Biology subjects

Lohmann, E.

Publications and source records attributed to Lohmann, E..

5 recordsLinked to original sources

bioRxiv2026

The methionine cycle sustains the mesenchymal phenotype of tumor cells and drives PDA progression

Mesenchymal traits are associated with poor prognosis in Pancreatic Ductal Adenocarcinoma (PDA), but direct targeting of mesenchymal tumor cells remains a challenge. Metabolic profiling of tumor cells isolated from murine PDA and liver metastases (LM) revealed that LM rely more on the methionine cycle than does primary PDA. This metabolic shift was specifically associated with increased activation of the methionine cycle in mesenchymal tumor cells compared to differentiated tumor cells. We show that the targeting of the key enzyme of the methionine cycle S-adenosylhomocysteine hydrolase (SAHH) in mesenchymal cells lowers the levels of homocysteine (Hcy) and glutathione, resulting in reduced antioxidant capacity, deregulated intracellular calcium homeostasis, and ultimately loss of mesenchymal markers. Together, these events decrease cell proliferation and invasion, blunting the tumorigenic and metastatic potential of SAHH-deficient cells, eventually impeding tumor growth and progression of the metastatic disease. Clinically, the high expression of SAHH in patients with mesenchymal PDA is correlated with poor survival, positioning SAHH as a potential therapeutic target to impede the pro-metastatic, mesenchymal phenotype of PDA.

cancer biology↗

bioRxiv2025

Build heatmaps of cell frequencies and marker intensities for correct interpretations

High-content cytometry is an important technique in clinical research, producing data that is rich and complex to analyze. The resulting clusters of cells must be profiled to determine their role and function, and analyzed to identify changes in cell frequency or marker intensity. The heat map is the most suitable tool for presenting this information in a synthetic way. However, its construction must be adapted to the information and the objective. Here we describe the step-by-step construction of heat maps of marker intensity and cell frequency using Excel, Phantasus or R, including the conversion of numbers to colors and the organization of rows and columns. Researchers who master these steps will be able to correctly interpret heat maps and derive the most benefit from high-content cytometry.

bioinformatics↗

bioRxiv2025

The extracellular matrix drives guanylate production and protects pancreatic cancer cells from oxaliplatin-induced DNA damage.

The excessive production of extracellular matrix (ECM) and the metabolic adaptations in pancreatic ductal adenocarcinoma (PDAC) contribute individually to enhanced chemoresistance, dramatic tumor progression and dismal patient survival. However, ECM-driven metabolic alterations that promote chemoresistance in PDAC are so far unexplored. Here, we use in-vitro-generated ECM bio-scaffolds that recapitulate cell-ECM interactions and induce broad metabolic alterations in PDAC cells. High-throughput integration of multi-omics datasets coupled with metabolic tracing showed that the ECM enhances the generation of guanylates in PDAC cells, the accumulation of which alleviates oxaliplatin-induced DNA damage, and boosts PDAC cell proliferation. These events are guided by the guanosine monophosphate (GMP)-producing enzymes Impdh and Gmps, the expression of which correlated with that of matrisomal and DNA repair genes in PDAC patient samples. We propose that targeting ECM-driven metabolic processes, like the enhanced Impdh activity, may be an effective therapeutic approach for PDAC patients that bypasses the negative side effects of direct targeting of the ECM itself.

cancer biology↗

bioRxiv2022

The E2F4/p130 repressor complex cooperates with oncogenic ΔNp73α to promote cell survival in human papillomavirus 38 E6/E7-transformed keratinocytes and in cancer cells

Tumor suppressor p53 and its related proteins, p63 and p73, can be synthesized as multiple isoforms lacking part of the N- or C-terminal regions. Specifically, high expression of the {Delta}Np73 isoform is notoriously associated with various human malignancies characterized by poor prognosis. This isoform is also accumulated by oncogenic viruses such as Epstein-Barr virus (EBV), as well as genus beta human papillomaviruses (HPV) that appear to be involved in carcinogenesis. To gain additional insight into {Delta}Np73 mechanisms, we have performed proteomics analyses using human keratinocytes transformed by the E6 and E7 proteins of the beta-HPV type 38 virus as an experimental model (38HK). We find that {Delta}Np73 associates with the E2F4/p130 repressor complex through a direct interaction with E2F4. This interaction is favored by the N-terminal truncation of p73 characteristic of {Delta}Np73 isoforms. Moreover, it is independent of the C-terminal splicing status, suggesting that it could represent a general feature of {Delta}Np73 isoforms (, {beta}, {gamma}, {delta}, {varepsilon}, {zeta}, {theta}, {eta}, and {eta}1). We also show that the {Delta}Np73- E2F4/p130 complex inhibits the expression of specific genes, including genes encoding for negative regulators of proliferation, both in 38HK and in HPV-negative cancer-derived cell lines. Consistently, silencing of E2F4 in 38HK and in cancer cells results in induction of senescence. In conclusion, we have identified and characterized a novel transcriptional regulatory complex that exerts pro-survival functions in transformed cells. IMPORTANCEThe TP53 gene is mutated in about 50% of human cancers. In contrast, the TP63 and TP73 genes are rarely mutated but rather expressed as {Delta}Np63 and {Delta}Np73 isoforms in a wide range of malignancies, where they act as p53 antagonists. Accumulation of {Delta}Np63 and {Delta}Np73, which is associated with chemoresistance, can result from infection by oncogenic viruses such as EBV or HPV. Our study focuses on the highly carcinogenic {Delta}Np73 isoform and uses a viral model of cellular transformation. We unveil a physical interaction between {Delta}Np73 and the E2F4/p130 complex involved in cell cycle control, which rewires the E2F4/p130 transcriptional program. Consistently, we find that E2F4 gains pro-survival functions in transformed cells expressing {Delta}Np73. This report shows, for the first time, that {Delta}Np73 isoforms acquire novel protein-protein interactions with respect to the TAp73 tumor suppressor. This situation is analogous to the gain-of-function interactions of p53 mutants supporting cellular proliferation.

cancer biology↗

bioRxiv2020

Bi-allelic variants in TSPOAP1, encoding the active zone protein RIMBP1, cause autosomal recessive dystonia

Dystonia is a debilitating hyperkinetic movement disorder, frequently transmitted as a monogenic trait. Here, we describe homozygous frameshift, nonsense and missense variants in TSPOAP1, encoding the active zone RIM-binding protein 1 (RIMBP1), as a novel genetic cause of autosomal recessive dystonia in seven subjects from three unrelated families. Subjects carrying loss-of-function variants presented with juvenile- onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy. Conversely, subjects carrying a pathogenic missense variant (p.Gly1808Ser) presented with isolated adult-onset focal dystonia. In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses. In vitro analysis of the p.Gly1808Ser variant showed larger spike-evoked calcium transients and enhanced neurotransmission, suggesting that RIMBP1-linked dystonia can be caused by either reduced or enhanced rates of spike-evoked release in relevant neural networks. Our findings establish a direct link between presynaptic RIMBP1 dysfunction and dystonia and highlight the critical role played by well-balanced neurotransmission in motor control and disease pathogenesis.

genetics↗