Biology subjects

Figueiredo, I.

Publications and source records attributed to Figueiredo, I..

5 recordsLinked to original sources

bioRxiv2025

ProMPt: A modular preclinical platform for functional modelling of prostate cancer heterogeneity and therapeutic vulnerabilities

Prostate cancer progression is driven by heterogenous genetic, phenotypic, and microenvironmental programs that remain challenging to model experimentally. Existing systems such as genetically engineered mouse models, xenografts, and patient-derived organoids have each advanced mechanistic insight but are limited by genetic scope, scalability, or lack of immune context. To overcome these constraints we developed ProMPt, a genetically-defined syngeneic mouse modelling platform that captures combinations of the most recurrent clinical prostate cancer genomic alterations to enable scalable in vitro and in vivo interrogation of prostate cancer evolution. Tumours derived from ProMPt organoids recapitulate the histologic and molecular diversity of human disease. Cross - species transcriptomic integration and multivariate single-cell analysis under defined culture permutations revealed conserved phenoscapes, highlighting a central role for MYC in disease progression and therapy resistance. Guided by these insights, preclinical intervention studies demonstrated that combined MAPK inhibition and blockade of protein translation synergistically suppressed tumour growth in castration-resistant models. This combination not only suppressed proliferation but also remodelled the tumour immune landscape, underscoring its dual epithelial and microenvironmental effects. Together, these findings establish ProMPt as a versatile framework for linking genotype, lineage plasticity, and therapeutic vulnerability in prostate cancer.

cancer biology↗

bioRxiv2025

TREM2 macrophages are associated with enhanced response to PD-1 blockade in human hepatocellular carcinoma

Macrophages are known to dampen tumor immunity. However, identifying druggable targets that modulate these cells to improve existing immunotherapies has been limited by a dearth of studies identifying macrophages that associate with pathological response to immune checkpoint blockade. To fulfill this unmet clinical need, we leveraged transcriptional and spatial profiling of specimens collected from a Phase II clinical trial studying neoadjuvant PD-1 blockade in patients with hepatocellular carcinoma (HCC). We determined that the intratumoral abundance of TREM2-expressing macrophages and serological levels of soluble TREM2 are elevated in patients who responded to PD-1 blockade, compared to non-responders. We validated these findings in a second HCC cohort and in the IMbrave150 trial. These highlight the robust potential for TREM2 macrophages to predict therapeutic responses of HCC to immunotherapy. Therefore, our study provides a novel basis for the use of TREM2 macrophages to strategize treatment for patients with HCC to maximize therapeutic benefit.

immunology↗

bioRxiv2025

MARQO pipeline resolves multiparametric cellular and spatial organization in cancer tissue lesions

Multiplex immunostaining analysis remains fragmented, underperforming, and labor-intensive despite tissue proteomic methodologies achieving ever-increasing marker complexity. Here we propose an open-source, semi-supervised automated pipeline that streamlines start-to-finish, single-cell resolution analysis of whole-slide tissue, named Multiplex-imaging Analysis, Registration, Quantification, and Overlaying (MARQO). We compared and validated MARQO using Multiplex Immunohistochemical Consecutive Staining on a Single Slide (MICSSS) using human tumor and adjacent normal tissue samples. Performance was compared with manually-curated pathologist determinations and quantification of multiple markers. We also optimized MARQO to analyze diverse tissue sizes (whole tissue, biopsy, tissue microarray) and staining approaches (singleplex immunohistochemistry, 20-color multiplex immunofluorescence) to determine marker co-expression patterns in multiple human solid cancer types. Lastly, we validated CD8 T cell enrichment in hepatocellular carcinoma responders to neoadjuvant cemiplimab in a phase II clinical trial, further demonstrating MARQOs ability to provide spatially-resolved in situ mechanisms by providing multiplex whole-slide single-cell resolution data.

immunology↗

bioRxiv2024

Dendritic cells type 1 control the formation, maintenance, and function of tertiary lymphoidstructures in cancer

Tertiary lymphoid structures (TLS) are organized immune cell aggregates that arise in chronic inflammatory conditions. In cancer, TLS are associated with better prognosis and enhanced response to immunotherapy, making these structures attractive therapeutic targets. However, the mechanisms regulating TLS formation and maintenance in cancer are incompletely understood. Using spatial transcriptomics and multiplex imaging across various human tumors, we found an enrichment of mature dendritic cells (DC) expressing high levels of CCR7 in TLS, prompting us to investigate the role of DC in the formation and maintenance of TLS in solid tumors. To address this, we developed a novel murine model of non-small cell lung cancer (NSCLC) that forms mature TLS, containing B cell follicles with germinal centers and T cell zones with T follicular helper cells (TFH) and TCF1+PD-1+ progenitor exhausted CD8+ T cells (Tpex). Here we show that, during the early stages of tumor development, TLS formation relies on IFN{gamma}-driven maturation of the conventional DC type 1 (cDC1) subset, their migration to tumor-draining lymph nodes (tdLN), and recruitment of activated T cells to the tumor site. As tumors progress, TLS maintenance becomes independent of T cell egress from tdLN, coinciding with a significant reduction of cDC1 migration to tdLN. Instead, mature cDC1 accumulate within intratumoral CCR7 ligand-enriched stromal hubs. Notably, timed depletion of cDC1 or disruption of their migration to these stromal hubs after TLS are formed alters TLS maintenance. Importantly, we found that cDC1-mediated antigen presentation to both CD4+ and CD8+ T cells and intact CD40 signaling, is critical for the maintenance of TLS, the preservation of the TFH cell pool, the formation of germinal center and the production of tumor-specific IgG antibodies. These findings underscore the key role of mature cDC1 in establishing and maintaining functional TLS within tumor lesions and highlight the potential for cDC1-targeting therapies as a promising strategy to enhance TLS function and improve anti-tumor immunity in patients with cancer.

immunology↗

bioRxiv2022

Targeting the BAG-1 family of co-chaperones in lethal prostate cancer.

Therapies that abrogate persistent androgen receptor (AR) signaling in castration resistant prostate cancer (CRPC) remain an unmet clinical need. The N-terminal domain (NTD) of the AR drives transcriptional activity in CRPC but is intrinsically disordered and remains a challenging therapeutic target. Therefore, inhibiting critical co-chaperones, such as BAG-1L, is an attractive alternative strategy. We performed druggability analyses demonstrating the BAG domain to be a challenging drug target. Thio-2, a tool compound, has been reported to bind the BAG domain of BAG-1L and inhibit BAG-1L-mediated AR transactivation. However, despite these data, the mechanism of action of Thio-2 is poorly understood and the BAG domain which is present in all BAG-1 isoforms has not been validated as a therapeutic target. Herein, we demonstrate growth inhibiting activity of Thio-2 in CRPC cell lines and patient derived models with decreased AR genomic binding and AR signaling independent of BAG-1 isoform function. Furthermore, genomic abrogation of BAG-1 isoforms did not recapitulate the described Thio-2 phenotype, and NMR studies suggest that Thio-2 may bind the AR NTD, uncovering a potential alternative mechanism of action, although in the context of low compound solubility. Furthermore, BAG-1 isoform knockout mice are viable and fertile, in contrast to previous studies, and when crossed with prostate cancer mouse models, BAG-1 deletion does not significantly impact prostate cancer development and growth. Overall, these data demonstrate that Thio-2 inhibits AR signaling and growth in CRPC independent of BAG-1 isoforms, and unlike previous studies of the activated AR, therapeutic targeting of the BAG domain requires further validation before being considered a therapeutic strategy for the treatment of CRPC.

molecular biology↗