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The small GTPase Rac1 (Ras‐related C3 botulinum toxin substrate 1) has been implicated in cancer progression and in the poor prognosis of various types of tumors. Rac1 SUMOylation occurs during epithelial‐mesenchymal transition (EMT), and it is required for tumor cell migration and invasion. Here we identify POTEE (POTE Ankyrin domain family member E) as a novel Rac1‐SUMO1 effector involved in breast cancer malignancy that controls invadopodium formation through the activation of Rac1‐SUMO1. POTEE activates Rac1 in the invadopodium by recruiting TRIO‐GEF (triple functional domain protein), and it induces tumor cell proliferation and metastasis in vitro and in vivo. We found that the co‐localization of POTEE with Rac1 is correlated with more aggressive breast cancer subtypes. Given its role in tumor dissemination, the leading cause of cancer‐related deaths, POTEE could represent a potential therapeutic target for these types of cancer. SUMOylation of the small GTPase Rac1 is essential for tumor cell dissemination. POTEE is identified as a novel Rac1‐SUMO1 effector, promoting breast cancer malignancy through invadopodium formation. POTEE activates Rac1 by recruiting TRIO‐GEF, increasing tumor cell metastasis in vitro and in vivo. Colocalization of POTEE and Rac1 correlates with aggressive breast cancer subtypes, suggesting POTEE as a potential therapeutic target.

Background Cancer-associated fibroblasts (CAFs) are the most abundant stromal cellular component in the tumor microenvironment (TME). CAFs contribute to tumorigenesis and have been proposed as targets for anticancer therapies. Similarly, dysregulation of SUMO machinery components can disrupt the balance of SUMOylation, contributing to tumorigenesis and drug resistance in various cancers, including breast cancer. We explored the role of SUMOylation in breast CAFs and evaluated its potential as a therapeutic strategy in breast cancer. Methods We used pharmacological and genetic approaches to analyse the functional crosstalk between breast tumor cells and CAFs. We treated breast CAFs with the SUMO1 inhibitor ginkgolic acid (GA) at two different concentrations and conditioned media was used to analyse the proliferation, migration, and invasion of breast cancer cells from different molecular subtypes. Additionally, we performed quantitative proteomics (SILAC) to study the differential signalling pathways expressed in CAFs treated with low or high concentrations of GA. We confirmed these results both in vitro and in vivo. Moreover, we used samples from metastatic breast cancer patients to evaluate the use of GA as a therapeutic strategy. Results Inhibition of SUMOylation with ginkgolic acid (GA) induces death in breast cancer cells but does not affect the viability of CAFs, indicating that CAFs are resistant to this therapy. While CAF viability is unaffected, CAF-conditioned media (CM) is altered by GA, impacting tumor cell behaviour in different ways depending on the overall degree to which SUMO1-SUMOylated proteins are dysregulated. Breast cancer cell lines exhibited a concentration-dependent response to conditioned media (CM) from CAFs. At a low concentration of GA (10 µM), there was an increase in proliferation, migration and invasion of breast cancer cells. However, at a higher concentration of GA (30 µM), these processes were inhibited. Similarly, analysis of tumor development revealed that at 10 µM of GA, the tumors were heavier and there was a greater degree of metastasis compared to the tumors treated with the higher concentration of GA (30 µM). Moreover, some of these effects could be explained by an alteration in the activity of the GTPase Rac1 and the activation of the AKT signalling pathway. The results obtained using SILAC suggest that different concentrations of GA affected cellular processes differentially, possibly influencing the secretome of CAFs. Treatment of metastatic breast cancer with GA demonstrated the use of SUMOylation inhibition as an alternative therapeutic strategy. Conclusion The study highlights the importance of SUMOylation in the tumor microenvironment, specifically in cancer-associated fibroblasts (CAFs). Targeting SUMOylation in CAFs affects their signalling pathways and secretome in a concentration-dependent manner, regulating the protumorigenic properties of CAFs.

Background/Objectives: Identifying the causes of sentinel lymph node biopsy (SLNB) failure in early-stage oral cavity squamous cell carcinoma (OCSCC) is essential for refining surgical protocols and optimizing patient selection. This study aimed to evaluate the diagnostic performance, predictors of false-negative (FN) results, and long-term oncological outcomes of SLNB in patients with early-stage OCSCC. Methods: A retrospective, single-centre cohort study was conducted on 220 patients with cT1–cT2 N0 M0 OCSCC who were surgically treated between 2017 and 2024. Preoperative lymphatic mapping was performed using 99mTc-nanocolloid and SPECT/CT. All sentinel lymph nodes (SLNs) underwent an ultrastaging protocol involving serial sectioning and immunohistochemistry. Diagnostic accuracy, survival outcomes, and clinicopathological predictors of FNs were analysed. Results: The SLN identification rate was 99.1%. Metastatic involvement was detected in 49 patients (22.3%), preventing 77.7% of the cohort from undergoing unnecessary neck dissection. Bilateral lymphatic drainage was observed in 55.9% of floor of the mouth tumours. During a median follow-up of 36 months, the diagnostic performance showed a sensitivity of 81.7%, a negative predictive value of 93.6%, and an overall accuracy of 95.0%. Analysis of the 11 FN cases showed that both depth of invasion (DOI) (6.0 mm vs. 3.0 mm; p = 0.010) and maximal tumour dimension (25 mm vs. 15 mm; p = 0.0008) were significant predictors of diagnostic failure. The five-year overall survival rate was significantly superior in patients with negative SLNs compared to the SLN-positive group (82% vs. 61%; p < 0.001). Conclusions: SLNB is an accurate and reliable staging tool for early-stage OCSCC, providing personalised lymphatic mapping that harmonizes oncological efficacy with the avoidance of overtreatment. However, an increased DOI and a larger tumour size significantly raise the risk of FN events, indicating the need for close postoperative surveillance in these high-risk subgroups.

The high grain yield of modern varieties (MV) respond to the increase in fossil-based inputs, and the widespread belief that they are more productive than old varieties (OV) is biased. This belief focuses only on marketable biomass, without considering the consequences on agroecosystem sustainability of the reductions in other portions of NPP. Additionally, field comparisons of OV and MV were normally conducted under industrialized farming conditions, which is detrimental for OV performance. Both trials carried out in this study comparing wheat OV and MV show that, under Mediterranean rainfed conditions and traditional organic management, aerial and belowground biomass production of OV is higher than that of MV, without significantly decreasing yield and enabling a better competition against weeds. From the data of our trials, bibliographic review and information from historical sources, we have reconstructed the NPP and destinations of biomass of Spanish wheat fields (1900–2000). Varietal replacement entailed the reduction in residues and unharvested biomass (UhB), which involved soil degradation in rainfed cereal fields and undermining heterotrophic trophic webs. Our results suggest that OV can increase the sustainability of rainfed Mediterranean agroecosystems at present through the improvement of soil quality, the reduction of herbicides use, and the recovery of biodiversity.