Biology subjects

Bozal-Basterra, L.

Publications and source records attributed to Bozal-Basterra, L..

3 recordsLinked to original sources

bioRxiv2025

Metabolic Alterations driven by PFKFB3 upregulation confer Resistance to Trastuzumab in HER2-Positive Breast Cancer.

AimsResistance to anti-HER2 therapies, particularly trastuzumab, remains a major obstacle in the treatment of HER2-positive (HER2+) breast cancer. This study aims to uncover novel mechanisms driving trastuzumab resistance with a focus on the immune component, key mediator of trastuzumab efficacy. MethodsWe developed an isogenic cell line-derived xenograft model to perform transcriptome-wide analyses of trastuzumab-sensitive and -resistant tumors. To validate key findings, we employed a 3D cancer-immune co-culture system capable of quantifying antibody-dependent cellular cytotoxicity (ADCC). ResultsTranscriptomic profiling revealed how trastuzumab treatment shifts tumor transcriptomes, including changes that remodel the metabolic landscape and distinct gene signatures associated with resistance, notably the upregulation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). Functional studies demonstrated that PFKFB3 promotes trastuzumab resistance by inducing metabolic rewiring and reducing ADCC. Silencing PFKFB3 restored immune-mediated cytotoxicity. Clinical dataset analyses confirmed that elevated PFKFB3 expression correlates with reduced overall and progression-free survival, and with incomplete pathological response to trastuzumab. ConclusionsPFKFB3 upregulation drives metabolic adaptations that confer resistance to trastuzumab in HER2+ breast cancer. These findings highlight PFKFB3 as a promising therapeutic target to overcome resistance and improve patient outcomes. HighlightsO_LIPFKFB3 upregulation promotes trastuzumab resistance in HER2+ breast cancer. C_LIO_LITranscriptomic profiling reveals metabolic shifts linked to resistance. C_LIO_LISilencing PFKFB3 restores ADCC and sensitizes cancer cells to trastuzumab. C_LIO_LIHigh PFKFB3 expression correlates with poor survival and treatment response. C_LIO_LIPFKFB3 is a potential therapeutic target to overcome trastuzumab resistance. C_LI

cancer biology↗

bioRxiv2024

The transcriptional landscape of metastatic hormone-naive prostate cancer

Metastatic hormone-naive prostate cancer (mHNPC) is an infrequent form of this tumour type that is characterized by metastasis at the time of diagnosis and accounts for 50% of prostate cancer-related deaths. Despite the extensive characterization of localized and metastatic castration resistant prostate cancer (mCRPC), the molecular characteristics of mHNPC remain largely unexplored. Here we provide the first extensive transcriptomics characterization of mHNPC. We generated discovery and validation bulk and single-cell RNA-Seq datasets and performed integrative computational analysis in combination with experimental studies. Our results provide unprecedented evidence of the distinctive transcriptional profile of mHNPC and identify stroma remodelling as a predominant feature of these tumours. Importantly, we discover a central role for the transcription factor SOX11 in triggering a heterotypic communication that is associated to the acquisition of metastatic properties. Our study will constitute an invaluable resource for a profound understanding of mHNPC that can influence patient management.

cancer biology↗

bioRxiv2019

LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is altered in Townes-Brocks Syndrome

Primary cilia are sensory organelles that are crucial for cell signaling during development and organ homeostasis. Cilia arise from the centrosome and their formation is governed by numerous regulatory factors. We show that the leucine-zipper protein LUZP1 localizes to the pericentriolar material and actin cytoskeleton. Using TurboID proximity labeling and pulldowns, LUZP1 associates with factors linked to centrosome and actin filaments. Loss of LUZP1 reduces F-actin levels, facilitating ciliogenesis and altering Sonic Hedgehog signaling, pointing to a key role in the cytoskeleton-cilia interdependency. Moreover, we show that LUZP1 interacts with a truncated form of the transcription factor SALL1 that causes Townes-Brocks Syndrome. TBS is characterized by digit, heart and kidney malformations and is linked in part to defective cilia. Truncated SALL1 increases the ubiquitin proteasome-mediated degradation of LUZP1. Alteration of LUZP1 levels may be a contributing factor to TBS, suggesting possible therapies using modulators of cilia and cytoskeletal function.

cell biology↗