Biology subjects

Baloyan, D.

Publications and source records attributed to Baloyan, D..

5 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

Sufficient levels of BECLIN1 are required for intestinal epithelial cell homeostasis and protection against unwanted intestinal inflammation

The prototypical autophagy regulator BECLIN1, orchestrates both autophagic and endocytic trafficking, and its homozygous deletion in the intestinal epithelium leads to intestinal disruption bearing similarities to inflammatory bowel disease (IBD). However, complete loss of BECLIN1 is rare in human disease. To model the effects of a partial reduction in BECLIN1, we examined mice with a monoallelic deletion of Becn1 in the intestinal epithelium, which decreased BECLIN1 protein levels by approximately 50%. Unlike the fatal phenotype following homozygous Becn1 deletion, the heterozygous mice were grossly normal, though they presented with significantly shorter small intestines. Gastrointestinal organoids derived from the mice also displayed disrupted endocytic trafficking and altered cytoskeletal dynamics resulting in mislocalisation of junctional proteins such as E-CADHERIN. In the mice, these changes were associated with impaired goblet cell function and maturation accompanied by abnormal mucin production, composition and secretion, resulting in compromised mucus barrier integrity. The mice also exhibited heightened susceptibility to dextran sulfate sodium (DSS)-induced colitis, emphasising the critical role of BECLIN1 in mediating protection against unregulated inflammation. Investigation of BECLIN1 levels in biopsies from patients with inflammatory bowel disease (IBD) revealed changes in its expression across distinct states of inflammation with reduced levels observed in highly inflamed regions in some patients, consistent with the gastrointestinal defects seen in mice with reduced BECLIN1. Hence, this study provides crucial insights into the multifaceted importance of BECLIN1 sufficiency in the intestinal epithelium to prevent pathophysiology. This highlights the potential of BECLIN1 as a biomarker and therapeutic target for IBD management.

cell biology↗

bioRxiv2023

Beclin1 is essential for intestinal homeostasis.

BECLIN1 is a component of Class III phosphatidylinositol 3-kinase complexes that orchestrates autophagy initiation and endocytic trafficking. Here we show intestinal epithelium-specific BECLIN1 deletion in adult mice led to rapid fatal enteritis with compromised gut barrier integrity, highlighting its intrinsic critical role in gut maintenance. BECLIN1-deficient intestinal epithelial cells exhibited extensive apoptosis, impaired autophagy, and stressed endoplasmic reticulum and mitochondria. Remaining absorptive enterocytes and secretory cells displayed morphological abnormalities. Deletion of the autophagy regulator, ATG7, failed to elicit similar effects, suggesting novel autophagy-independent functions of BECLIN1 distinct from ATG7. Indeed, organoids derived from BECLIN1 KO mice showed E-cadherin mislocalisation providing a mechanism linking endocytic trafficking mediated by Beclin1 and loss of intestinal barrier integrity. Our findings establish an indispensable role of BECLIN1 in maintaining mammalian intestinal homeostasis and uncover its involvement in endocytic trafficking in this process. Hence, this study has significant implications for our understanding of intestinal pathophysiology.

cell biology↗

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↗

bioRxiv2022

Inhibition of the tuft cell/ILC2 axis reduces gastric tumor development in mice

Although gastric cancer is a leading cause of cancer-related deaths, systemic treatment strategies remain scarce. Here we explore a metabolite-triggered circuit between epithelial tuft cells and innate lymphoid type 2 cells (ILC2) that is evolutionarily optimized for intestinal remodeling in response to helminth infection. We demonstrate that tuft cell-derived interleukin 25 (IL25) acts as an alarmin on ILC2s to induce the release of IL13 as a growth factor for tuft cells, and propose that this model drives early metaplastic remodeling and gastric tumor formation. Genetic ablation of tuft cells, ILC2s or antibody-mediated neutralization of IL13 or IL25 reduces the growth of established tumors. Thus, the tuft cell/ILC2 axis provides an opportunity to therapeutically inhibit preneoplastic lesions and early-stage gastric cancer through repurposing of antibody-mediated therapies. One-Sentence SummaryTuft cells and type 2 innate lymphoid cells offer a new therapeutic target in gastric disease.

cancer biology↗