Biology subjects

D'Alterio, C.

Publications and source records attributed to D'Alterio, C..

3 recordsLinked to original sources

bioRxiv2022

The septate junction component Bark beetle is required for Drosophila intestinal barrier function and homeostasis

Age-related loss of intestinal barrier function has been found across species, and the causes remain unknown. The intestinal epithelial barrier is maintained by tight junctions (TJs) in mammals and septate junctions (SJs) in insects. Specialized tricellular junctions (TCJs) are found at the nexus of three adjacent cell membranes, and we showed previously that aging results in mis-localization of the tricellular SJ (tSJ) component Gliotactin (Gli) in enterocytes (ECs) of the Drosophila melanogaster intestine. In embryonic epithelia, the tSJ protein Bark beetle (Bark) recruits Gli to tSJs, which prompted us to investigate Bark function in the intestine. Bark protein localization decreases at tSJs in aged flies. EC-specific bark depletion in young flies led to hallmarks of intestinal aging and shortened lifespan, whereas depletion of bark in progenitor cells reduced Notch activity, biasing differentiation toward the secretory lineage. Together, our data implicate Bark in EC maturation, maintenance of intestinal barrier integrity, and homeostasis. Understanding the assembly and maintenance of tSJs to ensure barrier integrity may lead to strategies to improve tissue integrity when function is compromised.

cell biology↗

bioRxiv2022

mTORC1 is required for differentiation of germline stem cells in the Drosophila melanogaster testis

Metabolism participates in the control of stem cell function and subsequent maintenance of tissue homeostasis. How this is achieved in the context of adult stem cell niches in coordination with other local and intrinsic signaling cues is not completely understood. The Target of Rapamycin (TOR) pathway is a master regulator of metabolism and plays essential roles in stem cell maintenance and differentiation. We observe differential expression of the Tor kinase in the Drosophila male germline, which correlates with restriction of mTORC1 activity to germline stem cells (GSCs) and early germ cells. Targeted RNAi-mediated downregulation of Tor in early germ cells causes a block and/or a delay in differentiation, resulting in an accumulation of germ cells with GSC-like features. These early germ cells also contain unusually large and dysfunctional autolysosomes. In addition, downregulation of Tor in adult male GSCs and early germ cells causes non-autonomous activation of mTORC1 in neighboring cyst cells, which correlates with a disruption in the coordination of germline and somatic differentiation. Our study identifies a previously uncharacterized role of the TOR pathway in regulating male germline differentiation.

developmental biology↗

bioRxiv2020

SDF-1/CXCR4 inhibition prevents paradoxical generation of cisplatin-induced pro-metastatic niches

Platinum-based chemotherapy remains widely used in advanced non-small cell lung cancer (NSCLC) despite its ineffectiveness in long-term control of metastasis. Here, we uncover the interconnected pathways subtending cisplatin-induced metastasis promotion. We report that cisplatin treatment of tumor-free mice results in bone-marrow expansion of CCR2+CXCR4+Ly6Chigh inflammatory monocytes (IM) concomitantly with increased levels in the lungs of stromal SDF-1, the CXCR4 ligand. In experimental metastasis assays, cisplatin-induced IM favor tumor cells extravasation and expansion of CD133+CXCR4+ metastasis initiating cells (MICs), facilitating lung metastasis formation. At the primary tumor, cisplatin reduces tumor size but induces tumor release of SDF-1 triggering MICs expansion and recruitment of pro-invasive CXCR4+ macrophages. Co-recruitment of MICs and CCR2+CXCR4+ IM at SDF-1-enriched distant sites also promotes spontaneous metastasis. Combination treatment with a CXCR4 inhibitor prevents cisplatin-induced IM/MICs recruitment and interaction thus precluding metastasis overgrowth. Finally, we observe in NSCLC patients specimens that SDF-1 levels are higher in platinum-treated samples and correlate with worse outcome. Our findings suggest a possible novel combination therapy based on CXCR4 blockade to control metastatic disease, paradoxically promoted by cisplatin.

cancer biology↗