Biology subjects

Celia-Terrassa, T.

Publications and source records attributed to Celia-Terrassa, T..

4 recordsLinked to original sources

bioRxiv2025

METTL3-mediated m6A modification of DNMT1 enhances ovarian cancer progression

High-grade serous carcinoma (HGSC), the most lethal subtype of ovarian cancer, is often diagnosed at advanced stages owing to its asymptomatic progression and lack of early detection markers. In this study, we identified a critical oncogenic role of the RNA methyltransferase METTL3 and the N6-methyladenosine (m6A) RNA modification pathway in HGSC. Depletion of METTL3 or its binding partner METTL14 impairs ovarian cancer proliferation and tumor progression. Mechanistically, m6A deposition enhances the translation of DNA methyltransferase DNMT1, an epigenetic repressor that silences tumor suppressor genes. Pharmacologic inhibition of DNMT1 led to DNA hypomethylation and upregulation of the tumor suppressors TNFAIP3 and FBXO32. Consistently, METTL3 depletion also increased the expression of these genes supporting a model in which METTL3 sustains oncogenesis by maintaining DNMT1 protein levels and repressing anti-tumor pathways. These findings position METTL3-mediated RNA modifications and DNMT1 as promising therapeutic targets in HGSC.

cancer biology↗

bioRxiv2025

Reconfiguration of tumor cells with LCOR transcription factor mRNA nanotherapy to enhance immunotherapy efficacy

Transcription factors (TFs) are generally deemed undruggable due to their structural complexity. mRNA technologies have paved the way to overcome this therapeutic limitation by enabling the development of mRNA protein replacement therapies. Here we explore the newly described TF activity of LCOR (Ligand-dependent corepressor), which suppresses tumor growth by inducing the antigen presentation machinery (APM) of the tumor cells and constrains cellular plasticity. These LCOR effects facilitate recognition of the tumor by the immune system and immune-mediated tumor cell death. To deliver Lcor mRNA into tumor cells, we have used poly {beta}-(amino esters) (pBAE) nanoparticles (NPs) for local delivery of Lcor mRNA in breast cancer primary tumor models. We have engineered pBAE-NPs with high potential for efficiently encapsulate mRNA and facilitate cellular uptake. Our results show optimal endosomal escape, which results in high transfection efficiency in vitro and in vivo, restoring LCOR function in tumor cells and engaging their APM. In preclinical triple-negative breast cancer (TNBC) models, the intratumoral delivery of Lcor mRNA led to a reduction in tumor growth. Importantly, the combination of Lcor mRNA-loaded NPs with anti-PDL1 or anti-CTLA4 immunotherapies eradicated most of the tumors in our preclinical TNBC model. Overall, our nanotherapeutic strategy emerges as an innovative TF-replacement therapy, leveraging the immunogenic effects of LCOR to eradicate breast cancer tumors when combined with immunotherapy. Gaphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/646434v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1814de3org.highwire.dtl.DTLVardef@207a08org.highwire.dtl.DTLVardef@2bddc1org.highwire.dtl.DTLVardef@1ebc3a2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

Neural crest-related NXPH1/α-NRXN signaling opposes neuroblastoma malignancy by inhibiting metastasis

Neuroblastoma is a pediatric cancer that can present as low- or high-risk tumors (LR-NBs and HR-NBs), the latter group showing poor prognosis due to metastasis and strong resistance to current therapy. NBs are known to originate from alterations to cells in the sympatho-adrenal lineage derived from the neural crest, but whether LR-NBs and HR-NBs differ in the way they exploit the transcriptional program underlying their developmental origin remains unclear. Here, we compared the transcriptional landscapes of primary samples of LR-NBs, HR-NBs and human fetal adrenal gland, and thereby identified the transcriptional signature associated to NB formation that further distinguishes LR-NBs from HR-NBs. The majority of the genes comprising this signature belong to the core sympatho-adrenal developmental program, are associated with favorable patient prognosis and with diminished disease progression. The top candidate gene of this list, Neurexophilin-1 (NXPH1), encodes a ligand of the transmembrane receptors -Neurexins (-NRXNs). Our functional in vivo and in vitro assays reveal that NXPH1/-NRXN signaling has a dual impact on NB behavior: whereas NXPH1 and -NRXN1 promote NB tumor growth by stimulating cell proliferation, they conversely inhibit the ability of NB cells to form metastases. Our findings uncover a module of the neural crest-derived sympatho-adrenal developmental program that opposes neuroblastoma malignancy by impeding metastasis, and pinpoint NXPH1/-NRXN signaling as a promising target to treat HR-NBs.

neuroscience↗

bioRxiv2021

Chemotherapy induces a YAP1-dependent fetal conversion to human Colorectal Cancer cells that is predictive of poor patient outcome

Current therapy against colorectal cancer is based on DNA-damaging agents that eradicate highly proliferative malignant cells. Whether sublethal chemotherapy affects tumor cell behavior and impacts on patient outcome is primarily unstudied. We now show that sublethal chemotherapy imposes a quiescent-like state to p53 wildtype human colorectal cancer (CRC) cells that is linked to the acquisition of a fetal phenotype downstream of YAP1, similar to that observed after intestinal damage. CRC cells displaying this fetal phenotype exhibit tumor- initiating activity comparable to untreated cells but superior metastatic capacity. Notably, nuclear YAP1 accumulation, or detection of the fetal signature in tumors predict poor prognosis in CRC patients carrying p53 wildtype tumors. Collectively, our results uncover a potential adverse response of tumor cells to suboptimal chemotherapy, and identify nuclear YAP1 and fetal conversion of colorectal tumors as biomarkers for prognosis and therapy prescription. Statement of significanceChemotherapy induces a quiescent-like phenotype to colorectal cancer cells that is linked to the acquisition of a YAP1-dependent fetal signature. Notably, this signature is predictive of patient outcome in different cohorts of human colorectal cancer.

cancer biology↗