disruption of oxidative phosphorylation without a concomitant change in glycolysis and an increase in succinate levels in several distinct in vivo models of T cell mediated gastrointestinal damage such as GVHD, IBD and ICB mediated colitis. Metabolic flux studies, complemented by imaging and protein analyses identified a critical role for IEC intrinsic succinate dehydrogenase A (SDHA), a component of mitochondrial complex II, in causing these metabolic alterations that contributed to the severity of intestinal damage. The critical mechanistic role of IEC intrinsic SDHA was confirmed by complementary chemical and genetic reduction of SDHA and with IEC specific deletion of SDHA. Further in vitro and in vivo mechanistic studies demonstrated that loss of SDHA in IECs was mediated by the perforin-granzyme from the T cells. The loss of SDHA was also validated in human clinical samples. These data identify a critical role for the alteration of the IEC specific mitochondrial complex II component SDHA in the regulation of the severity of T cell mediated intestinal diseases.

immunology↗