Roussel, T. | bioRxiv Science

bioRxiv2024

Bola-amphiphilic dendrimer empowers imatinib to target metastatic ovarian cancer stem cells via beta-catenin-HRP2 signaling axis

Ovarian cancer is the leading cause of death among all gynecological malignancies, and drug resistance renders the current chemotherapy agents ineffective for patients with advanced metastatic tumors. We report an effective treatment strategy for targeting metastatic ovarian cancer involving a nanoformulation (Bola/IM) - bola-amphiphilic dendrimer (Bola)-encapsulated imatinib (IM) - to target the critical mediator of ovarian cancer stem cells (CSCs) CD117 (c-Kit). Bola/IM offered significantly more effective targeting of CSCs compared to IM alone, through a novel and tumor-specific {beta}-catenin/HRP2 axis, allowing potent inhibition of cancer cell survival, stemness and metastasis in metastatic and drug-resistant ovarian cancer cells. Promising results were also obtained in clinically relevant patient-derived ascites and organoids, alongside high tumor-oriented accumulation and favorable pharmacokinetic properties in mouse models. Furthermore, Bola/IM displayed synergistic anticancer activity when combined with the first-line chemotherapeutic drug cisplatin in patient-derived xenograft mouse models, without any adverse effects. Our findings support the use of Bola/IM as a nanoformulation to empower IM, providing targeted and potent treatment of metastatic ovarian cancer. Our study thus represents a significant advancement towards addressing the unmet medical need for improved therapies targeting this challenging disease.

cancer biology↗

bioRxiv2024

Limnospira (Cyanobacteria) chemical fingerprint reveals local molecular adaptation

Limnospira can colonize a wide variety of environments (e.g., freshwater, brackish, alkaline or alkaline-saline water) and develop dominant and even permanent blooms that limit over-shadowed adjacent phototrophs diversity, especially in alkaline and saline environments. Previous phylogenomic analysis of Limnospira allowed us to distinguish two major phylogenetic clades (I and II) but failed to clearly segregate strains according to their respective habitats in terms of salinity or biogeography. In the present work, we attempt to determine whether Limnospira displays metabolic signatures specific to its different habitats, particularly brackish or alkaline-saline ecosystems, and question the impact of accessory gene repertoires on respective chemical adaptations. The study of the metabolomic diversity of 93 strains of Limnospira from the Paris Museum Collection, grown under standardized lab culture conditions, showed clearly distinct chemical fingerprints that were correlated with the respective biogeographic origins of the strains. The molecules that most distinguish the different Limnospira geographic groups are sugars, lipids, peptides, photosynthetic pigments, and antioxidant molecules. Interestingly, these molecule enrichments might represent adaptation traits to the local conditions encountered in their respective sampling environments concerning salinity, light and oxidative stress. We hypothesize that within extreme environments, such as those colonized by Limnospira, a large set of flexible genes can provide remarkable adaptation to specific local environmental conditions (e.g., salinity, light, and oxidative pressure). Thus, the occurrence within Limnospira population genomes of a specific set of flexible genes potentially involved in the production of certain metabolites may provide valuable adaptative traits that may support the bloom persistence beyond environmental condition variations. ImportanceLimnospira are ubiquitous cyanobacteria able to colonize and dominate a wide range of alkaline-saline environments around the world according to remarkable adaptative strategies. Phylogenomic analysis of Limnospira platensis allowed to distinguish two major phylogenetic clades (I and II) but failed to clearly segregate strains following their habitats in terms of salinity or biogeography. One can presume that the genes found within this variable portion of the genome of these clades could be involved in L. platensis adaptation to local environmental conditions. In the present paper, we attempt to determine whether Limnospira platensis displays metabolic signatures specific to its different habitats, particularly brackish or alkalinesaline ecosystems, and question the impact of accessory gene repertoire on respective chemical adaptation.

microbiology↗