Biology subjects

Nassour, I.

Publications and source records attributed to Nassour, I..

4 recordsLinked to original sources

bioRxiv2026

Tumor context determines ARID1A effects on gastric cancer immunity

The role of ARID1A in cancer immune evasion remains uncertain, with prior studies reaching opposing conclusions. In addition, previous work has shown that the role of ARID1A in cell-autonomous tumorigenesis is context-dependent. Using isogenic murine gastric cancer models, we found that in vivo Arid1a loss in an autochthonous genetically engineered mouse model of gastric cancer conferred T cell-dependent immune evasion, while in vitro deletion did not. Mechanistically, tumor Arid1a loss reprogrammed the tumor microenvironment into an immune desert through suppression of GM-CSF secretion and interferon-{gamma} responsiveness. These changes were not observed when Arid1a was deleted in vitro. In human gastric cancer, an immune-cold phenotype was restricted to ARID1A mutants in the genomically stable subtype, while ARID1A loss in the chromosomal instability subtype was associated with variable immune profiles. These results demonstrate that tumor ARID1A loss does not intrinsically confer pro- or anti-tumor immune properties and instead is determined by tissue context.

cancer biology↗

bioRxiv2020

Arid1a loss potentiates pancreatic β-cell regeneration through activation of EGF signaling

The dynamic regulation of {beta}-cell abundance is poorly understood. Since chromatin remodeling plays critical roles in liver regeneration, these mechanisms could be generally important for regeneration in other tissues. Here we show that the ARID1A mammalian SWI/SNF complex subunit is a critical regulator of {beta}-cell regeneration. Arid1a is highly expressed in quiescent {beta}-cells but is physiologically suppressed when {beta}-cells proliferate during pregnancy or after pancreas resection. Whole-body Arid1a knockout mice were protected against streptozotocin induced diabetes. Cell-type and temporally specific genetic dissection showed that {beta}-cell specific Arid1a deletion could potentiate {beta}-cell regeneration in multiple contexts. Transcriptomic and epigenomic profiling of mutant islets revealed increased Neuregulin-ERBB-NR4A signaling. Functionally, ERBB3 overexpression in {beta}-cells was sufficient to protect against diabetes, and chemical inhibition of ERBB or NR4A was able to block increased regeneration associated with Arid1a loss. mSWI/SNF complex activity is a barrier to {beta}-cell regeneration in physiologic and disease states.

genetics↗

bioRxiv2019

Hispanic/Latino gastric adenocarcinoma patients have distinct molecular profiles including a high rate of germline CDH1 mutations

Hispanic/Latino patients have a higher incidence of gastric cancer and worse cancer-related outcomes as compared to patients of other backgrounds. Whether there is a molecular basis for these disparities is unknown, as very few Hispanic/Latino patients were included in previous studies. We performed a large, integrated genomic analysis of gastric cancer samples from Hispanic/Latino patients. Whole-exome sequencing (WES) and RNA sequencing were performed on 57 Hispanic/Latino gastric cancer patient samples. Germline analysis was conducted on 83 patients. Functional testing of CDH1 germline mutations was performed in Chinese hamster ovary cells. Tumors from Hispanic/Latino patients were significantly enriched for the genomically-stable subtype (as defined by The Cancer Genome Atlas), compared to Asians and Whites (65% vs 21% vs 20%, P < 0.001). Transcriptomic analysis identified molecular signatures that were prognostic. Of the 43 Hispanic/Latino patients with diffuse-type gastric cancer, 7 (16%) had germline mutations in CDH1. Mutation carriers were significantly younger than non-carriers (41 vs 50 years, P < 0.05). E-cadherin expression was reduced in 5 of 6 mutation carrier tumor samples available for analysis. In silico algorithms predicted 5 variants were deleterious. For the two variants that were predicted to be benign, we demonstrated that the mutations conferred increased migratory capability, suggesting pathogenicity. Hispanic/Latino gastric cancer patients possess unique genomic landscapes. This includes a high rate of CDH1 germline mutations that may partially explain their aggressive clinical phenotypes. Individualized screening, genetic counseling, and treatment protocols based on patient ethnicity and race may be necessary.

cancer biology↗

bioRxiv2018

Mitotic Regulators and the SHP2-MAPK Pathway Promote Insulin Receptor Endocytosis and Feedback Regulation of Insulin Signaling

Insulin controls glucose homeostasis and cell growth through bifurcated signaling pathways. Dysregulation of insulin signaling is linked to diabetes and cancer. The spindle checkpoint controls the fidelity of chromosome segregation during mitosis. Here, we show that insulin receptor substrate 1 and 2 (IRS1/2) cooperate with spindle checkpoint proteins to promote insulin receptor (IR) endocytosis through recruiting the clathrin adaptor complex AP2 to IR. A phosphorylation switch of IRS1/2 orchestrated by extracellularly regulated kinase 1 and 2 (ERK1/2) and Src homology phosphatase 2 (SHP2) ensures selective internalization of activated IR. SHP2 inhibition blocks this feedback regulation and growth-promoting IR signaling, prolongs insulin action on metabolism, and improves insulin sensitivity in mice. We propose that mitotic regulators and SHP2 promote feedback inhibition of IR, thereby limiting the duration of insulin signaling. Targeting this feedback inhibition can improve insulin sensitivity.

cell biology↗