Biology subjects

Erdem, M.

Publications and source records attributed to Erdem, M..

6 recordsLinked to original sources

bioRxiv2026

A mixture of plant polyphenols unexpectedly aggravates liver metastasis of colorectal cancer in mice

Epidemiological studies suggest that vegetarian diets are associated with lower cancer incidence and mortality, an effect attributed in part to phytochemicals such as polyphenols and carotenoids. Although numerous in vitro experiments and investigations using immunodeficient rodent models report tumor-suppressive activities of phytochemicals, their impact on tumor progression in immunocompetent hosts remains insufficiently understood. Here, we examined the influence of a defined plant phytochemical mixture (PPM) on the growth of colon cancer liver metastases, both in vitro and in immunocompetent mice. Consistent with the prevailing literature, treatment of the murine colon cancer cell line MC38 with the PPM significantly reduced cell proliferation and survival in vitro. Strikingly, however, administration of the PPM to mice bearing MC38-derived hepatic metastases markedly accelerated tumor growth. Immunohistochemical analyses revealed a significantly increased accumulation of immune cells--specifically CD45 leukocytes and F4/80 macrophages--at the periphery of the metastatic lesions in PPM-treated animals. To assess the functional relevance of this inflammatory response, the PPM was combined with the anti-inflammatory drug prednisolone. This intervention resulted in significantly reduced metastatic burden, supporting the notion that the PPM exacerbates tumor progression through enhanced peritumoral inflammation. These findings highlight the importance of validating observations from cell culture and immunodeficient models in fully immunocompetent systems. They further emphasize that the immunomodulatory effects of plant phytochemicals warrant careful and comprehensive investigation.

cancer biology↗

bioRxiv2025

InteracTor: Feature Engineering and Explainable AI for Profiling Protein Structure-Interaction-Function Relationships

Characterizing protein families structural and functional diversity is essential for understanding their biological roles. Traditional analyses often focus on primary and secondary structures, which may not fully capture complex protein interactions. Here we introduce InteracTor, a novel toolkit that extracts multimodal features from protein three-dimensional (3D) structures, including interatomic interactions like hydrogen bonds, van der Waals forces, and hydrophobic contacts. By integrating Explainable AI (XAI) techniques, we quantified the importance of the extracted features in the classification of protein structural and functional families. InteracTors interpretable features enable mechanistic insights into the determinants of protein structure, function, and dynamics, offering a transparent means to assess their predictive power within machine learning models. Interatomic interaction features extracted by InteracTor demonstrated superior predictive power for protein family classification compared to features based solely on primary or secondary structure, revealing the importance of considering specific tertiary contacts in computational protein analysis. This work provides a robust framework for future studies aiming to enhance the capabilities of models for protein function prediction and drug discovery. AUTHOR SUMMARYInteracTor is a computational toolkit designed to enhance our understanding of protein structure and function by focusing on three-dimensional (3D) structural interactions. Unlike traditional approaches that primarily rely on sequence or secondary structure data, InteracTor extracts biologically meaningful features such as hydrogen bonds, van der Waals forces, and hydrophobic contacts, which are critical for protein stability and dynamics. By integrating these features into machine learning models alongside explainable AI methods, InteracTor provides interpretable insights into how specific structural interactions influence protein behavior. Our results demonstrate that tertiary structure features significantly improve the accuracy of protein family classification compared to sequence-based methods alone, underscoring the importance of considering 3D interactions in computational protein analyses. The toolkits modular design makes it adaptable for diverse applications, including drug discovery and protein engineering. In a broader context, InteracTor bridges the gap between computational biology and practical applications in medicine and biotechnology by offering a transparent and robust framework for analyzing proteins at a molecular level. This work represents a step forward in leveraging structural data to advance predictive modeling and biological discovery.

bioinformatics↗

bioRxiv2020

Enhanced inflammatory response mediated by parenchymal cells associates with resistance towards mTOR inhibition

Activation of the mTOR pathway is frequently found in cancer, but mTOR inhibitors have thus far failed to demonstrate significant antiproliferative efficacy in the majority of cancer types. Besides cancer cell-intrinsic resistance mechanisms, it is conceivable that mTOR inhibitors impact on non-malignant host cells in a manner that ultimately supports resistance of cancer cells. Against this background, we sought to analyze the functional consequences of mTOR inhibition in hepatocytes for the growth of metastatic colon cancer. To this end, we established a liver epithelial cell (LEC)-specific knock-out (KO) of mTOR (mTORLEC mice). We used these mice to characterize the growth of colorectal liver metastases with and without partial hepatectomy to model different clinical settings. While the LEC-specific loss of mTOR remained without effect on metastasis growth in intact liver, partial liver resection resulted in the formation of larger metastases in mTORLEC mice compared to wildtype controls. This was accompanied by significantly enhanced inflammatory activity in LEC-specific mTOR KO livers after partial liver resection. Analysis of NF-{kappa}B target gene expression and immunohistochemistry of p65 displayed a significant activation of NF-{kappa}B in mTORLEC mice, suggesting a functional importance of this pathway for the observed inflammatory phenotype. Taken together, we show an unexpected acceleration of liver metastases upon deletion of mTOR in liver epithelial cells. Our results support the notion that non-malignant host cells can contribute to resistance against mTOR inhibitors and encourage to test if anti-inflammatory drugs are able to improve the efficacy of mTOR inhibitor for cancer therapy.

cancer biology↗

bioRxiv2018

Macrophages protect against loss of adipose tissue during cancer cachexia

Cancer cachexia represents a central obstacle in medical oncology as it is associated with poor therapy response and reduced overall survival. Systemic inflammation is considered to be a key driver of cancer cachexia, however, clinical studies with anti-inflammatory drugs failed to show a robust cachexia-inhibiting effect. To address this contradiction, we investigated the functional importance of innate immune cells for hepatocellular carcinoma (HCC)-associated cachexia. To this end, we used a transgenic HCC mouse model intercrossed with mice harboring a defect in myeloid cell-mediated inflammation. We identified robust cachexia in the HCC mouse model as evidenced by a marked loss of visceral fat and lean mass. Computed tomography-based analyses demonstrated that a subgroup of human HCC patients displays reduced visceral fat mass, complementing the murine data. While the myeloid cell-mediated inflammation defect resulted in reduced expression of pro-inflammatory cytokines in the serum of HCC-bearing mice, this unexpectedly did not translate into diminished, but rather enhanced cachexia-associated fat loss. Defective myeloid cell-mediated inflammation was associated with decreased macrophage abundance in visceral adipose tissue, suggesting a role for local macrophages in the regulation of cancer-induced fat loss. Taken together, myeloid cell-mediated inflammation displays a rather unexpected beneficial function in a murine HCC model. These results demonstrate that immune cells are capable of protecting the host against cancer-induced tissue wasting, adding a further layer of complexity to the pathogenesis of cachexia and providing a potential explanation for the contradictory results of clinical studies with anti-inflammatory drugs.

cancer biology↗

bioRxiv2018

Kinetic modelling of quantitative proteome data predicts metabolic reprogramming of liver cancer

Metabolic alterations can serve as targets for diagnosis and therapy of cancer. Due to the highly complex regulation of cellular metabolism, definite identification of metabolic pathway alterations remains challenging and requires sophisticated experimentation. Here, we applied a comprehensive kinetic model of the central carbon metabolism (CCM) to characterize metabolic reprogramming in murine liver cancer. We show that relative differences of protein abundances of metabolic enzymes obtained by mass spectrometry can be used to scale maximal enzyme capacities. Model simulations predicted tumor - specific alterations of various components of the CCM, a selected number of which were subsequently verified by in vitro and in vivo experiments. Furthermore, we demonstrate the ability of the kinetic model to identify metabolic pathways whose inhibition results in selective tumor cell killing. Our systems biology approach establishes that combining cellular experimentation with computer simulations of physiology-based metabolic models enables a comprehensive understanding of deregulated energetics in cancer.

systems biology↗

bioRxiv2018

Non-canonical HIF-1 stabilization is essential for intestinal tumorigenesis

The hypoxia-inducible transcription factor HIF-1 is appreciated as a promising target for cancer therapy. However, conditional deletion of HIF-1 and HIF-1 target genes in cells of the tumor microenvironment can result in accelerated tumor growth, calling for a detailed characterization of the cellular context to fully comprehend HIF-1s role in tumorigenesis. We dissected cell type-specific functions of HIF-1 for intestinal tumorigenesis by lineage-restricted deletion of the Hif1a locus. Intestinal epithelial cell-specific Hif1a loss reduced activation of wnt/{beta}-catenin, tumor-specific metabolism and inflammation, significantly inhibiting tumor growth. Deletion of Hif1a in myeloid cells reduced the expression of fibroblast-activating factors in tumor-associated macrophages resulting in decreased abundance of tumor-associated fibroblasts and robustly reduced tumor formation. Interestingly, hypoxia was detectable only sparsely and without spatial association with nuclear HIF-1 in intestinal adenomas, pointing towards a functional importance of hypoxia-independent, i.e. non-canonical HIF-1 stabilization that has not been previously appreciated. This adds a further layer of complexity to the regulation of HIF-1 and suggests that hypoxia and HIF-1 stabilization can be uncoupled in cancer. Collectively, our data show that HIF-1 is a pivotal pro-tumorigenic factor for intestinal tumor formation, controlling key oncogenic programs in both the epithelial tumor compartment and the tumor microenvironment.

cancer biology↗