Biology subjects

Eissmann, M. F.

Publications and source records attributed to Eissmann, M. F..

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↗

bioRxiv2024

Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within Interleukin-6 family cytokines

Although aberrant activation of the KRAS and PI3K pathway alongside TP53 mutations account for frequent aberrations in human gastric cancers, neither the sequence nor the individual contributions of these mutations have been clarified. Here, we establish an allelic series of mice to afford conditional expression in glandular epithelium of KrasG12D; Pik3caH1047R or Trp53R172H and/or ablation of Pten or Trp53. We find that KrasG12D;Pik3caH1047Ris sufficient to induce adenomas, and that lesions progress to carcinoma when also harboring Pten-deletions. Additional challenge with either Trp53 loss- or gain-of-function alleles further accelerated tumor progression and triggered metastatic disease. While tumor-intrinsic STAT3 signaling in response to gp130 family cytokines remained as a gatekeeper for all stages of tumor development, metastatic progression required a mutant Trp53-induced interleukin (IL)-11 to IL-6 dependency switch. Consistent with poorer survival of patients with high IL6 expression, we identify IL6/STAT3 signaling as a therapeutic vulnerability for TP53-mutant gastric cancer.

cancer 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↗

bioRxiv2021

EHF is essential for epidermal and colonic epithelial homeostasis and suppresses Apc-initiated colonic tumorigenesis

BackgroundEts homologous factor (EHF) is a member of the epithelial-specific Ets (ESE) transcription factors. EHF is specifically expressed in epithelial tissues, however its role in development and epithelial homeostasis is largely uncharacterized. MethodsWe generated a novel mouse strain in which the Ets DNA binding domain (exon 8) of Ehf was flanked by loxP sites (EhfLox/Lox). To inactivate Ehf in the whole body, EhfLox/Lox mice were crossed to CMVCre mice, which were then bred out to generate germline Ehf null (Ehf-/-) mice. To inactivate Ehf specifically in the intestinal epithelium, EhfLox/Lox mice were bred to tamoxifen-inducible VillinCre-ERT2 mice. EhfLox/Lox mice were also crossed to tamoxifen-inducible Cdx2CreERT2; ApcLox/+ mice to determine the impact of Ehf deletion on Apc-initiated colon cancer development. ResultsTranscripts encoding the Ets binding domain of EHF were effectively deleted in all tissues in Ehf-/- mice. Ehf-/- mice were born at the expected Mendelian ratio, but showed reduced body weight gain and developed a series of pathologies during their lifespan that led the majority of Ehf-/- mice to reach an ethical endpoint within one year of age. Most prominent of these were the development of papillomas in the chin, and abscesses in the preputial glands (males) or vulvae (females) which showed evidence of Staphylococcus and Proteus infection. Consistent with the development of papillomas, the epidermis of Ehf-/- mice showed evidence of mild hyperplasia. A subset of Ehf-/- mice also developed cataracts and corneal ulcers. EHF is highly expressed in the colonic epithelium and Ehf-/- mice displayed increased susceptibility to dextran sodium sulphate-induced colitis. This phenotype was confirmed in intestinal-specific Ehf knockout mice, and histopathological analyses revealed reduced numbers of goblet cells and extensive transcriptional reprogramming in the colonic epithelium. Finally, colon-specific deletion of Ehf enhanced Apc-initiated adenoma development, unveiling a novel, tumour suppressive role for EHF in colorectal cancer. ConclusionThe Ets DNA-binding domain of EHF is essential for post-natal homeostasis of the epidermis and colonic epithelium, and functions as a tumour suppressor in the colon.

cell biology↗