Biology subjects

Carissimo, A.

Publications and source records attributed to Carissimo, A..

4 recordsLinked to original sources

bioRxiv2024

A circuit involving the lncRNA MB3 and the driver genes MYC and OTX2 inhibits apoptosis in Group 3 Medulloblastoma by regulating the TGF-β pathway via HMGN5

BackgroundGroup 3 (G3) is one of the most common, aggressive and fatal subtypes of the paediatric cerebellar tumour Medulloblastoma (MB), primarily driven by the MYC oncogene. Targeting MYC has long been challenging and this, combined with our incomplete understanding of G3 MB molecular bases, has hindered the development of effective targeted therapies. Long noncoding RNAs (lncRNAs), with their extensive oncogenic roles, cancer-specific expression, and connection to MYC biology, offer opportunities for unravelling this complexity and providing new insights and therapeutic targets. MethodologyUsing genome-wide, molecular and cellular assays, we characterised the activity of the MYC-dependent, anti-apoptotic lncRNA lncMB3 in G3 MB cells. ResultsThrough transcriptomic and interactomic analyses, we clarified lncMB3 function and mode-of-action. LncMB3 controls the TGF-{beta} pathway, critically altered in G3 medulloblastomagenesis. This regulation occurs via the direct coding-noncoding RNA interaction between lncMB3 and the mRNA for the epigenetic factor HMGN5, with both sharing targets in the TGF-{beta} cascade. This axis converges on apoptosis through OTX2, another G3 MB driver gene, and photoreceptor lineage genes. Synergistic effects between lncMB3 targeting and cisplatin treatment underscores the relevance of this regulatory network in vitro. Finally, we propose novel ferritin-based nanocarriers as efficient delivery tools for antisense oligonucleotides targeting lncMB3. ConclusionsLncMB3 emerges as a central node linking MYC amplification to apoptosis inhibition through a circuit involving RNA-based mechanisms, G3 MB key drivers and underexplored factors. This integrated framework deepens our understanding of G3 MB molecular underpinnings and lay the foundation for translating lncRNA research into potential applications.

cancer biology↗

bioRxiv2024

Computational identification of small molecules for increased gene expression by synthetic circuits in mammalian cells

Engineering mammalian cells with synthetic circuits is leading the charge in next generation biotherapeutics and industrial biotech innovation. However, applications often depend on the cells productive capacity, which is limited by the finite cellular resources available. We have previously shown that cells engineered with incoherent feedforward loops (iFFL-cells) operate at higher capacity than those engineered with the open loop (OL). Here, we performed RNA-sequencing on cells expressing the iFFL and utilized DECCODE, an unbiased computational method, to match our data with thousands of drug-induced transcriptional profiles. DECCODE identified compounds that consistently enhance expression of both transiently and stably expressed genetic payloads across various experimental scenarios and cell lines, while also reducing external perturbations on integrated genes. Further, we show that drug treatment enhances the rate of AAV and lentivirus transduction, facilitating the prototyping of genetic devices for gene and cell therapies. Altogether, despite limiting intracellular resources is a pervasive, and strongly cell-dependent problem, we provide a versatile tool for a wide range of biomedical and industrial applications that demand enhanced productivity from engineered cells.

synthetic biology↗

bioRxiv2020

CHOP-c-JUN complex plays a critical role in liver proteotoxicity induced by mutant Z alpha-1 antitrypsin.

Alpha-1 antitrypsin (AAT) deficiency is a common genetic disorder with lung and liver involvement. Most patients carry the Z allele in SERPINA1 that encodes a mutant AAT (ATZ) forming hepatotoxic polymers. We found CHOP upregulation and activation in both mouse (PiZ) and human livers expressing ATZ. Compared to controls, juvenile PiZ/Chop-/- mice showed reduction in hepatic ATZ and transcriptional response to endoplasmic reticulum stress, as consequence of CHOP-mediated increase of SERPINA1 transcription. CHOP was found to upregulate SERPINA1 though binding with c-JUN on SERPINA1 regulatory elements, thus aggravating hepatic accumulation of ATZ. Increased CHOP levels were detected in diseased livers of children homozygous for the Z allele. Compared to adults, AAT deficiency in infants has different severity and prognosis. Based on our findings, CHOP-c-JUN complex upregulates SERPINA1 transcription and play an important role in the hepatic disease pathogenesis by increasing the burden of proteotoxic ATZ, particularly in the pediatric population.

genetics↗

bioRxiv2019

Synthetic lethality screening reveals FDA-approved drugs that overcome ATP7B-mediated tolerance of tumor cells to cisplatin

Tumor resistance to chemotherapy represents an important challenge in modern oncology. Although platinum (Pt)-based drugs have demonstrated excellent therapeutic potential, their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms includes increased cisplatin sequestration/efflux by the copper-transporting ATPase, ATP7B. However, targeting ATP7B to reduce Pt tolerance in tumors could represent a serious risk because suppression of ATP7B might compromise copper homeostasis, as happens in Wilson disease.\n\nTo circumvent ATP7B-mediated Pt tolerance we employed a high-throughput screen (HTS) of an FDA/EMA-approved drug library to detect safe therapeutic molecules that promote cisplatin toxicity in the resistant ovarian carcinoma cell line IGROV-CP20. Using a synthetic lethality approach we identified and validated three hits (Tranilast, Telmisartan and Amphotericin B) that could reduce cisplatin resistance. All three drugs induced Pt-mediated DNA damage and inhibited either expression or trafficking of ATP7B in a tumor-specific manner. Global transcriptome analyses showed that Tranilast and Amphotericin B affect expression of genes operating in several pathways that confer tolerance to cisplatin. In the case of Tranilast, these included key molecular players operating in the distribution of platinum to different intracellular compartments. In particular, Tranilast was found to suppress ATOX1 and, as a consequence, ATOX1-mediated trafficking of ATP7B in response to cisplatin.\n\nConsidering the well-known safety profiles of Tranilast, Telmisartan and Amphotericin B, these drugs emerge as potential candidates that might be used for the rapid development of new therapeutic strategies to overcome resistance of tumors to Pt-based chemotherapy.

cancer biology↗