Biology subjects

Garcia-Pedrero, J. M.

Publications and source records attributed to Garcia-Pedrero, J. M..

4 recordsLinked to original sources

bioRxiv2026

NGFR-driven suppression of antigen presentation limits CD8+ T cell immunity and response to checkpoint blockade

Immune checkpoint blockade has revolutionized cancer therapy; however, numerous tumors remain resistant by adopting cellular states that impede immune recognition. In this study, we identify the nerve growth factor receptor (NGFR) as a regulator of immune evasion in head and neck squamous cell carcinoma (HNSCC). Genetic ablation of Ngfr resulted in impaired tumor growth in immunocompetent MOC2 HNSCC, while pharmacological inhibition with THX-B reduced primary tumor growth and spontaneous metastatic dissemination. Single-cell profiling of MOC2 tumors demonstrated that Ngfr loss redirected tumor cells away from invasive EMT-like states and enhanced antigen-processing and presentation programs. This was accompanied by increased presentation of tumor antigens and expansion of effector CD8+ T-cells in vivo. Functionally, CD8+ T-cell depletion, Batf3 deficiency, and JAK1/2 inhibition restored the growth of Ngfr-deficient tumors, indicating that NGFR loss exposes tumors to CD8+ T-cell-mediated control through a JAK-associated antigen-presentation program. Notably, NGFR blockade sensitized otherwise resistant MOC2 tumors to anti-PD1 therapy, and the combination of THX-B with anti-PD1 significantly improved tumor control and survival. In human HNSCC, spatial profiling revealed that NGFR+ tumor regions exhibited reduced HLA-DR expression and limited CD3+ T-cell infiltration. Notably, an NGFR-associated antigen-presentation signature stratified survival and response in HNSCC patients undergoing immune checkpoint blockade. Interestingly, this signature was also linked to improved outcomes in melanoma patients. We also observed a significant increase in the effector CD8+ T-cell fraction in melanoma NGFR KO tumors linked to a significant decrease in tumor growth. These findings position NGFR as a regulator of tumor immune visibility and support NGFR inhibition as a strategy to enhance immunotherapy response.

cancer biology↗

bioRxiv2026

Functional proteomics identifies targetable cancer-associated fibroblast programs in head and neck cancer

Head and neck squamous cell carcinoma (HNSCC) remains clinically challenging, with limited molecularly targeted options and a strong dependence on the tumor microenvironment. Cancer-associated fibroblasts (CAFs) are major stromal regulators that shape tumor progression, extracellular matrix remodeling, invasion, and therapeutic response. However, how CAF heterogeneity and plasticity translate into distinct tumor-promoting functions and targetable vulnerabilities remains insufficiently defined. Here, we integrated patient-matched primary CAFs and normal fibroblasts with 3D functional assays, tumor-stroma co-culture models, quantitative extracellular matrix analysis, whole-proteome profiling, and pharmacological perturbation. Primary fibroblast populations displayed marked interpatient heterogeneity and context-dependent plasticity in invasion, contractility, and responsiveness to tumor-derived signals, whereas enhanced fibronectin-rich matrix deposition and disorganization emerged as a conserved CAF-associated feature. Both normal fibroblasts and CAFs promoted HNSCC cell invasion in a population-dependent manner, whereas CAFs consistently induced less compact and more dispersed tumor nest architectures. Integrative functional analyses identified distinct CAF phenotypes characterized by either invasive and matrix-remodeling activity or high responsiveness to tumor-derived cues. Proteomic profiling revealed recurrent enrichment of adhesion, cytoskeletal, and extracellular matrix programs and guided the selection of pharmacological inhibitors aimed at modulating specific CAF-mediated pro-tumoral functions. Pharmacological targeting selectively altered these functions: CHI3L1 inhibition disrupted fibronectin matrix deposition, broad phosphodiesterase inhibition increased matrix alignment, and FZD7 inhibition consistently blocked tumor-induced CAF invasion across all tested populations. These findings define functionally distinct and pharmacologically targetable CAF programs in HNSCC and support stromal-directed interventions as a rational component of future combination treatment strategies.

cancer biology↗

bioRxiv2025

Loss of Gαq reshapes key fibroblast traits and drives matrix remodeling and aggressive progression of oral cancer tumors

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive cancer, with limited therapeutic options and a high mortality rate, primarily due to metastasis and recurrence. Tumor-stroma interactions, and namely cancer-associated fibroblasts (CAFs), are pivotal in shaping HNSCC progression. CAFs remodel the extracellular matrix (ECM) and secrete factors and vesicles that promote tumor growth and metastasis. The interplay between autophagy and endosomal/exosomal pathways has been suggested to regulate cellular secretory functions, but their potential involvement in HNSCC progression remains poorly understood. Since we have recently uncovered Gq as a key modulator of autophagy, we have investigated the impact of Gq loss on fibroblast functionality and on its crosstalk with oral HNSCC cells. We report that the absence of Gq rewires murine embryonic fibroblasts towards CAF-like traits, leading to an increased pro-tumorigenic capacity of co-cultured human oral cancer cells through enhanced collagen I deposition and ECM remodeling. Strikingly, fibroblasts lacking Gq display a shift in the balance of intracellular trafficking, degradative and secretory pathways. Exosomes released from Gq-deficient fibroblasts show a marked enrichment in tumor-growth factor receptors and can facilitate aberrant tumor growth of HNSCC cells. Gq-silenced fibroblasts promote the formation of "railroad-tracks" structures around HNSCC cells, enhancing their migratory and invasive capabilities both in vitro and in vivo, and reduced Gq expression in human HNSCC CAFs correlates with enhanced tumor progression. Overall, our data put forward Gq as a key regulator of the HNSCC tumor microenvironment by modulating fibroblast plasticity and functionality.

cancer biology↗

bioRxiv2023

VAV2-DEPENDENT REGULATION OF RIBOSOME BIOGENESIS IN KERATINOCYTES AND ORAL SQUAMOUS CELL CARCINOMA

VAV2 is an activator of RHO GTPases that promotes and maintains regenerative proliferation-like states in normal keratinocytes and oral squamous cell carcinoma (oSCC) cells, respectively. Here, we demonstrate that VAV2 also plays critical roles in the regulation of ribosome biogenesis in those cells, a program associated with poor prognosis of human papilloma virus negative oSCC patients. Mechanistic analyses indicate that VAV2 regulates this process in a catalysis-dependent manner using a conserved pathway composed of the GTPases RAC1 and RHOA, members of the PAK and ROCK family kinases, and the transcriptional factors c-MYC and YAP/TAZ. This pathway directly promotes RNA polymerase I activity and the ensuing synthesis of 47S pre-rRNA precursors. This process is further consolidated by the upregulation of ribosome biogenesis factors and the acquisition of the YAP/TAZ-dependent cell undifferentiation state. Finally, we show that RNA polymerase I is a therapeutic Achilles heel for both keratinocytes and hnSCC patient derived cells endowed with high VAV2 catalytic activity. Collectively, these findings highlight the therapeutic potential of the VAV2 and ribosome biogenesis pathways in both preneoplastic and late progression stages of oSCC.

cancer biology↗