Rachele Rossi

Fenretinide [N-(4-hydroxyphenyl) retinamide, 4-HPR] is a synthetic retinoid known for decades for its antitumor activity and favorable toxicological profile. In vitro and in vivo studies have demonstrated that fenretinide has broad-spectrum anticancer potential, eliciting multiple biological effects and acting as a multi-target compound that influences both tumor cells and the tumor microenvironment. However, the clinical application of fenretinide has been hampered by unfavorable physicochemical properties, such as poor solubility and low bioavailability, leading to highly variable outcomes in clinical studies. The development of novel fenretinide nanoformulations based on drug encapsulation in nanomicelles has helped overcome bioavailability limitations and improve anticancer efficacy in preclinical studies, thereby paving the way for new clinical opportunities. Moreover, recent studies have shown that fenretinide restrains the cancer stem cell compartment and promotes tumor cell dormancy, suggesting its potential use in dormancy-inducing strategies aimed at preventing and/or controlling metastatic disease. Here, we provide an overview of fenretinide’s mechanisms of action in cancer cells, summarize the available clinical evidence and discuss advances achieved with novel formulations. Finally, we discuss the potential integration of fenretinide at different stages of clinical management, with particular emphasis on its prospective use as a chemopreventive strategy or as a therapeutic option for disease control.

The differentiation/maturation trajectories of different blood cell types stemming from a CD34⁺ common ancestor takes place in different biologically relevant multidimensional spaces. Here, we generated microRNA and cytokine profiles from highly purified populations of hematopoietic progenitors/precursors derived from cord blood hematopoietic stem/progenitor cells. MicroRNA and cytokine landscapes were then analyzed to find their mutual relationships under the hypothesis that the highly variable miRNome corresponds to the ‘force field’ driving the goal of a stable phenotype (here corresponding to the cytokine abundance pattern) typical of each cell kind. The high dimensionality and lack of linearity of the hematopoietic process pushed us to adopt a distance–geometry approach to compare different trajectories, while a complex network analysis was instrumental in revealing the fine structure of microRNA–cytokine relations. Importantly, the approach enabled us to identify a limited number of factors (represented either by microRNAs or cytokines) corresponding to crucial nodes responsible for connecting distinct interaction modules. Subtle changes in ‘master nodes’, keeping the connections between different regulatory networks, may therefore be crucial in influencing hematopoietic differentiation. These findings highlight the extremely interconnected network structures underlying hematopoiesis regulation and identify key factors in the microRNA/cytokine landscape that may be potentially crucial for influencing network stability.

Background: Prevention and treatment of metastatic breast cancer (BC) is an unmet clinical need. The retinoic acid derivative fenretinide (FeR) was previously evaluated in Phase I-III clinical trials but, despite its excellent tolerability and antitumor activity in preclinical models, showed limited therapeutic efficacy due to poor bioavailability. We recently generated a new micellar formulation of FeR, Bionanofenretinide (Bio-nFeR) showing enhanced bioavailability, low toxicity, and strong antitumor efficacy on human lung cancer, colorectal cancer, and melanoma xenografts. In the present study, we tested the effect of Bio-nFeR on a preclinical model of metastatic BC. Methods: We used BC cell lines for in vitro analyses of cell viability, cell cycle and migratory capacity. For in vivo studies, we used HER2/neu transgenic mice (neuT) as a model of spontaneously metastatic BC. Mice were treated orally with Bio-nFeR and at sacrifice primary and metastatic breast tumors were analyzed by histology and immunohistochemistry. Molecular pathways activated in primary tumors were analyzed by immunoblotting. Stem cell content was assessed by flow cytometry, immunoblotting and functional assays such as colony formation ex vivo and second transplantation assay in immunocompromised mice. Results: Bio-nFeR inhibited the proliferation and migration of neuT BC cells in vitro and showed significant efficacy against BC onset in neuT mice. Importantly, Bio-nFeR showed the highest effectiveness against metastatic progression, counteracting both metastasis initiation and expansion. The main mechanism of Bio-nFeR action consists of promoting tumor dormancy through a combined induction of antiproliferative signals and inhibition of the mTOR pathway. Conclusion: The high effectiveness of Bio-nFeR in the neuT model of mammary carcinogenesis, coupled with its low toxicity, indicates this formulation as a potential candidate for the treatment of metastatic BC and for the adjuvant therapy of BC patients at high risk of developing metastasis.

The biological complexity of cancer represents a tremendous clinical challenge, resulting in the frequent failure of current treatment protocols. In the rapidly evolving scenario of a growing tumor, anticancer treatments impose a drastic perturbation not only to cancer cells but also to the tumor microenvironment, killing a portion of the cells and inducing a massive stress response in the survivors. Consequently, treatments can act as a double-edged sword by inducing a temporary response while laying the ground for therapy resistance and subsequent disease progression. Cancer cell dormancy (or quiescence) is a central theme in tumor evolution, being tightly linked to the tumor’s ability to survive cytotoxic challenges, metastasize, and resist immune-mediated attack. Accordingly, quiescent cancer cells (QCCs) have been detected in virtually all the stages of tumor development. In recent years, an increasing number of studies have focused on the characterization of quiescent/therapy resistant cancer cells, unveiling QCCs core transcriptional programs, metabolic plasticity, and mechanisms of immune escape. At the same time, our partial understanding of tumor quiescence reflects the difficulty to identify stable QCCs biomarkers/therapeutic targets and to control cancer dormancy in clinical settings. This review focuses on recent discoveries in the interrelated fields of dormancy, stemness, and therapy resistance, discussing experimental evidences in the frame of a nonlinear dynamics approach, and exploring the possibility that tumor quiescence may represent not only a peril but also a potential therapeutic resource.

The processes leading to the emergence of new species are poorly understood in marine plankton, where weak physical barriers and homogeneous environmental conditions limit spatial and ecological segregation. Here, we combine molecular and ecological information from a long‐term time series and propose Pseudo‐nitzschia allochrona, a new cryptic planktonic diatom, as a possible case of speciation by temporal segregation. The new species differs in several genetic markers (18S, 28S and ITS rDNA fragments and rbcL) from its closest relatives, which are morphologically very similar or identical, and is reproductively isolated from its sibling species P. arenysensis. Data from a long‐term plankton time series show P. allochrona invariably occurring in summer–autumn in the Gulf of Naples, where its closely related species P. arenysensis, P. delicatissima, and P. dolorosa are instead found in winter–spring. Temperature and nutrients are the main factors associated with the occurrence of P. allochrona, which could have evolved in sympatry by switching its phenology and occupying a new ecological niche. This case of possible speciation by time shows the relevance of combining ecological time series with molecular information to shed light on the eco‐evolutionary dynamics of marine microorganisms.

Lung cancer is the leading cause of cancer death worldwide. Despite significant advances in research and therapy, a dismal 5-year survival rate of only 10–20% urges the development of reliable preclinical models and effective therapeutic tools. Lung cancer is characterized by a high degree of heterogeneity in its histology, a genomic landscape, and response to therapies that has been traditionally difficult to reproduce in preclinical models. However, the advent of three-dimensional culture technologies has opened new perspectives to recapitulate in vitro individualized tumor features and to anticipate treatment efficacy. The generation of lung cancer organoids (LCOs) has encountered greater challenges as compared to organoids derived from other tumors. In the last two years, many efforts have been dedicated to optimizing LCO-based platforms, resulting in improved rates of LCO production, purity, culture timing, and long-term expansion. However, due to the complexity of lung cancer, further advances are required in order to meet clinical needs. Here, we discuss the evolution of LCO technology and the use of LCOs in basic and translational lung cancer research. Although the field of LCOs is still in its infancy, its prospective development will likely lead to new strategies for drug testing and biomarker identification, thus allowing a more personalized therapeutic approach for lung cancer patients.

Our study focuses on bacterial communities associated with two benthic, epiphytic dinoflagellates, Gambierdiscus australes and Ostreopsis cf. ovata, isolated from coastal waters of Las Palmas, Gran Canaria, and grown in clonal cultures. The goal was to characterize the stable bacterial consortia found within the phycosphere of each dinoflagellate species and establish into which functional group they fell. High‐throughput sequencing (HTS) results highlighted a higher bacterial diversity in O. ovata compared with G. australes. Alphaproteobacteria dominated in both dinoflagellates with Marivita and Labrenzia as the most represented OTUs in Ostreopsis and Gambierdiscus, respectively, and Thalassospira and Oceanicaulis well represented in both species. Based on SIMPER analyses, Labrenzia and the Phycispherales SM1A02, dominant in Gambierdiscus and Ostreopsis, respectively, accounted for the most significant difference between the two microbiomes. The microbiomes described here differed from those described for the same dinoflagellate species in other studies, which could depend on differences in environmental conditions, macroalgal substrate, and/or growth stage or bloom phase of the microalgal hosts. The distinct bacterial communities associated with the two potentially toxic dinoflagellates, isolated from the same site and sampling event and cultivated under the same conditions, suggest different modalities of interaction and interexchange between bacteria and their hosts.

The emergence of new species is poorly understood in marine plankton, where the lack of physical barriers and homogeneous environmental conditions limit spatial and ecological segregation. Here we combine molecular and ecological information from a long term time series and propose Pseudo-nitzschia allochrona , a new cryptic diatom, as a possible case of speciation by temporal segregation. The new species differs in several genetic markers (18S, LSU and ITS rDNA fragments and rbc L) and is reproductively isolated from its closest relative, which is morphologically identical. Data from a long term plankton time series show Pseudo-nitzschia allochrona invariably occurring in summer-autumn in the Gulf of Naples, where its sister species are instead found in winter-spring. Temperature and nutrients are the main factors associated with the occurrence of P. allochrona , which could have evolved in sympatry by switching its phenology and occupying a new ecological niche. This case of possible speciation by time shows the relevance of combining ecological time series with molecular information to shed light on the eco-evolutionary dynamics of marine microorganisms.

Europe is experiencing a third wave of COVID-19 due to the spread of highly transmissible SARS-CoV-2 variants. A number of positive and negative factors constantly shape the rates of COVID-19 infections, hospitalization, and mortality. Among these factors, the rise in increasingly transmissible variants on one side and the effect of vaccinations on the other side create a picture deeply different from that of the first pandemic wave. Starting from the observation that in several European countries the number of COVID-19 infections in the second and third pandemic wave increased without a proportional rise in disease severity and mortality, we hypothesize the existence of an additional factor influencing SARS-CoV-2 dynamics. This factor consists of an immune defence against severe COVID-19, provided by SARS-CoV-2-specific T cells progressively developing upon natural exposure to low virus doses present in populated environments. As suggested by recent studies, low-dose viral particles entering the respiratory and intestinal tracts may be able to induce T cell memory in the absence of inflammation, potentially resulting in different degrees of immunization. In this scenario, non-pharmaceutical interventions would play a double role, one in the short term by reducing the detrimental spreading of SARS-CoV-2 particles, and one in the long term by allowing the development of a widespread (although heterogeneous and uncontrollable) form of immune protection.

Blooms of the toxic dinoflagellates Ostreopsis have become common along rocky shores of the Mediterranean Sea. In addition to health problems for beach-goers, Ostreopsis toxins may accumulate in benthic marine animals used for human consumption, which however at times have shown signals of stress and even mortality. In order to elucidate the actual relationships between Ostreopsis and benthic invertebrates, we exposed mussels Mytilus galloprovincialis and sea urchins Paracentrotus lividus from the Gulf of Naples to cultures and natural material of O. cf. ovata and assessed feeding and adverse effects on the animals, along with their acquired toxicity. Mussels exposed to O. cf. ovata for 24 hours filtered the microalgae at different rates, depending on both mussel size and microalgal density, and became weakly toxic in some cases. Under longer exposure most animals died and all survivors were toxic. Detoxification of a naturally toxic mussel populations from an area affected by O. cf. ovata blooms took more than two weeks. Sea urchins fed with the red alga Asparagopsis taxiformis epiphytised by O. cf. ovata did not show damages and became mildly toxic in some cases. However, the direct exposure of sea urchins to O. cf. ovata cultures caused the partial or total loss of the spines in a density-dependent way, with the death of the animals at the highest microalgal concentrations. Milder effects were registered with sonicated cultures or toxin extracts. Our results indicate that the balance between toxicity and animal health in these invertebrates depends on the mode and intensity of exposure to the toxic microalga, while the response varies between the two species but also within the same species. This scenario matches the variety of responses of benthic populations recorded in the natural environment in areas affected by O. cf. ovata blooms.