Biology subjects

Hergueta-Redondo, M.

Publications and source records attributed to Hergueta-Redondo, M..

3 recordsLinked to original sources

bioRxiv2022

Mast cells impair melanoma cell homing and metastasis by inhibiting HMGA1 secretion.

Metastatic disease is the major cause of death from cancer. From the primary tumor, cells remotely prepare the environment of the future metastatic sites by secreted factors and extracellular vesicles. During this process, known as pre-metastatic niche formation, immune cells play a crucial role. Mast cells are hematopoietic bone marrow-derived innate immune cells whose function in lung immune response to invading tumors remains to be defined. We found reduced melanoma lung metastasis in mast cell deficient mouse models (Wsh and MCTP5-Cre-RDTR), supporting a pro-metastatic role for mast cells in vivo. However, due to evidence pointing to their antitumorigenic role, we studied the impact of mast cells in melanoma cell function in vitro. Surprisingly, in vitro co-culture of bone-marrow derived mast cells with melanoma cells showed that they have an intrinsic anti-metastatic activity. Mass spectrometry analysis of melanoma-mast cell co-cultures secretome showed that HMGA1 secretion by melanoma cells was significantly impaired. Consistently, HMGA1 knock down in B16-F10 cells reduced their metastatic capacity in vivo. Importantly, analysis of HMGA1 expression in human melanoma tumors showed that metastatic tumors with high HMGA1 expression are associated with reduced overall and disease-free survival. Moreover, we show that HMGA1 is reduced in the nuclei and enriched in the cytoplasm of melanoma metastatic lesions when compared to primary tumors. These data suggest that high HMGA1 expression and secretion from melanoma cells promotes metastatic behavior. Targeting HMGA1 expression intrinsically or extrinsically by mast cells actions reduce melanoma metastasis. Our results pave the way to the use of HMGA1 as anti-metastatic target in melanoma as previously suggested in other cancer types.

cancer biology↗

bioRxiv2021

Characterization of plasma circulating small extracellular vesicles in patients with metastatic solid tumors and newly diagnosed brain metastasis.

PurposeNearly 40% of the advanced cancer patients will present brain metastases during the course of their disease, with a 2-year life expectancy of less than 10%. Immune system impairment, including the modulation of both STAT3 and PD-L1, is one of the hallmarks of brain metastases. Liquid biopsy could offer several advantages in brain metastases management, such as the possibility of non-invasive dynamic monitoring. Extracellular vesicles (EVs) have been recently proposed as novel biomarkers especially useful in liquid biopsy due to their secretion in biofluids and their role in cell communication during tumor progression. Materials and MethodsThe main aim of this work was to characterize the size and protein cargo of plasma circulating EVs in patients with solid tumors and their correlation with newly diagnosed brain metastases, in addition to their association with other relevant clinical variables. ResultsWe analyzed circulating EVs in the plasma of 123 patients: 42 patients with brain metastases, 50 without brain metastases and 31 healthy controls. Patients with newly diagnosed brain metastases had a lower number of circulating EVs in the plasma and a higher protein concentration in small EVs (sEVs) compared to patients without brain metastases and healthy controls. Interestingly, melanoma patients with brain metastases presented decreased STAT3 activation and increased PD-L1 levels in circulating sEVs compared to patients without central nervous system metastases. ConclusionsDecreased STAT3 activation and increased PD-L1 in plasma circulating sEVs identify melanoma patients with brain metastasis. Statement of translational relevanceBrain metastases are critical for outcomes and quality of life in almost 50% of oncological patients, generally associated with a poor short-term prognosis. Early or preventive diagnosis of this complication represents an unmet need. There is a necessity of discovering new biomarkers that could aid to predict disease outcome. In this study, we analyzed plasma circulating extracellular vesicles (EVs) from a cohort of 92 patients with different solid tumors (lung, breast, kidney cancer and melanoma) and found that newly diagnosed patients with brain metastases presented lower number of circulating particles and a higher protein concentration in small extracellular vesicles (sEVs) compared to patients without brain metastases and healthy controls. Out of all groups analyzed, melanoma patients with brain metastases presented decreased STAT3 activation and increased PD-L1 levels in circulating sEVs compared to patients without central nervous system metastases. The data presented in this work suggest that circulating sEVs may represent the immunosuppressive status of newly diagnosed brain metastases characterized by the reduced phospho-STAT3 (pSTAT3) and increased PD-L1, although the origin of these molecules found in circulating sEVs remains to be uncovered.

cancer biology↗

bioRxiv2021

Inactivation of EMILIN-1 by proteolysis and secretion in small extracellular vesicles favors melanoma progression and metastasis.

Several studies have demonstrated that melanoma-derived extracellular vesicles (EVs) are involved in lymph node metastasis; however, the molecular mechanisms involved are not defined completely. Here, we found that EMILIN-1 is proteolyzed and secreted in small EVs (sEVs) as a novel mechanism to reduce its intracellular levels favoring metastasis in lymph node metastatic cells. Interestingly, we observed that EMILIN-1 has intrinsic tumor and metastasis suppressive-like properties reducing effective migration, cell viability, primary tumor growth and metastasis in mouse melanoma models. Finally, analysis in human melanoma samples showed that tumor cells with high levels of EMILIN-1 are reduced in metastatic lesions compared to primary tumors or nevi. Overall, our analysis suggests that the inactivation of EMILIN-1 by proteolysis and secretion in sEVs reduce its intrinsic tumor suppressive activities in melanoma favoring tumor progression and metastasis.

cancer biology↗