Biology subjects

Munoz-Espin, D.

Publications and source records attributed to Munoz-Espin, D..

5 recordsLinked to original sources

bioRxiv2025

Identification of senescence-associated drivers of tumour growth and progression using a novel microarray platform

Senescence and the senescence associated secretory phenotype (SASP) are implicated in promoting early tumorigenesis but due to the complexity of SASP it has been difficult to identify the responsible factors. We used canonical SASP factors on our microenvironment microarray (MEMA) platform to systematically identify SASP-associated drivers of tumorigenesis in breast and lung cancer cells. We found multiple SASP factors enhanced the proliferation and overall cell numbers for both lung and breast cells grown on the MEMA, and that there was significant overlap in SASP-associated growth-promoting factors between the two different cell types. We validated the ability of several factors, including IL-6, TGF-{beta} and EGF, to drive growth in in vitro assays. Interestingly, these factors were effective in driving growth and survival in cells that were altered (either immortalized or fully transformed) but not in normal cells and impacted breast cells differently depending on the age of the patient. RNAseq identified upregulation of wound-healing and stem-cell programs in SASP factor-treated cells. Many of these same SASP factors were present in conditioned media collected from senescent cells, which enhanced the growth of both lung and breast cancer cells, and inhibitors of the specific SASP factors partially reduced growth. Similarly, targeted inhibition of EGF partially reduced lung tumour growth in xenografts when senescent but not normal fibroblasts were co-implanted. Our findings have identified core SASP drivers of tumorigenesis and suggest that effective tumorigenesis driven by SASP is multifactorial and requires alterations in the target cells to achieve maximal response.

cancer biology↗

bioRxiv2025

Mechanisms of resistance to VHL loss-induced genetic and pharmacological vulnerabilities

The von Hippel-Lindau tumor suppressor (VHL) is a component of a ubiquitin ligase complex that normally controls cellular responses to hypoxia. Endogenous VHL is also utilized by proteolysis-targeting chimera (PROTAC) protein degraders, a promising class of anti-cancer agents. VHL is broadly essential for cell proliferation, yet it is a key tumor suppressor in renal cell carcinoma. To understand the functional consequences of VHL loss, and to identify targeted approaches for the elimination of VHL null cells, we have used genome-wide CRISPR-Cas9 screening in human renal epithelial cells. We find that, upon VHL loss, the HIF1A/ARNT complex is the central inhibitor of cellular fitness, suppressing mitochondrial respiration, and that VHL null cells show HIF1A-dependent molecular vulnerabilities that can be targeted pharmacologically. Combined VHL/HIF1A inactivation in breast and esophageal cancer cells can also provide resistance to ARV-771, a VHL-based bromodomain degrader that has anti-cancer activity. HIF1A stabilization can thus provide opportunities for early intervention in neoplastic VHL clones, and the VHL-HIF1A axis may be relevant for the development of resistance to the emerging class of PROTAC-based cancer therapies.

cancer biology↗

bioRxiv2023

Failed reprogramming of transformed cells due to induction of apoptosis and senescence impairs tumor progression in lung cancer

Cell reprogramming to pluripotency applied to the study of cancer has identified transformation and pluripotency as two independent and incompatible cell fates. A detailed knowledge of the relationship between transformation and reprogramming could lead to the identification of new vulnerabilities and therapeutic targets in cancer. Here, we explore this interplay and find that OSKM expression limits tumor cell growth by inducing apoptosis and senescence. We identify Oct4 and Klf4 as the main individual reprogramming factors responsible for this effect. Mechanistically, the induction of cell cycle inhibitor p21 downstream of the reprogramming factors acts as mediator of cell death and senescence. Using a variety of in vivo systems, including allografts, orthotopic transplantation and KRAS-driven lung cancer mouse models, we demonstrate that OSKM expression impairs tumor growth and reduces tumor burden.

cell biology↗

bioRxiv2023

In Vivo Monitoring of Cellular Senescence by Photoacoustic and Fluorescence Imaging Utilizing a Nanostructured Organic Probe

Senescent cells accumulate in multiple age-related disorders, including cancer, exacerbating the pathological manifestations, and the eradication of these cells has emerged as a promising therapeutic strategy. Despite the impact of senescence in diseases, the development of tools to monitor the senescent burden in vivo remains a challenge due to their suboptimal specificity, translatability, and tissue penetrance. Here, we have designed a nanostructured organic probe (NanoJaggs) based on biocompatible indocyanine green dye (ICG) building blocks forming J-aggregates, which possess distinct spectral properties allowing both fluorescence and photoacoustic tomography (PAT) detection. We show that NanoJaggs are taken up by an active process of endocytosis and exhibit selective accumulation at the lysosomal compartment in several in vitro models for senescence. Finally, NanoJagg probe is validated in two in vivo studies including live PAT imaging and shows remarkable specificity to tumours with chemotherapy-induced senescence compared to untreated proliferative tumors. In vitro, ex vivo and in vivo all indicate that NanoJaggs are a clinically translatable tool for detection of senescence and their robust PAT signal makes them suitable for longitudinal monitoring of the senescent burden in solid tumors after chemo or radiotherapy.

cancer biology↗

bioRxiv2022

A tumour-promoting senescent secretome triggered by platinum chemotherapy exploits a targetable TGFβR1/Akt-mTOR axis in lung cancer

Platinum-based chemotherapy is commonly used for non-small cell lung cancer (NSCLC) treatment, yet clinical outcomes remain poor. Cellular senescence and its associated secretory phenotype (SASP) can have multiple tumour-promoting activities, although these are largely unexplored in lung cancer. Here we show that cisplatin-derived SASP enhances the malignant phenotype of lung cancer cells. Using xenograft, orthotopic and KrasG12V-driven murine NSCLC models, we demonstrate that cisplatin-induced senescent cells strongly promote tumour progression. Mechanistically, we find that a TGF-{beta}-enriched SASP drives pro-proliferative effects through TGF{beta}R1 and Akt/mTOR pathway activation. We validate the translational relevance of chemotherapy-induced SASP using clinical NSCLC samples from patients who received neoadjuvant platinum-based chemotherapy. Importantly, TGF{beta}R1 inhibition with galunisertib or senolytic treatment significantly reduces tumour promotion driven by cisplatin-induced senescence. Finally, we demonstrate, using distinct murine NSCLC models, that addition of TGFBR1 inhibitors to platinum-based chemotherapy reduces tumour burden and improves survival, providing pre-clinical proof-of-concept for future trial designs.

cancer biology↗