Biology subjects

Afshar-Sterle, S.

Publications and source records attributed to Afshar-Sterle, S..

4 recordsLinked to original sources

bioRxiv2026

Circulating inflammatory ILC2s as a biomarker of gastric cancer progression

Gastric cancer is frequently diagnosed at an advanced stage, contributing to poor patient outcomes and highlighting the need for blood-based biomarkers that can detect disease earlier and track progression. We previously showed that a tuft cell-IL25-type 2 innate lymphoid cell (ILC2) circuit promotes gastric metaplasia and gastric tumour development, but whether this pathway gives rise to a circulating ILC2 population remained unknown. Here, we show that IL25-responsive inflammatory ILC2s (iILC2s) emerge in the blood across gastric disease progression and are selectively associated with gastric tumour contexts. Using multiple mouse models spanning SPEM, early gastric adenoma, and advanced gastric cancer, we found that circulating ILC2s increased progressively with disease severity, with the dominant increase occurring in the IL17RB+ iILC2 subset. This response was not observed in pancreatic or ovarian tumour models, indicating that circulating iILC2 mobilisation is not a general consequence of tumour burden. Instead, mobilisation was linked to gastric disease and accompanied by increased ILC2 accumulation in distal mucosal tissues. Genetic tuft cell ablation or therapeutic blockade of IL25 or IL13 significantly reduced circulating iILC2s, demonstrating that this response depends on the tuft cell-IL25 circuit. In vivo, mobilised iILC2s were associated with enhanced growth of distal tumour implants, supporting a functional contribution beyond the primary gastric site. Translationally, circulating ILC2s were elevated in patients with gastric inflammatory disease and gastric cancer, with the IL25-responsive subset predominating. Circulating ILC2s also showed strong discriminatory power between gastric cancer patients and healthy controls in ROC analysis, supporting their potential utility as a blood-based biomarker. Together, these findings identify circulating iILC2s as a systemic hallmark of gastric tuft cell-ILC2 signalling and establish their mechanistic and translational relevance in gastric cancer.

cancer biology↗

bioRxiv2025

Bacteriophage FNU1 negates Fusobacterium nucleatum induced cell growth and chemotherapy resistance in gastrointestinal cancer cells.

Fusobacterium nucleatum is an oncobacterium capable of promoting the growth and chemotherapy resistance of colonised tumours. Although F. nucleatum is usually susceptible to a range of antibiotics, these have been associated with worse outcomes when administered with anti-neoplastic chemotherapy. Bacteriophages are viewed as natural alternatives to antibiotics that provide bacterial-specific targeting. In this study, we demonstrated that gastric tumour tissues and cells expressed Gal-GalNac molecules that facilitate binding of the fap2 receptor on F. nucleatum, leading to increased cancer cell proliferation and migratory potential. We then employed an F. nucleatum specific bacteriophage, FNU1, to limit the effects of this oncobacteria in colon cancer and gastric cancer cell models. We demonstrated that FNU1 was able to negate the F. nucleatum-dependent growth stimulatory effects, migratory ability, induction of reactive oxygen species, and autophagy in these cell lines. F. nucleatum also inhibited apoptosis in co-cultures with colon and gastric cancer cells, and FNU1 acted synergistically with the chemotherapy agents 5-fluorouracil and oxaliplatin to induce apoptosis in these models. Treatments with bacteriophage FNU1, therefore, have the potential to augment existing cancer therapy, and further testing in animal models is warranted.

microbiology↗

bioRxiv2022

The kinase activity of the cancer stem cell marker DCLK1 drives gastric cancer progression by reprogramming the stromal tumor landscape

Gastric cancer (GC) is the 3rd leading cause of cancer mortality worldwide, therefore providing novel diagnostic and treatment options is crucial for at risk groups. The serine/threonine kinase doublecortin-like kinase 1 (DCLK1) is a proposed driver of GC with frequent amplification and somatic missense mutations yet the molecular mechanism how DCLK1 mediates tumorigenesis is poorly understood. We report how DCLK1 expression orchestrates complementary cancer cell intrinsic and extrinsic processes leading to a comprehensive pro-invasive and pro-metastatic reprogramming of cancer cells and tumor stroma in a DCLK1 kinase-dependent manner. Mechanistically, we identify the chemokine CXCL12 as a key promoter of the pro-tumorigenic properties downstream of DCLK1. Importantly, inhibition of the DCLK1 kinase domain reverses the pro-tumorigenic and pro-metastatic phenotype. Together, this study establishes DCLK1 as a promising, targetable master regulator of GC. TeaserDCLK1 is a druggable cancer driver of GC

cancer biology↗

bioRxiv2021

Dual MAPK and HDAC inhibition rewires the apoptotic rheostat to trigger colorectal cancer cell death

The EGFR/RAS/MEK/ERK signalling pathway (ERK/MAPK) is hyper-activated in most colorectal cancers (CRCs). A current limitation of inhibitors of this pathway is that they primarily induce cytostatic effects in CRC cells. Nevertheless, these drugs do induce expression of pro-apoptotic factors, suggesting they may prime CRC cells to undergo apoptosis. As histone deacetylase inhibitors (HDACi) induce expression of multiple pro-apoptotic proteins, we examined whether they could synergize with ERK/MAPK inhibitors to trigger CRC cell apoptosis. Combined MEK/ERK and HDAC inhibition synergistically induced apoptosis in CRC cell lines and patient-derived tumour organoids in vitro, and attenuated Apc-initiated adenoma formation in vivo. Mechanistically this effect was mediated through induction of the BH3-only pro-apoptotic proteins BIM and BMF. Importantly, we demonstrate that this treatment paradigm can be tailored to specific MAPK genotypes in CRCs, by combining HDACi with EGFR, KRASG12C or BRAFV600 inhibitors in KRAS/BRAFWT; KRASG12C, BRAFV600E CRC cell lines respectively. These findings identify a novel ERK/MAPK genotype-targeted treatment paradigm for colorectal cancer.

cancer biology↗