Biology subjects

Fusilier, Z.

Publications and source records attributed to Fusilier, Z..

4 recordsLinked to original sources

bioRxiv2025

Myeloid reprogramming by poly(I:C) recruits progenitor-exhausted CD8+ T cells and sensitizes rhabdoid tumors to PD-1 blockade

Immune exclusion remains a major barrier to effective immunotherapy in solid tumors. Given the abundance and plasticity of tumor-associated macrophages (TAMs) in many tumors, including pediatric tumors, we investigated whether TLR3 activation could reprogram them to facilitate immune access. Single-cell and spatial profiling in a mouse model of rhabdoid tumors showed that they are dominated by TLR3-expressing TAMs, whose depletion delays tumor growth. Treatment with the TLR3 agonist poly(I:C) promotes immune cell infiltration, including progenitor-exhausted CD8+ T cells, by multiple mechanisms including the reduction and reprogramming of immunosuppressive TAMs, promoting nitric-oxide production by peritumoral macrophages, and inducing CXCL9/10 production. Combined poly(I:C) and PD-1 blockade elicited durable, complete tumor rejection. Human macrophages from tumor biopsies showed conserved TLR3 responsiveness, underscoring translational potential. These findings uncover a mechanism by which TLR3-driven myeloid reprogramming transforms immune-excluded tumors into checkpoint-responsive ones, revealing a therapeutic path to overcome resistance to PD-1 blockade.

immunology↗

bioRxiv2025

Magnetite Nanoparticle Photothermal Therapy in a Pancreatic Tumor-on-Chip: A Dual-Action Approach Targeting Cancer Cells and their Microenvironment

The application of magnetite nanoparticles (MagNPs) for photothermal therapy (MagNP-PTT) has recently expanded in cancer treatment. This study introduces MagNP-PTT in a tumor-on-chip model to target highly aggressive pancreatic ductal adenocarcinoma (PDAC). A tumor-on-chip system was developed using PANC-1 PDAC cells embedded in a collagen type I extracellular matrix and cultured for one week to form tumor spheroids. This platform serves as the foundation for applying PTT in a model system that is aimed to mimic the native tumor microenvironment. MagNPs efficiently penetrate the tumor spheroids, achieving controlled heating via near-infrared (NIR) light. By adjusting nanoparticle concentration and laser power, temperature increments of 2{degrees}C between 38-48{degrees}C were established. Temperatures above 44{degrees}C significantly increased cell death, while lower temperatures allowed partial recovery. Beyond inducing cancer cell death, MagNP-PTT altered the extracellular matrix, and triggered a slight epithelial-mesenchymal transition marked by increased vimentin expression. These findings highlight MagNP-PTT as a dual-action therapy, targeting both tumor cells and their microenvironment, offering a novel approach for overcoming stromal barriers in pancreatic cancer treatment. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC="FIGDIR/small/636875v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@9b9c20org.highwire.dtl.DTLVardef@272c7aorg.highwire.dtl.DTLVardef@1d91021org.highwire.dtl.DTLVardef@1b1ea8d_HPS_FORMAT_FIGEXP M_FIG SYNOPSIS TABLE OF CONTENTS C_FIG

cancer biology↗

bioRxiv2025

Macrophages restrict tumor permissiveness to immune infiltration by controlling local collagen topography through a Tcf4-Collagen3 fibrotic axis

During tumorigenesis, the extracellular matrix (ECM), which constitutes the structural scaffold of tissues, is profoundly remodeled. While the impact of such remodeling on tumor growth and invasion has been extensively investigated, much less is known on the consequences of ECM remodeling on tumor infiltration by immune cells. By combining tissue imaging and machine-learning, we here show that the localization of T lymphocytes and neutrophils, which orchestrate antitumor immune responses, can be predicted by defined topographical features of fibrillar collagen networks. We further show that these collagen topographies result from the activation of a fibrotic pathway controlled by the transcription factor Tcf4 upon depletion of tumor-associated macrophages at late tumor stages. This pathway promotes the deposition of collagen 3 by both tumor and stromal cells, resulting in intermingled collagen networks that favor intra-tumoral T cell and neutrophil localization. Importantly, analysis of human colorectal cancer public bulk RNAseq databases showed a strong correlation between Tcf4 and collagen 3, as well as between the expression of these genes and tumor infiltration by T lymphocytes and neutrophils, attesting the clinical relevance of our findings. This study highlights the key structural role of macrophages on the tumor extracellular matrix and identifies collagen network topographies as a major regulator of tumor infiltration by immune cells.

immunology↗

bioRxiv2024

Signaling downstream of tumor-stroma interaction regulates mucinous colorectal adenocarcinoma apicobasal polarity

Mucinous colorectal carcinoma (MUC CRC) dissemination into the tumor stroma and metastasis to multiple organs, including the peritoneum, is associated with poor prognosis. Disseminating MUC CRCs exhibit either a conventional apical-in or an inverted apical-out polarity phenotype that influence patient outcome. Identifying the mechanisms controlling MUC CRC polarity is critical to understand disease progression. Here, we analyze patient-derived MUC CRC xenografts, with apical-in or apical-out polarity, ex vivo or within collagen gels to mimic the peritumoral stroma. Single-cell analyses reveal 2{beta}1-integrin as a key collagen-binding receptor in these models. Collagen-2{beta}1-integrin interaction activates Src and ERK/MAPK signaling and upregulates the expression of SorLA, an endosomal sorting receptor. SorLA supports apical-in polarity and carcinoma-stroma interactions by promoting integrin recycling to the plasma membrane and HER2/HER3 expression through a positive feedback mechanism. Accordingly, we observe positive correlation between HER2, HER3 and SorLA in patient samples with the highest HER2 expression in apical-in-presenting tissues. Treatment of tumor spheres with clinically relevant HER2/HER3-targeting antibodies reverts sphere polarity and impedes collagen remodeling and adhesion to mouse peritoneum. This SorLA--integrin--HER2/HER3 signaling axis may represent a basis for MUC CRC-patient stratification and shed light on other carcinomas with similar apical-out phenotypes.

cancer biology↗