Introduction

Gastric chief cells can re-enter the cell cycle after injury through paligenosis, a conserved regenerative program regulated by mTORC1. This process involves (1) cellular degradation, (2) induction of progenitor genes (spasmolytic polypeptide-expressing metaplasia, SPEM), and (3) cell cycle re-entry. Dysregulated paligenosis contributes to gastric cancer, but mechanisms governing this reprogramming remain incompletely understood. Here, we investigated the role and regulation of YAP1, a key effector of the Hippo pathway, during paligenosis.

Aims & Methods

Our objectives were to determine whether YAP1 is activated during paligenosis, define its role, and identify upstream regulators. Using a mouse model of injury-induced paligenosis (via high-dose tamoxifen, HDTAM, intraperitoneal injection), we analyzed YAP1 activation and Hippo pathway dynamics via proteomics, single-cell RNA sequencing, western blot, immunohistochemistry, and immunofluorescence. To dissect upstream signaling, we employed a series of genetically engineered mouse models targeting Hippo pathway components.

Results

YAP1 is rapidly activated (via dephosphorylation) during the early stage of paligenosis. Functional assays revealed that YAP1 (and its paralog, TAZ) are necessary and sufficient to drive chief cell reprogramming. Among upstream kinases, only STK38 activity mirrored YAP1 activation patterns. STK38 is essential for YAP1 activation and is degraded via autophagy during transition to stage 2. Notably, STK38 harbors a UFM1/LC3-interacting region (LIR) domain and is targeted to autophagosomes. We found that MIST1 induces UFM1, which protects STK38 from autophagic degradation. In Mist1^−/− mice, reduced UFM1 correlates with heightened basal autophagy, STK38 loss, and constitutive YAP1 activation. Furthermore, STK38 interacts with NF2, similar to canonical Hippo kinases, modulating YAP1 regulation.

Conclusion

We identify a novel MIST1–UFM1–STK38 axis that regulates YAP1 activity in an autophagy-dependent manner during paligenosis. STK38 acts as a non-canonical Hippo kinase whose stability dictates YAP1 activation. These findings uncover new layers of Hippo pathway regulation and highlight the dynamic control of YAP1 during gastric epithelial regeneration.

Introduction

Upper GI involvement in Crohn’s disease (CD) is thought to occur in 13% to 15% of cases. However, despite expansion of the therapeutic armamentarium for CD over the last 30 years, there continues to be minimal data on optimal therapeutic strategies for upper GI CD. This knowledge gap presents major clinical challenges in managing this subset of patients.

Aims & Methods

We conducted an extensive systematic review using multiple databases investigating pharmacological or dietary interventions for patients with upper GI CD. We included fully published, English-language studies that compared at least two active interventions with a placebo from 1990 to 2025. Due to the lack of a standardized definition for “upper GI” CD, we included studies that reported data on CD affecting the esophagus to the jejunum. We excluded studies that included <10 upper GI CD patients, reported data for “small bowel CD” in general or limited to ileal CD, or did not report data separately for upper GI CD. There is no age limitation.

Results

Among 1206 citations, 14 observational studies (11 retrospective, 3 prospective) and 1 post hoc of an RCT met our inclusion criteria, amounting to 487 patients with UGI CD. Majority of patients had concomitant ileocolonic involvement. Five studies with 137 patients had esophageal CD. Follow-up ranged from 1 to 28 years. Interventions and reported outcomes varied. Steroids (mainly prednisone) and anti-TNF, either alone or in combination, showed the highest rates of success for clinical improvement, endoscopic healing and histologic remission for upper GI CD compared to other therapies. Other therapies used, alone or in combination, were EEN, PPI, H2RA, immunomodulators (azathioprine, 6-mercaptopurine), 5-ASA, anti-integrins, and anti-IL 12/23, showing moderate to minimal improvement in clinical or endoscopic response and remission. (Table)

Conclusion

Our comprehensive literature search of comparative studies highlights an almost void of evidence to inform therapeutic strategies in upper GI CD. Steroids and anti-TNF showed the best outcomes, but only from small observational, uncontrolled studies. Data for biologics and advanced therapies remain limited highlighting a large unmet need.

Disclosure

Financial Disclosures:
MC: none.
DA: none.
YY: has received consulting fees from Alimentiv.
VJ: has received consulting/advisory board fees from AbbVie, Alimentiv, Anaptyis Bio, Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Eli Lilly, Endpoint Health, Enthera, Ensho, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GlaxoSmithKline, Genentech, Gilead, Innomar, JAMP, Janssen, Merck, Metacrine, Mylan, MRM Health, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus Biosciences, Reistone Biopharma, Roche, Roivant, Sandoz, Second Genome, Sorriso, Synedgen, Takeda, TD Securities, Teva, Topivert, Ventyx, Vividion; speaker’s fees from, Abbvie, Ferring, Bristol Myers Squibb, Galapagos, Janssen Pfizer Shire, Takeda, Tillotts, Fresenius Kabi
RS: has received consulting fees from AbbVie, Alimentiv and Takeda.

Introduction

Recently, a Japanese expert consensus introduced oncological resectability criteria for hepatocellular carcinoma (HCC) [1]. Notably, these criteria do not incorporate the concept of unresectable tumors, but rather classify borderline resectability into two distinct subgroups, defined from the therapeutic perspective of hepatic resection. Based on these classifications, resectability is categorized into three groups: resectable (R), borderline resectable 1 (BR1), and borderline resectable 2 (BR2).

Aims & Methods

In this study, we aimed to assess the clinical outcomes of patients with HCC who were treated with atezolizumab plus bevacizumab (Atezo/Bev) in a real-world context, categorized by oncological resectability criteria. Between May 2018 and May 2024, a total of 1,055 patients with unresectable HCC were treated with Atezo/Bev across 26 institutions in Japan. Of these, 467 met the following inclusion criteria: (1) Child–Pugh class A, (2) Atezo/Bev administered as the first-line systemic therapy, (3) Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1, (4) BR1 or BR2 classification, (5) treatment conducted within a clinical trial setting, and (6) availability of complete clinical data.

Results

Of 467 patients, 102 (21.8%) were women, and 365 (78.2%) were men. The median age was 74.0 (69.0–79.0) years. Patients were categorized into BR1 (n=153 [32.8%]) and BR2 (n=314 [67.2%]) groups. The median follow-up period was 14.3 (7.5–24.0) months. The median progression-free survival (PFS) was 9.0 months in the BR1 group and 6.8 months in the BR2 group (p = 0.014). Multivariable analysis identified the following independent prognostic factors for PFS: age ≥75 years (hazard ratio [HR], 1.309; 95% confidence interval [CI], 1.057–1.622; p=0.014), albumin–bilirubin (ALBI) grade 2 or 3 (HR, 1.494; 95%CI, 1.201–1.859; p<0.001), neutrophil-to-lymphocyte ratio (NLR) ≥3 (HR, 1.289; 95%CI, 1.030–1.613; p=027), α-fetoprotein (AFP) ≥100 ng/mL (HR, 1.523; 95%CI, 1.214–1.912; p<0.001), and BR2 classification (HR, 1.360; 95%CI, 1.076–1.718; p=0.010). The median overall survival (OS) was 25.3 months in the BR1 group and 22.3 months in the BR2 group (p = 0.048). Similarly, multivariable analysis identified the following independent prognostic factors for OS: age ≥75 years (HR, 1.522; 95%CI, 1.155–2.007; p=0.033), ALBI grade 2 or 3 (HR, 2.411; 95%CI, 1.802–3.224; p<0.011), NLR ≥3 (HR, 1.635; 95%CI, 1.233–2.169; p<0.011), AFP ≥100 ng/mL (HR, 1.530; 95%CI, 1.152–2.032; p=0.003), and BR2 classification (HR, 1.421; 95%CI, 1.048–1.927; p=0.024). When oncological resectability factors (tumor number and size, vascular invasion, and extrahepatic spread) were incorporated into the multivariable analysis, major vascular invasion emerged as a significant predictor of both PFS (HR, 3.188; 95%CI, 2.051–4.953; p<0.011) and OS (HR, 2.650; 95%CI, 1.541–4.556; p<0.001). No significant differences were observed between the BR1 and BR2 groups regarding concomitant or subsequent treatments following Atezo/Bev therapy, as indicated by the Sankey diagram (p = 0.391).

Conclusion

Among HCC patients with a low probability of surgical resection (i.e., those classified as BR1 or BR2) undergoing Atezo/Bev treatment, vascular invasion serves as a critical prognostic factor for tumor progression. Moreover, beyond tumor progression, preserved liver function also plays a pivotal role in determining the prognosis of patients treated with Atezo/Bev.

References

1. Akahoshi K, Shindoh J, Tanabe M, Ariizumi S, Eguchi S, Okamura Y, et al. Oncological Resectability Criteria for Hepatocellular Carcinoma in the Era of Novel Systemic Therapies: The Japan Liver Cancer Association and Japanese Society of Hepato-Biliary-Pancreatic Surgery Expert Consensus Statement 2023. Liver Cancer 2024; 13: 1–11.

Disclosure

Toshifumi Tada: lecture fees from AbbVie, AstraZeneca, Eisai, and Chugai
Atsushi Hiraoka: lecture fees from Eisai, Bayer, Eli Lilly, and Otsuka
Hidenori Toyoda: lecture fees from AbbVie, Eisai, Gilead, Terumo, and Bayer

Introduction

The adhesion G protein-coupled receptor F5 (ADGRF5) belongs to seven-transmembrane receptor family which action seems to be crucial for various cancers and immune response [1-3]. Nevertheless, limited efforts have been made to explore ADGRF5 significance in gastrointestinal cancers.

Aims & Methods

The aim of the study was to assess the significance of ADGRF5 for macrophages function and its impact on gastrointestinal cancer progression. Bone marrow of wild type (WT) and ADGRF5 knockout (KO) mice was used to isolate macrophage population employing differentiation medium. M1 and M2 macrophage phenotype was obtained by polarization of naïve macrophages with a mixture of lipopolysaccharide (LPS) with interferon γ (IFN-γ) and interleukin (IL) 4, respectively. Macrophage phenotype was confirmed using real-time PCR. In vivo studies employing MC38 and PK5L1940 cell-derived allograft murine model of colon and pancreas cancers, respectively, were performed. Multiplex analysis was used to explore secretome in media obtained from tumors.

Results

In murine model of colon cancer, animals with ADGRF5 KO developed significantly smaller tumors which was accompanied by enhanced secretion of macrophage-related cytokines (such as macrophage colony-stimulating factor) in colon tumors compared to WT animals. Ex vivo analysis revealed overexpression of IL-12, nitric oxidase synthase 2 and tumor necrosis factor α in M1 macrophages with ADGRF5 KO compared with WT macrophages under LPS with IFN-γ treatment. In contrast, lower expression of arginase 1 was noted in M2 macrophages with ADGRF5 KO compared with WT macrophages treated with IL-4. In vivo studies employing allograft model of colon and pancreas cancers revealed that the administration of ADGRF5 KO macrophages led to a reduction in tumor size when compared to WT macrophages.

Conclusion

Collectively, ADGRF5 appears to be crucial regulator of gastrointestinal cancer progression through regulating macrophage function. Our study also noted that ADGRF5 depletion reprograms macrophages into M1 phenotype which is responsible for anti-tumor activity.

References

[1] Jacenik D., Hikisz P., Beswick E.J., Fichna J. The clinical relevance of the adhesion G protein-coupled receptor F5 for human diseases and cancers. Biochim Biophys Acta Mol Basis Dis. 2023; 1869: 166683. doi:10.1016/j.bbadis.2023.166683
[2] Kubo F., Ariestanti D.M., Oki S., Fukuzawa T., Demizu R., Sato T., Sabirin R. M., Hirose S., Nakamura N. Loss of the adhesion G-protein coupled receptor ADGRF5 in mice induces airway inflammation and the expression of CCL2 in lung endothelial cells. Respir Res. 2019; 20: 11. doi:10.1186/s12931-019-0973-6
[3] Tang X., Jin R., Qu G., Wang X., Li Z., Yuan Z., Zhao C., Siwko S., Shi T., Wang P., Xiao J., Liu M., Luo J. GPR116, an adhesion G-protein-coupled receptor, promotes breast cancer metastasis via the Gαq-p63RhoGEF-Rho GTPase pathway. Cancer Res, 2013; 73: 6206–6218. doi:10.1158/0008-5472.CAN-13-1049