Biology subjects

Favre, G.

Publications and source records attributed to Favre, G..

4 recordsLinked to original sources

bioRxiv2026

Integrated field and laboratory assessment of Swiss grapevine cultivar susceptibility to flavescence doree reveals a central role for plant-vector interactions

Cultivar susceptibility strongly influences the epidemiology of vector-borne plant diseases, and understanding cultivar-specific variation can inform management strategies. This is particularly relevant for flavescence doree, an incurable grapevine disease associated with a phytoplasma and transmitted by the leafhopper Scaphoideus titanus. In this study, we investigated the susceptibility of the main Swiss varieties, by combining controlled insect-mediated inoculation experiments with complementary field analyses conducted at progressively finer spatial scales. Together, these approaches allowed us to compare both infection probability and phytoplasma relative titre under standardised transmission conditions with disease incidence and relative titre under natural epidemiological conditions. For most cultivars, laboratory results were broadly consistent with field observations. However, a marked discrepancy emerged in the relative infection pattern between the two main grapevine cultivars grown in Switzerland: Chasselas and Pinot Noir. Under controlled conditions, they did not differ significantly in either their probability of infection or the phytoplasma relative titre, indicating no detectable difference in susceptibility to phytoplasma infection. In contrast, Pinot Noir consistently showed higher disease incidence than Chasselas under natural conditions. This pattern was observed across all spatial scales examined, from regional surveys to neighbouring vineyard plots, and was mirrored by higher phytoplasma relative titres. Importantly, under controlled conditions, S. titanus mortality during the one-week inoculation period was significantly higher on Chasselas than on Pinot Noir, indicating that Chasselas may provide a less favourable host for S. titanus. Together, these findings support the hypothesis that differences in field disease incidence between these cultivars may arise from differences in vector performance rather than intrinsic susceptibility to phytoplasma infection. This highlights the importance of considering plant-vector interactions, alongside susceptibility to infection, when assessing cultivar-specific vulnerability to vector-borne plant diseases.

plant biology↗

bioRxiv2026

Persistent TOP1 cleavage complexes in drug-tolerant cells drive adaptive resistance to EGFR-targeted therapies in lung cancer

Resistance to targeted cancer therapies often arises from drug-tolerant cells (DTCs), which survive treatment by entering a non-proliferative state. Over time, DTCs can acquire mutations that contribute to cell reproliferation, but how non-proliferating DTCs accumulate such mutations remains unclear. Here, we show that EGFR inhibition in EGFR-mutated lung cancer transiently downregulates tyrosyl-DNA phosphodiesterase 1 (TDP1), a repair enzyme that resolves abortive topoisomerase I cleavage complexes (TOP1ccs). In DTCs, elevated reactive oxygen species promote TOP1cc trapping, while TDP1 downregulation impairs their repair, driving TOP1cc accumulation, resistance mutation acquisition, and cell reproliferation. We further find that TDP1 expression is absent in approximately 25% of EGFR-mutated lung cancers. In TDP1-deficient cells, combining EGFR inhibition with a sublethal concentration of topotecan, which further increases TOP1ccs, abolishes cell reproliferation. Together, these findings establish persistent TOP1cc accumulation as a driver of therapy-induced mutagenesis linking drug tolerance to adaptive resistance, and reveal TDP1 loss as a targetable vulnerability in EGFR-mutated lung cancers. TeaserA drug-tolerant state that fuels mutagenesis and resistance also creates a transient vulnerability.

molecular biology↗

bioRxiv2022

DNA methylome combined with chromosome cluster-oriented analysis provides an early signature for cutaneous melanoma aggressiveness

Aberrant DNA methylation is a well-known feature of tumours and has been associated with metastatic melanoma. However, since melanoma cells are highly heterogeneous, it has been challenging to use affected genes to predict tumour aggressiveness, metastatic evolution, and patients outcomes. We hypothesized that common aggressive hypermethylation signatures should emerge early in tumorigenesis and should be shared in aggressive cells, independent of the physiological context under which this trait arises. We compared paired melanoma cell lines with the following properties: (i) each pair comprises one aggressive counterpart and its parental cell line, and (ii) the aggressive cell lines were each obtained from different host and their environment (human, rat, and mouse), though starting from the same parent cell line. Next, we developed a multi-step genomic pipeline that combines the DNA methylome profile with a chromosome cluster-oriented analysis. A total of 229 differentially hypermethylated genes were commonly found in the aggressive cell lines. Genome localization analysis revealed hypermethylation peaks and clusters, identifying eight hypermethylated gene promoters for validation in tissues from melanoma patients. Five CpG identified in primary melanoma tissues were transformed into a DNA methylation score that can predict survival (Log-rank test, p=0.0008). This strategy is potentially universally applicable to other diseases involving DNA methylation alterations.

cancer biology↗

bioRxiv2022

Farnesyltransferase inhibition overcomes the adaptive resistance to osimertinib in EGFR-mutant NSCLC

Drug-tolerant "dormant" cells (DTC) have emerged as one of the major non-genetic mechanisms driving resistance to targeted therapy in lung cancer, although the sequence of events leading to entry and exit from dormancy remain poorly described. Here, we performed real-time monitoring of the cell cycle dynamics during the adaptive response to Epidermal Growth Factor Receptor tyrosine kinase inhibitors (EGFR-TKi) in a panel of EGFR-mutated lung cancer cell lines. We identified a rare population of S/G2 cycling cells (referred to as early escapers) that emerged in the first hours of treatment amongst stably arrested and progressively dying G1 cells. We determined that early escapers evolved from a non-proliferative differentiated alveolar type 1 (AT1) phenotype which was invariably associated with cytoskeletal remodeling through Rho/ROCK pathway activation. Using a panel of Rho-pathway inhibitors, we found that the farnesyltransferase inhibitor tipifarnib induced a complete clearance of EGFR-TKi-induced DTC thus fully preventing relapse in vitro. Using a xenograft model and a PDX model of EGFRL858R/T790M lung cancer, co-treatment with tipifarnib prevented relapse to osimertinib for up to 6 months with no evidence of toxicity. Among the farnesylated proteins regulated during osimertinib treatment, concomitant inhibition of RHOE and LaminB1 was sufficient to recapitulated FTIs effect. Osimertinib and tipifarnib co-treatment completely suppressed the emergence of AT1 phenotype, prevented mitosis of S/G2-treated cells and increased the apoptotic response through activation of ATF4-CHOP-dependent Integrated Stress Response (ISR) pathway. Our data strongly support the use of tipifarnib in combination with osimertinib in patients to effectively and durably prevent relapse.

cancer biology↗