Biology subjects

Araos Henriquez, J.

Publications and source records attributed to Araos Henriquez, J..

4 recordsLinked to original sources

bioRxiv2026

TGF-β- and IL-1-dependent fibroblast states differentially shape pancreatic cancer microenvironments and metastasis

Pancreatic ductal adenocarcinoma (PDAC) contains heterogeneous cancer-associated fibroblast (CAF) populations, including interleukin 1 (IL-1)-dependent inflammatory CAFs (iCAFs) and transforming growth factor beta (TGF-{beta})-dependent myofibroblastic CAFs (myCAFs), whose functions at primary and metastatic sites remain incompletely defined. Here, we genetically disrupted IL-1 or TGF-{beta} signalling in fibroblast activation protein (FAP)-expressing CAFs arising from a shared cellular origin to determine how myCAF and iCAF states shape PDAC progression and microenvironments. Depletion of TGF-{beta}-dependent myCAFs, but not IL-1-dependent iCAFs, did not alter primary tumour growth or local metastatic dissemination but significantly reduced liver and lung metastases. Matched primary tumours and liver metastasis analyses also revealed site-specific stromal responses to TGF-{beta} signalling disruption. Experimental models of liver metastasis colonisation and outgrowth indicated that the reduced metastatic phenotype was linked primarily to alterations within pancreatic tumours rather than to impaired malignant cell outgrowth at metastatic sites. Single-cell RNA-sequencing of myCAF-depleted primary tumours revealed extensive transcriptional reprogramming across fibroblast, immune and malignant compartments, highlighting the complexity of assigning myCAF-to-malignant cell signalling mechanisms in vivo. To resolve this crosstalk, we co-cultured PDAC organoids with pancreatic stellate cells engineered to remain in myCAF or iCAF states. Cross-model transcriptomic analyses, together with genetic and pharmacological perturbation studies, showed that myCAF-derived TGF-{beta} directly promotes epithelial-to-mesenchymal transition signalling in PDAC malignant cells, providing a candidate mechanism for the reduced metastasis observed upon myCAF depletion in vivo. These findings reveal distinct, context-dependent roles for TGF-{beta}- and IL-1-dependent CAF states and identify myCAF-derived TGF-{beta} signalling as a stromal mechanism promoting malignant cell plasticity.

cancer biology↗

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↗

bioRxiv2022

ERBB-activated myofibroblastic cancer-associated fibroblasts promote local metastasis of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Cancer-associated fibroblasts (CAFs) are recognized potential therapeutic targets, but poor understanding of these heterogeneous cell populations has limited the development of effective treatment strategies. We previously identified TGF-{beta} as a main driver of myofibroblastic CAFs (myCAFs). Here, we show that EGFR/ERBB2 signaling is induced by TGF-{beta} in myCAFs through an autocrine process mediated by the ERBB ligand amphiregulin. Inhibition of this ERBB-signaling network in PDAC organoid-derived cultures and mouse models impacts distinct CAF subtypes, providing insights into mechanisms underpinning their heterogeneity. Remarkably, ERBB-activated myCAFs promote local PDAC metastasis in mice, unmasking functional significance in myCAF heterogeneity. Finally, analyses of other cancer datasets suggest these processes might operate in other malignancies. These data provide functional relevance to CAF heterogeneity and identify a potential target for preventing local tumor invasion in PDAC.

cancer biology↗