Biology subjects

Brais, R.

Publications and source records attributed to Brais, R..

5 recordsLinked to original sources

bioRxiv2026

Cross-species graph-embedding unmasks the ageing microenvironment as a key determinant of pancreatic cancer malignant cell biology and therapy response

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis and is characterised by an extensive pro-tumorigenic stroma. Although most PDAC cases occur in older patients, the impact of ageing on malignant-stromal interactions and therapy response remains poorly understood. Here, we established orthotopically-grafted organoid-derived PDAC models across three murine age groups to characterise changes in the PDAC stroma and malignant cells with ageing. Cross-species analyses of tumour transcriptomes using a graph-embedding approach showed that integrating mouse models of different ages better captures the diversity of human PDAC, and that aged models more faithfully recapitulate the biology of older patients with PDAC. We also demonstrated that aged PDAC models have a more inflammatory stroma than that of younger tumours, shaping the malignant cell transcriptome. Finally, graph-embedding identified IRAK4 as a candidate therapeutic vulnerability in aged, but not young, KRAS- and p53-mutant PDAC, which we validated in preclinical drug studies. These findings highlight how ageing is a critical determinant of PDAC biology and associated therapeutic vulnerabilities, which should be an important consideration when designing disease models for preclinical development of precision therapies.

cancer biology↗

bioRxiv2025

Multi-stromal organoid co-cultures model pancreatic cancer and pancreatitis epithelial cell-fibroblast heterogeneity

Malignant cell-fibroblast cross-talks modulate disease progression and therapy response of pancreatic ductal adenocarcinoma (PDAC). Our knowledge of the heterogeneous nature of PDAC cancer-associated fibroblasts (CAFs) has significantly increased over the last few years. Yet, whether CAFs in PDAC differ from fibroblasts in pancreatic inflammation remains poorly understood. Chronic pancreatitis - a prolonged inflammatory state of the pancreas - is a risk factor for PDAC and is characterised by abundant fibroblasts. Thus, dissecting pancreatic fibroblast and epithelial cell reprogramming in malignancy relative to inflammation could inform new preventative, diagnostic and therapeutic strategies for PDAC. Here, we studied how pancreatic malignancy and inflammation differently shape fibroblast heterogeneity and their crosstalk with epithelial cells. We analysed human samples and mouse models of pancreatitis and PDAC and leveraged new murine pancreatitis-derived epithelial organoids to establish pancreatitis and PDAC organoid/multi-stroma co-cultures comprising pancreatic stellate cells, fibroblasts and mesothelial cells. We demonstrate that a combination of in vitro and in vivo models better captures epithelial cell and fibroblast markers of human pancreatitis and PDAC compared to mouse models alone. Finally, we identify PDAC and pancreatitis epithelial cell-specific reprogramming of stromal cells of different origin, and we infer the contribution of these distinct stromal cell types to fibroblasts in PDAC and pancreatitis in vivo. Together, our study highlights different epithelial cell-fibroblast heterogeneity in PDAC and pancreatitis, and provides new platforms for the identification of markers and epithelial-stromal interdependencies of these diseases.

cancer biology↗

bioRxiv2024

SMAD4 and KRAS status shape malignant-stromal crosstalk in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) contains an extensive stroma that modulates response to therapy, contributing to the dismal prognosis associated with this cancer. Evidence suggests that the stromal composition of PDAC is shaped by mutations within malignant cells; however, most pre-clinical models of PDAC are driven by KrasG12D and mutant Trp53 and have not assessed the contribution of other known oncogenic drivers, including KRASG12V and alterations in CDKN2A and SMAD4. To increase understanding of malignant cell-stroma crosstalk in PDAC, we analyzed Trp53-mutant mouse models driven by KrasG12D or KrasG12V in which Smad4 was wild-type or deleted. KrasG12D; Smad4-deleted PDAC developed a fibro-inflammatory rich stroma with increased JAK/STAT malignant cell signaling and an enhanced therapeutic response to JAK/STAT inhibition. In stark contrast, the stroma of Smad4-deleted KrasG12V PDAC was differently altered, and the malignant compartment lacked JAK/STAT signaling dependency. Thus, malignant cell genotype impacts malignant-stromal phenotype in PDAC, directly affecting therapeutic efficacy. STATEMENT OF SIGNIFICANCEUnderstanding malignant cell-stroma crosstalk in PDAC has focused on models containing KrasG12D and mutant Trp53. Here, we show that PDAC driven by KrasG12D or KrasG12Vin which Smad4 is deleted display differences in malignant-stromal signaling and treatment sensitivity, highlighting the importance of understanding genotype-phenotype relationships for precision PDAC therapy.

cancer biology↗

bioRxiv2022

The heterogeneous distribution of extracellular adenosine reveals a myeloid-dependent axis, shaping the immunosuppressive microenvironment in pancreatic ductal adenocarcinoma

The prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) remains extremely poor. It has been suggested that the adenosine pathway contributes to the ability of PDAC to evade the immune system and its resistance to immunotherapies (Immuno-Oncology Therapy, IOT), by generating extracellular adenosine (eAdo). Using genetically engineered allograft models of PDAC in syngeneic mice with differential immune infiltration and response to IOT, we showed enrichment of the adenosine pathway in tumour-infiltrating immune cells (in particular, myeloid populations). Using MS-Imaging, we showed that extracellular adenosine distribution is heterogeneous in tumours, with high concentrations in hypoxic margins that surround necrotic areas, associated with a rich myeloid infiltration, demonstrated using Imaging Mass Cytometry (IMC). Pro-tumorigenic M2 macrophages express high levels of the Adora2a receptor; particularly in the IOT resistant model. Blocking the in vivo formation and function of eAdo (Adoi), using a combination of anti-CD73 antibody and an Adora2a inhibitor slowed tumour growth and reduced metastatic burden. In addition, blocking the adenosine pathway improved the efficacy of combinations of cytotoxic agents or immunotherapy. Finally, Adoi remodelled the tumour microenvironment (TME), as evidenced by reduced infiltration of M2 macrophages and Tregs. RNAseq analysis showed that genes related to immune modulation, hypoxia and tumour stroma were downregulated following Adoi and a specific adenosine signature derived from this is associated with a poorer prognosis in patients with PDAC. The formation of eAdo appears to promote the development of the immunosuppressive TME in PDAC, contributing to its resistance to conventional and novel therapies. Therefore, inhibition of the adenosine pathway may represent a strategy to modulate the stroma and improve therapy response in patients with PDAC.

cancer biology↗

bioRxiv2019

Temporal inhibition of autophagy reveals segmental reversal of aging with increased cancer risk

Autophagy is an important cellular degradation pathway with a central role in metabolism as well as basic quality control, two processes inextricably linked to aging. A decrease in autophagy is associated with increasing age, yet it is unknown if this is causal in the aging process, and whether autophagy restoration can counteract these aging effects. Here we demonstrate that systemic autophagy inhibition induces the premature acquisition of age-associated phenotypes and pathologies in mammals. Remarkably, autophagy restoration provides a near complete recovery of morbidity and a significant extension of lifespan, however, at the molecular level this rescue appears incomplete. Importantly autophagy-restored mice still succumb earlier due to an increase in spontaneous tumor formation. Thus our data suggest that chronic autophagy inhibition confers an irreversible increase in cancer risk and uncovers a biphasic role of autophagy in cancer development being both tumor suppressive and oncogenic, sequentially.

cancer biology↗