Biology subjects

Maiques, O.

Publications and source records attributed to Maiques, O..

4 recordsLinked to original sources

bioRxiv2025

Early overactivation of non-muscle myosin II during adaptation to combined BRAF and MEK inhibitors in dedifferentiating cutaneous melanomas

Cutaneous melanoma is a very aggressive type of skin cancer with remarkable phenotypic plasticity that contributes to adaptation and resistance to targeted therapies against the MAPK pathway. Previous research described that non-muscle myosin II (NMII) of the actomyosin cytoskeleton, which is essential for cell migration and metastasis, is overactivated in BRAF inhibitor-resistant melanomas. Since the combination of BRAF and MEK inhibitors (BMi) is the current standard of care, we investigated if and how NMII activity is regulated during adaptation to BMi. Here, we find that most dedifferentiating BMi-resistant melanomas overactivate NMII compared to their parental counterparts. NMII activity generally increases during the first 2 weeks of BMi treatment, and it is followed by elevated total NMII levels due partly to transcriptional modulation. Although ERK activity rebounds with similar kinetics, NMII overactivation is not prevented by ERK inhibition but by blockade of ROCK. In melanomas that hyperdifferentiate during adaptation to BMi, NMII activity is not increased upon BMi treatment due, in part, to MITF. We also find that co-targeting NMII along BMi in some melanomas reduces survival of drug-tolerant persister cells, which would delay the development of resistance. Therefore, our study identifies elevated NMII activity as a potential marker of adaptation to MAPK in some melanoma subpopulations, and also provide an approach to delay the emergence of resistance to MAPK-targeted therapy.

cancer biology↗

bioRxiv2025

Coenzyme A homeostasis regulates hypoxic signalling via UBFD1in triple-negative breast cancer

Hypoxia-inducible factors (HIFs) orchestrate cellular responses to oxygen deprivation and are frequently activated in triple-negative breast cancer (TNBC), driving metastasis and poor prognosis1,2. However, the full mechanisms of how HIFs are activated are not completely understood. It has been long noted that certain tumours have decreased levels of coenzyme A compared to surrounding tissues3,4, but the functional consequences of this remain unknown. Here, we identify Coenzyme A Synthase (CoAsy) as a novel regulator of HIF signalling. We demonstrate that CoAsy loss stabilises HIF-1 and HIF-2 independently of the canonical oxygen sensing pathway. Proximity-labelling proteomics revealed that CoAsy deficiency disrupts the association between HIF-1 and the proteasome through UBFD1, a novel CoA-binding protein that scaffolds HIF for degradation. UBFD1s CoA-dependent interaction with HIF- is mediated by its PH domain, which undergoes CoAlation, an understudied post-translational modification. COASY loss of heterozygosity occurs in [~]1/3 of breast cancer patients and correlates with increased HIF activity, lack of hormone receptor expression and poor patient outcome. In vivo studies confirm that restoring CoAsy expression in tumours suppresses metastasis to the lung. These findings uncover a critical metabolic checkpoint regulating hypoxic signalling and identify CoAsy as a potential biomarker and therapeutic target in aggressive breast cancers.

molecular biology↗

bioRxiv2021

LAP1 regulates nuclear plasticity to enable constrained migration

Metastasis involves dissemination of cancer cells away from a primary tumour and colonisation at distal sites. During this process, cancer cells must negotiate multiple physical constraints imposed by the microenvironment and tissue structure. The biophysical properties of the nucleus must be tuned since they pose a challenge to constrained migration. By analysing nuclear genes upregulated during the acquisition of metastatic potential, we discovered increased expression of the inner nuclear membrane protein LAP1 in metastatic melanoma cells and at the invasive fronts of human primary tumours and in metastases. Human cells express two LAP1 isoforms (LAP1B and LAP1C), which differ in their amino terminus. We found that whereas the longer isoform, LAP1B, binds more strongly to nuclear lamins and has restricted motility within the nuclear envelope, the shorter isoform, LAP1C, favours nuclear envelope blebbing and allows migration through constraints. We propose that LAP1 renders the nucleus plastic and enhances melanoma aggressiveness.

cell biology↗

bioRxiv2021

Early mismatch between cancer cells and their tumour microenvironment blocks long term growth

Cancer cells thrive embedded in a fine-tuned cellular and extracellular environment or tumour microenvironment (TME). There is a general understanding of a co-evolution between cancer cells and their surrounding TME, pointing at a functional connection between cancer cells characteristics and the perturbations induced in their surrounding tissue. However, whether this functional connection needs to be set from the start or if aggressive cancer cells can always be dominating their microenvironment has never been formally proven with a dedicated experimental setting where malignant cells can be challenged to grow in a different TME from the one they would naturally create. Here we generated an experimental setting where we transiently perturb the secretory profile of aggressive breast cancer cells without affecting their intrinsic growth ability. This led to the initial establishment of an atypical TME. Interestingly, even if initially tumours are formed, this atypical TME evolves to impair long term in vivo cancer growth. Using a combination of in vivo transcriptomics, protein arrays and in vitro co-cultures, we found that the atypical TME culminates in the infiltration of macrophages with STAT1high activity. These macrophages show strong anti-tumoural functions which reduce long-term tumour growth, despite lacking canonical M1 markers. Importantly, gene signatures of the mesenchymal compartment of the TME, as well as the anti-tumoural macrophages show striking prognostic power-correlating with less aggressive human breast cancers.

cancer biology↗