GPT-4 as a biomedical simulator.

Background: Computational simulation of biological processes can be a valuable tool for accelerating biomedical research, but usually requires extensive domain knowledge and manual adaptation. Large language models (LLMs) such as GPT-4 have proven surprisingly successful for a wide range of tasks. This study provides proof-of-concept for the use of GPT-4 as a versatile simulator of biological systems.

Combining ferroptosis induction with MDSC blockade renders primary tumours and metastases in liver sensitive to immune checkpoint blockade.

Objective: Investigating the effect of ferroptosis in the tumour microenvironment to identify combinatory therapy for liver cancer treatment.

Design: Glutathione peroxidase 4 (GPx4), which is considered the master regulator of ferroptosis, was genetically altered in murine models for hepatocellular carcinoma (HCC) and colorectal cancer (CRC) to analyse the effect of ferroptosis on tumour cells and the immune tumour microenvironment. The findings served as foundation for the identification of additional targets for combine therapy with ferroptotic inducer in the treatment of HCC and liver metastasis.

Colon tumour cell death causes mTOR dependence by paracrine P2X4 stimulation.

Solid cancers exhibit a dynamic balance between cell death and proliferation ensuring continuous tumour maintenance and growth. Increasing evidence links enhanced cancer cell apoptosis to paracrine activation of cells in the tumour microenvironment initiating tissue repair programs that support tumour growth, yet the direct effects of dying cancer cells on neighbouring tumour epithelia and how this paracrine effect potentially contributes to therapy resistance are unclear. Here we demonstrate that chemotherapy-induced tumour cell death in patient-derived colorectal tumour organoids causes ATP release triggering P2X4 (also known as P2RX4) to mediate an mTOR-dependent pro-survival program in neighbouring cancer cells, which renders surviving tumour epithelia sensitive to mTOR inhibition.

Expansion of T memory stem cells with superior anti-tumor immunity by Urolithin A-induced mitophagy.

T memory stem cells (T) display increased self-renewal and prolonged survival capabilities, thus preventing T cell exhaustion and promoting effective anti-tumor T cell responses. T cells can be expanded by Urolithin A (UA), which is produced by the commensal gut microbiome from foods rich in ellagitannins and is known to improve mitochondrial health. Oral UA administration to tumor-bearing mice conferred strong anti-tumor CD8 T cell immunity, whereas ex vivo UA pre-treated T cells displayed improved anti-tumor function upon adoptive cell transfer.

Image-guided radiotherapy in an orthotopic mouse model of rectal cancer.

Radiobiology research in rectal cancer has been limited to cell lines, patient-derived organoids (PDOs), or xenografts. Here, we describe a protocol which recapitulates more efficiently the complex contributions of the tumor microenvironment. This approach establishes a preclinical mouse model of rectal cancer by intrarectal transplantation of genetically modified organoids into immunocompetent mice followed by precise image-guided radiotherapy (IGRT) of organoid-induced tumors.

ACO/ARO/AIO-21 - Capecitabine-based chemoradiotherapy in combination with the IL-1 receptor antagonist anakinra for rectal cancer Patients: A phase I trial of the German rectal cancer study group.

Purpose: Recent advances in the treatment algorithm of locally advanced rectal cancer (LARC) have significantly improved complete response (CR) rates and disease-free survival (DFS), but therapy resistance, with its substantial impact on outcomes and survival, remains a major challenge. Our group has recently unraveled a critical role of interleukin-1α (IL-1α) signaling in activating inflammatory cancer-associated fibroblasts (iCAFs) and mediating radiation-induced senescence, extracellular matrix (ECM) accumulation, and ultimately therapy resistance. We here summarize the recently initiated ACO/ARO/AIO-21 phase I trial, testing the IL-1 receptor antagonist (IL-1 RA) anakinra in combination with fluoropyrimidine-based chemoradiotherapy (CRT) for advanced rectal cancer.

Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer.

Standard cancer therapy targets tumor cells without considering possible damage on the tumor microenvironment that could impair therapy response. In rectal cancer patients we find that inflammatory cancer-associated fibroblasts (iCAFs) are associated with poor chemoradiotherapy response. Employing a murine rectal cancer model or patient-derived tumor organoids and primary stroma cells, we show that, upon irradiation, interleukin-1α (IL-1α) not only polarizes cancer-associated fibroblasts toward the inflammatory phenotype but also triggers oxidative DNA damage, thereby predisposing iCAFs to p53-mediated therapy-induced senescence, which in turn results in chemoradiotherapy resistance and disease progression.

Disruption of Prostaglandin E2 Signaling in Cancer-Associated Fibroblasts Limits Mammary Carcinoma Growth but Promotes Metastasis.

Unlabelled: The activation and differentiation of cancer-associated fibroblasts (CAF) are involved in tumor progression. Here, we show that the tumor-promoting lipid mediator prostaglandin E2 (PGE2) plays a paradoxical role in CAF activation and tumor progression. Restricting PGE2 signaling via knockout of microsomal prostaglandin E synthase-1 (mPGES-1) in PyMT mice or of the prostanoid E receptor 3 (EP3) in CAFs stunted mammary carcinoma growth associated with strong CAF proliferation.

A Wnt-Induced Phenotypic Switch in Cancer-Associated Fibroblasts Inhibits EMT in Colorectal Cancer.

Tumor progression is recognized as a result of an evolving cross-talk between tumor cells and their surrounding nontransformed stroma. Although Wnt signaling has been intensively studied in colorectal cancer, it remains unclear whether activity in the tumor-associated stroma contributes to malignancy. To specifically interfere with stromal signals, we generated Wnt-independent tumor organoids that secrete the Wnt antagonist Sfrp1.

Myeloid Cell-Derived Reactive Oxygen Species Induce Epithelial Mutagenesis.

Increased oxidative stress has been suggested to initiate and promote tumorigenesis by inducing DNA damage and to suppress tumor development by triggering apoptosis and senescence. The contribution of individual cell types in the tumor microenvironment to these contrasting effects remains poorly understood. We provide evidence that during intestinal tumorigenesis, myeloid cell-derived HO triggers genome-wide DNA mutations in intestinal epithelial cells to stimulate invasive growth.