Biology subjects

Baer, R.

Publications and source records attributed to Baer, R..

5 recordsLinked to original sources

bioRxiv2025

Oncogenic RAS activity is linked to immune priming and adenosine-driven immune evasion in lung adenocarcinoma

Lung adenocarcinoma (LUAD) is a leading cause of cancer death worldwide, with RAS signalling as a key oncogenic driver. Although KRAS mutations have been linked to immune evasion in preclinical models, the relationship between RAS activity and tumour immunity or response to immunotherapy in patients remains unclear. Here, we applied our previously validated RAS84 transcriptional signature to stratify LUAD patient cohorts and dissect the immune landscape associated with RAS signalling. We report that tumours with elevated RAS activity exhibited features of immune priming, including increased immune infiltration, interferon response, and immune checkpoint gene expression, and showed improved progression-free survival in an independent cohort of patients treated with anti-PD-1. Yet, in both LUAD tumours and cell lines, RAS activity also correlated with elevated immunosuppressive interstitial adenosine mediated by transcriptional regulation of several components of the adenosinergic pathway. In orthotopic pre-clinical models of high-RAS activity lung tumours, blocking adenosine signalling delayed tumour growth and improved response to anti-PD-1 and KRAS inhibition, with a significant effect on innate immunity. This study reveals a dual role for RAS signalling in tumour progression, fostering a pro-immunogenic environment whilst simultaneously dampening anti-tumoural immunity via mechanisms including extracellular adenosine accumulation. Stratifying patients based on RAS transcriptional activity, rather than genetic alterations alone, could inform immunotherapy strategies and improve clinical outcomes.

cancer biology↗

bioRxiv2025

Anatomy and habitat shape the oxygen sensing machinery of angiosperms

Hypoxia sensing via the Cys/Arg branch of the N-degron pathway (Cys-NDP) is central for flooding responses in plants, yet how evolutionary and ecological factors have shaped the core oxygen sensing mechanism remains poorly understood. Leveraging the publication of multiple angiosperm genomes, we systematically analysed known Cys-NDP components in 55 angiosperms spanning aquatic, epiphytic, xerophytic, and mesophytic lineages. We also complemented this survey with hypoxia profiling and transcriptomic analyses in a selected panel of plants. This comparative effort revealed variation in Cys-NDP components, with Plant Cysteine Oxidases (PCOs) and group VII Ethylene Response Factors (ERFVIIs) emerging as major sources of diversification. Aquatic monocots displayed complete loss of A-type PCOs and dramatic expansion of a novel clade of ERFVIIs (HREaqua), frequently accompanied by loss or modification of the Cys-degron, uncoupling them from oxygen-dependent turnover. By contrast, xerophytes and epiphytes retained core Cys-NDP elements but showed shared hypoxia-induced gene expression, suggesting endogenous developmental or metabolic pressures for pathway conservation in habitats with limited flooding risk. Across all species, we identified a conserved transcriptional core of 11 orthogroups, including fermentation enzymes and regulatory factors, highlighting the early recruitment of these genes to hypoxia responses. Functional assays confirmed contributions of conserved MYB and LBD transcription factors to hypoxia tolerance in Arabidopsis. Together, our results demonstrate that both habitat and anatomy influence the evolution and deployment of oxygen-sensing networks in angiosperms. While persistent submergence promoted diversification of ERFVIIs and PCOs, retention of the core pathway across lineages points to fundamental roles in coping with endogenous oxygen gradients and fluctuations.

plant biology↗

bioRxiv2023

PI3Kα activity in PHGDH-low pancreatic epithelial cells limits tissue proliferative regeneration in cancer promoting conditions

ObjectiveIncreased consumption of meat is an epidemiologically validated risk condition for pancreatic cancer development, but the underlying mechanisms and whether it is related to induction of epithelial cell plasticity are unknown. DesignExperimental protocol to test the influence of high consumption of meat was compared to pancreatic inflammation experimental models. To determine the molecular drivers promoting pancreatic cell plasticity, we compared transcriptomics data sets from human samples of pancreatic inflammation and pancreatic cancer (PDAC) prone to plasticity and validated in vivo, ex vivo and in vitro the main identified target. ResultsMeat-enriched diet promoted plasticity of pancreatic acinar cells, that transdifferentiated in duct-like cells, and presented PI3K activation. We identified a selective PI3K activation gene signature enriched with plasticity. In this signature, PHGDH, which encodes an enzyme responsible for amino acid serine synthesis, was differentially expressed. High level of PHGDH in acinar cells was necessary for the proliferative action of PI3K sustained by an increased maximal mitochondrial capacity and decreased cyclin-dependent inhibitor p27 level. PHGDH level was decreased in transdifferentiated acinar cells. In this context, active PI3K promoted cell plasticity but decreased the number of cycling cells. Both epithelial-restricted genetic inactivation of PI3K and full PI3K inhibition by pharmacological dosage reduced inflammation-induced tissue damage, while a pharmacological PI3K activator promoted PanIN precancer lesion development. ConclusionMeat-enriched diet promoted plasticity. Blockage of plasticity by PI3K inhibition provoked an increased rate of acinar cell proliferation that had a beneficial impact on the tissue microenvironment less prone to precancer lesion development. What is already known on this topicIt is now well accepted that inflammatory conditions predispose to pancreatic tumour development; increased consumption of red and processed meat is an epidemiologically validated risk condition, but the underlying mechanisms are unknown. What this study addsWe identify PI3K activation as a common molecular pathway activated by increased consumption of red and processed meat and by inflammatory condition to promote pancreatic plasticity and precancer lesion development. How this study might affect research, practice or policyAs we show that treatments with the clinically available PI3K inhibitor block pancreatic plasticity under inflammatory stress while maintaining pancreas mass and limiting inflammatory reaction damage, they may represent an efficient and safe preventive interception drug in patients at risk of developing pancreatic cancer. PI3K pro-cancer action is exacerbated by the loss of serine synthesis enzyme; hence, diets that alter amino acid synthesis should be tightly controlled in those patients.

pathology↗

bioRxiv2023

Inactive PARP1 causes embryonic lethality and genome instability in a dominant-negative manner.

PARP1 is recruited and activated by DNA strand breaks, catalyzing the generation of poly-ADP-ribose (PAR) chains from NAD+. PAR relaxes chromatin and recruits other DNA repair factors, including XRCC1 and DNA Ligase 3, to maintain genomic stability. Here we show that, in contrast to the normal development of Parp1-null mice, heterozygous expression of catalytically inactive Parp1 (E988A, Parp1+/A) acts in a dominant-negative manner to disrupt murine embryogenesis. As such, all the surviving F1 Parp1+/A mice are chimeras with mixed Parp1+/AN (neoR retention) cells that act similarly to Parp1+/-. Pure F2 Parp1+/A embryos were found at Mendelian ratios at the E3.5 blastocyst stage but died before E9.5. Compared to Parp1-/- cells, genotype and expression-validated pure Parp1+/A cells retain significant ADP-ribosylation and PARylation activities but accumulate markedly higher levels of sister chromatin exchange and mitotic bridges. Despite proficiency for homologous recombination and non-homologous end-joining measured by reporter assays and supported by normal lymphocyte and germ cell development, Parp1+/A cells are hypersensitive to base damages, radiation, and Topoisomerase I and II inhibition. The sensitivity of Parp1+/A cells to base damages and Topo inhibitors in particular exceed Parp1-/- controls. The findings show that the enzymatically inactive PARP1 protein has a dominant negative role and establishes a clear physiological difference between PARP1 inactivation vs. deletion. As a result, the enzymatically inactive PARP1 has a much more deteriorating impact on normal tissues than previously estimated, providing a mechanism for the on-target side effect of PARP inhibitors used for cancer therapy. Significance StatementPARP1 is the primary target of PARP enzymatic inhibitors. The use of PARP inhibitors for cancer therapy is based not only on the extreme sensitivity of BRCA1/2-deficient cancer cells to PARP1 inhibition but also on the nonessential role of PARP1 in normal tissues. Here we show that in contrast to the normal development of Parp1-null mice, the mouse model expressing the catalytically inactive Parp1 on only one allele (E988A, Parp1+/A) dies embryonically with high levels of genomic instability. The results reveal the severe dominant-negative impact of catalytically inactive PARP1, indicating the presence of enzymatically inactive PARP1 is much more damaging to normal tissues than previously anticipated. These findings provide a mechanism for clinical PARP inhibitors unexpected normal tissue toxicity.

genetics↗

bioRxiv2020

Pancreatic Cancer Intrinsic PI3Kα Activity accelerates Metastasis and rewires Macrophage Component

Pancreatic ductal adenocarcinoma (PDAC) patients frequently suffer from undetected micrometastatic disease. This clinical situation would greatly benefit from additional investigation. Therefore, we set out to identify key signalling events that drive metastatic evolution from the pancreas. We researched a gene signature that could discriminate localised PDAC from confirmed metastatic PDAC and devised a preclinical protocol using circulating cell-free DNA (cfDNA) as an early biomarker of micro-metastatic disease to validate the identification of key signalling events. Amongst actionable markers of disease progression, the PI3K pathway and a distinctive PI3K activation signature predict PDAC aggressiveness and prognosis. Pharmacological or tumour-restricted genetic PI3K-selective inhibition prevented macro-metastatic evolution by inhibiting tumoural cell migratory behaviour independently of genetic alterations. We found that PI3K inhibition altered the quantity and the species composition of the lipid second messenger PIP3 produced, with selective reduction of C36:2 PI-3,4,5-P3. PI3K inactivation prevented the accumulation of protumoural CD206-positive macrophages in the tumour-adjacent tissue. Tumour-cell intrinsic PI3K therefore promotes pro-metastatic features that could be pharmacologically targeted to delay macro-metastatic evolution. The paper explainedPROBLEM Pancreatic cancer is one of the most lethal solid cancers characterised by rapid progression after primary tumour detection by imaging. Key signalling events that specifically drives this rapid evolution into macro-metastatic disease are so far poorly understood. RESULT With two unbiased approaches to patient data analysis, higher PI3K pathway and more specifically higher PI3K activation signature can now be identified in the most aggressive pancreatic cancer primary tumours, that lead to earlier patient death. Our in vitro data showed that PI3K is a major positive regulator of tumour cell escape from the primary tumour: tumour-intrinsic PI3K activity enables actin cytoskeleton remodelling to escape the pancreatic tumour. We chose to use two preclinical models of pancreatic cancer to validate that PI3K is a target for delaying evolution of PDAC. The first one mimicked pancreatic patient micrometastatic disease that is undetected by echography and consisted in treating mice presenting echography detected primary tumours combined with increased circulating DNA as a blood biomarker of the most aggressive tumours. The second model consisted in studying the tumour cell implantation and their early proliferation in metastatic organ after injection in blood. We treated both preclinical models with a clinically relevant PI3K -selective inhibitor (BYL-719/Alpelisib), that is currently being tested in pancreatic cancer patients (without any patient selection). We found that PI3K activity drives evolution of micrometastatic disease towards macro-metastatic stage in both models: inhibition of PI3K delayed primary tumour and micro-metastasis evolution. Finally, PI3K activity increases protumoural characteristics in peritumoural immune cells via tumour cell-intrinsic cytokine production that could facilitate metastatic evolution. IMPACT Circulating tumour DNA represents a strong independent biomarker linked to relapse and poor survival in solid cancer patients. A clinical study in resected PDAC patients with micrometastatic disease characterised by high circulating tumoural DNA levels is needed to assess if PI3K-selective inhibitors significantly delay metastatic progression and death. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/307884v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@a5a8b4org.highwire.dtl.DTLVardef@1e6e18dorg.highwire.dtl.DTLVardef@e22859org.highwire.dtl.DTLVardef@1c7148b_HPS_FORMAT_FIGEXP M_FIG Pancreatic ductal adenocarcinoma requires tumour-intrinsic PI3K activity to accelerate inflammatory metastatic disease. Biorender illustration. C_FIG

cancer biology↗