Biology subjects

Araujo, A. R.

Publications and source records attributed to Araujo, A. R..

3 recordsLinked to original sources

bioRxiv2025

Multi-omics analysis of TNBC organoids identifies phosphorylation of the membrane trafficking machinery as a key event associated with FER-mediated invasion

Triple Negative Breast Cancer (TNBC) is characterised by unfavourable outcome due to the combination of its metastatic propensity, chemo-refractory behaviour and the lack of effective targeted interventions. Expression of the feline sarcoma-related (FER) kinase constitutes an independent prognostic factor that correlates with poor patient survival. FER promotes invasive behaviour in TNBC cells by regulating endosomal sorting and recycling (ESR) of adhesion proteins. Yet, the ESR machinery supporting invasion in TNBC, particularly within 3D environments, remains poorly understood. Here, we used FER-expressing TNBC patient-derived xenograft organoids (PDXOs) and MDA-MB-231 cells to identify the membrane trafficking machinery promoting invasion. Using a combination of proteomics, phospho-proteomics, and single cell RNA-sequencing, we show that the invasion of FER-expressing PDXO cells in collagen-I is mainly associated with the differential phosphorylation of membrane trafficking regulators, including SEC16A and a marked increase in Rab4-positive tubules. SEC16A depletion impairs cell invasion and reduces the number of focal adhesions and Rab4-positive tubules. Importantly, FER regulates SEC16A levels and localization, specifically in TNBC. Altogether, we identified SEC16A as a key player in FER-driven TNBC invasion, highlighting the membrane trafficking machinery as a promising target for the development of new therapeutic strategies.

cancer biology↗

bioRxiv2025

Prenatal exposure to environmental stressors alters gut macrophage development and gastrointestinal function of male offspring

Gastrointestinal (GI) dysfunction is a frequently reported comorbidity of neurodevelopmental disorders (NDDs). Early-life inflammatory challenges from the environment (e.g. infection, toxicants) can increase risk for NDDs but the impact of such stressors on the developing GI tract is not well understood. We investigated possible mechanisms by which GI comorbidities occur in response to environmental stressors using our well-characterized model of combined gestational exposure to air pollution (diesel exhaust particles, DEP) and maternal stress (MS), which induces social deficits in male but not female offspring. We show that DEP/MS disrupts normal GI development, leading to altered small intestine morphology in neonatal males, but not females. Recent evidence shows that resident macrophages of the gut prune enteric neurons during a precise postnatal window. We found decreased pruning of gut enteric neurons by the resident macrophages of the muscularis externa in DEP/MS exposed males at postnatal day 14. In line with this, we saw the expression of motor neuron-associated genes spike in males at the same postnatal time point following DEP/MS exposure. Finally, we assessed the motor function of the GI tract of these animals and observed dysmotility in DEP/MS males only. Taken together, these findings establish intestinal macrophages as a mediator of GI development that is sensitive to early-life perturbations from the environment, highlighting a potential mechanism connecting NDDs with comorbid GI dysfunction.

developmental biology↗

bioRxiv2025

Feedback regulation between FOXM1 and APC/CCdh1 determines the changes in cell cycle dynamics during aging

Aging is characterised by a loss of regenerative capacity, though it remains elusive how aged proliferating cells slowdown cycling eventually becoming senescent. We previously found that repression of the FOXM1 transcription factor accounts for mitotic decline during aging due to a global transcriptional shutdown of mitotic genes in proliferating cells. Intriguingly, a 1.5-fold increase in both cell cycle and mitosis durations was observed in elderly cells in deviancy to a previous study showing mitosis to be temporally insulated from variability in earlier cell cycle phases due to the robustness of the positive feedback loop controlling CDK1-Cyclin B1 activity. Thus, we asked if molecular thresholds controlling cell cycle phase transitions become unfitted with aging. Here, we used live-cell imaging of primary human dermal fibroblasts of advancing age donors in combination with high-throughput image analysis, to investigate age-related changes in cell cycle dynamics. Interestingly, we found mitosis insularity to be gradually lost along aging due to defective switch-like activation of CDK1 at mitotic entry driven by FOXM1 repression. Moreover, we found the levels of FZR1/Cdh1 co-activator of APC/C, the E3-ubiquitin ligase directing the proteolytic degradation of FOXM1 at mitotic exit, to increase with advancing age. Importantly, FZR1/Cdh1 repression was shown to restore cell cycle fitness and FOXM1 levels in aged proliferating cells, preventing the accumulation of cell cycle inhibitors and senescence markers in their progeny. Thus, changes in FOXM1 and APC/CCdh1 interlinked activities account for the loss of proliferative capacity and senescence accrual during aging, thereby delivering useful markers and/or targets to explore in anti-aging approaches.

cell biology↗