Biology subjects

Farin, H. F.

Publications and source records attributed to Farin, H. F..

5 recordsLinked to original sources

bioRxiv2025

Synergistic targeting of cancer cells through simultaneous inhibition of key metabolic enzymes

As cancer cell specific rewiring of metabolic networks creates potential therapeutic opportunities, we conducted a synthetic lethal screen utilizing inhibitors of metabolic pathways. Simultaneous administration of (R)-GNE-140 and BMS-986205 (Linrodostat) preferentially halted proliferation of ovarian cancer cells, but not of their non-oncogenically transformed progenitor cells. While (R)-GNE-140 inhibits lactate dehydrogenase (LDH)A/B and thus effective glycolysis, BMS-986205, in addition to its known inhibitory activity on Indoleamine 2,3-dioxygenase (IDO1), also restricts oxidative phosphorylation (OXPHOS), as revealed here. BMS-986205, which is being tested in multiple Phase III clinical trials, inhibits the ubiquinone reduction site of respiratory complex I and thus compromises mitochondrial ATP production. The energetic catastrophe caused by simultaneous interference with glycolysis and OXPHOS resulted in either cell death or the induction of senescence in tumor cells, with the latter being eliminated by senolytics. The frequent synergy observed with combined inhibitor treatment was comprehensively confirmed through testing on tumor cell lines from the DepMap panel and on human colorectal cancer organoids. These experiments revealed highly synergistic activity of the compounds in a third of the tested tumor cell lines, correlating with alterations in genes with known roles in metabolic regulation and demonstrating the therapeutic potential of metabolic intervention.

cancer biology↗

bioRxiv2023

ZEB1-dependent modulation of fibroblast polarization governs inflammation and immune checkpoint blockade sensitivity in colorectal cancer

The EMT-transcription factor ZEB1 is heterogeneously expressed in tumor cells and in cancer-associated fibroblasts (CAFs) in colorectal cancer (CRC). While ZEB1 in tumor cells regulates metastasis and therapy resistance, its role in CAFs is largely unknown. Combining fibroblast-specific Zeb1 deletion with immunocompetent mouse models of CRC, we observe that inflammation-driven tumorigenesis is accelerated, whereas invasion and metastasis in sporadic cancers is reduced upon fibroblast-specific loss of Zeb1. Single-cell transcriptomics, histological and in vitro characterization reveal a crucial role in CAF polarization, promoting myofibroblastic features whilst restricting inflammatory activation. Zeb1 deficiency impairs collagen deposition and CAF barrier function but increases cytokine production, jointly promoting lymphocyte recruitment and immune checkpoint activation. Strikingly, the Zeb1-deficient CAF repertoire sensitizes to immune checkpoint inhibition, pointing to a therapeutic opportunity of targeting ZEB1 in CAFs and its usage as a prognostic biomarker. Collectively, we demonstrate that ZEB1-dependent plasticity of CAFs suppresses anti-tumor immunity and promotes metastasis.

cancer biology↗

bioRxiv2022

V0-ATPase downregulation induces MVID-like brush border defects independently of apical trafficking in the mammalian intestine

SummaryIntestinal microvillus atrophy is a major cause of enteropathies such as idiopathic or congenital diarrhea that are often associated with severe morbidity. It can be caused by genetic disorders, inflammatory diseases, toxins or pathogens. In particular, Microvillus inclusion disease (MVID) is characterized by a chronic intractable diarrhea and a severe microvillus atrophy. It is triggered by mutations in MYO5B, STX3, MUNC18.2 or UNC45A which alter epithelial polarity by affecting apical trafficking in intestinal epithelial cells. Furthermore, we recently established that the depletion of the V0 sector of the V-ATPase complex induces an MVID-like phenotype in C. elegans. In this study we investigated the function of the V0-ATPase complex in mouse intestinal organoids. We found that its depletion also triggers a very severe microvillus atrophy in this model. Furthermore, we established that the polarity of intestinal cells is affected in a patient carrying mutations in TCIRG1 which encodes a V0-ATPase subunit. However, V0- ATPase depletion does not recapitulate other MVID-specific phenotypes such as subapical vesicle accumulation and Rab11+ endosomes mislocalization. Finally, we found that the apical localization of the V0-ATPase is disrupted in MVID patients. Altogether these results suggest a role for the V0-ATPase in microvillus atrophy which might be independent from apical trafficking.

cell biology↗

bioRxiv2022

Functional precision profiling reveals non-mutational rewiring of kinase signaling networks in colorectal cancer

BackgroundDespite major advances in the development of targeted therapies, precision (immuno)oncology approaches for patients with colorectal cancer continue to lag behind other solid cancers. Functional precision oncology - a strategy that is based on perturbing primary tumor cells from cancer patients with drugs - could provide an alternate road forward to personalize treatment. MethodsWe extend here the functional precision oncology paradigm to measuring phosphoproteome landscapes using patient-derived organoids (PDOs). We first employed steady-state multi-omics (exome sequencing, RNA sequencing, and proteomics) and single-cell characterization of the PDOs. The PDOs were then perturbed with kinase inhibitors (MEKi, PI3Ki, mTORi, TBKi, BRAFi, and TAKi), and large-scale phosphoproteomics profiling using data-independent acquisition was carried out. Further, we used imaging mass-cytometry-based single-cell proteomic profiling of the primary tumors to characterize cellular composition of the tumor-microenvironment (TME) and to quantify heterocellular signaling crosstalk. ResultsWe show that kinase inhibitors induce profound off-target effects resulting in a crosstalk with oncogenic and immune-related pathways. Reconstruction of the topologies of the kinase networks revealed that the patient-specific rewiring of the central EGFR-RAS-MAPK network is unaffected by mutations. Moreover, we show non-genetic heterogeneity of the PDOs and patient- and inhibitor-specific upregulation of stemness and differentiation genes by kinase inhibitors. We complemented our functional profiling by spatial proteomics profiling of the primary tumors using imaging mass cytometry. We quantify spatial heterocellular crosstalk and tumor-immune cell interactions, showing an avoidance of PD1+ immune cells and PD-L1+ tumor cells. ConclusionsCollectively, we provide a multi-modal framework for inferring tumor cell intrinsic signaling and external signaling from the TME to inform precision (immuno)-oncology in colorectal cancer.

cancer biology↗

bioRxiv2019

Competitive inhibitors of Ras effector binding

The small GTPases H, K and NRas are molecular switches that are indispensable for the correct regulation of cellular proliferation and growth. Mutations in Ras are associated with cancer and result in unwanted activation of signaling processes caused by aberrant recruitment of downstream effector proteins. In this study, we have engineered variants of the Ras-binding domain (RBD) of CRAF kinase that bind with highly improved affinity the effector binding site of Ras. Structural characterization demonstrates how the engineered RBD variants outcompete effector binding and inhibit Ras signaling in cells leading to apoptosis, growth arrest and senescence. The optimized RBD variants provide new insights in Ras biology and enabled the functional stratification of Ras dependency in patient-derived colorectal cancer organoids. One sentence summaryInhibition of effector kinase binding to Ras induces senescence in non-tumorigenic cells and reveals Ras dependency in patient-derived cancer organoids.

cancer biology↗