Biology subjects

Cairo, S.

Publications and source records attributed to Cairo, S..

4 recordsLinked to original sources

bioRxiv2025

Identification and Credentialing of Patient Derived Xenograft Models of Invasive Lobular Breast Carcinoma using Multi-omics and Histopathology assessment

Breast cancer is a heterogeneous disease with numerous histological subtypes. Invasive lobular cancer (ILC) is the most common special subtype, accounting for 10-15% of all breast cancers. The pathognomonic feature of ILC is the loss of E-cadherin (CDH1), which leads to a unique single-file growth pattern of discohesive cells. Although ILCs show better prognostic factors than the most common No Special Type (NST) of breast cancer, patients with ILC have worse long-term outcomes, which is not well understood. In this study, we aimed to identify and characterize Patient-Derived Xenograft (PDX) models of ILC based upon the presence of truncating CDH1 mutations and/or low CDH1 mRNA expression among 128 human breast cancer PDX models. We selected 8 PDX models for validation using Immunohistochemical (IHC) analysis for E-Cadherin, p120, ER, PR, and HER2. We confirmed that seven of these PDX models are indeed ILC while one was identified as mixed NST-ILC PDX. Molecular analysis of the confirmed ILC PDX models showed enrichment of truncating CDH1 mutations, significantly lower levels of CDH1 mRNA expression and predominantly luminal subtypes compared to NST PDX models, in line with the molecular characteristics of human ILC disease. The commonly altered genes in the ILC PDX models included PIK3CA (57%), CDH1 (57%) and TP53 (57%) among others. Our study confirms and characterizes new ILC PDX models, offering valuable tools to advance our understanding of human ILC biology and support the development of innovative treatment strategies.

cancer biology↗

bioRxiv2025

The Role of Phenotypic Plasticity in Adaptation to Treatment and Prospective Plasticity Drivers in Hepatoblastoma

Hepatoblastoma (HB) is a paediatric liver cancer, associated with one of the lowest mutational burdens compared to other cancers. Despite this, HBs exhibit diverse phenotypes. It has been proposed that hijacking of early developmental plasticity is especially relevant to chemotherapy response in childhood cancers, however the underlying mechanisms of plasticity in HB remain poorly understood. Plasticity in HB requires investigation after treatment at a more granular temporal scale to further elucidate its role in treatment adaptation. In this work, we aim to study the role of plasticity in treatment adaptation and its underlying mechanisms by integrating heritable and expressed static DNA barcode technology with single-cell sequencing. The synergy between these approaches allows for simultaneous lineage tracing of single clones and phenotyping of single cells. We identify the phenotypic states that exist in HB preclinical models and explore the phenotypic transitions that occur following treatment, which could be important for cells to survive, persist and eventually recover. Expression and accessibility landscapes reveal prospective targets that could be markers or drivers of the plasticity which enables treatment adaptation in HB. By homing in on the clonal, transcriptomic and epigenetic dynamics post treatment, these results examine in greater detail the role of plasticity in treatment adaptation in HB.

cancer biology↗

bioRxiv2023

Ribonucleotide Reductase Subunit Switching in Hepatoblastoma Drug Response and Relapse

Prognosis of children with high-risk hepatoblastoma (HB), the most common pediatric liver cancer, remains poor. In this study, we found ribonucleotide reductase (RNR) subunit M2 (RRM2) was one of the key genes supporting cell proliferation in high-risk HB. While standard chemotherapies could effectively suppress RRM2 in HB cells, they induced a significant upregulation of the other RNR M2 subunit, RRM2B. Computational analysis revealed distinct signaling networks RRM2 and RRM2B were involved in HB patient tumors, with RRM2 supporting cell proliferation and RRM2B participating heavily in stress response pathways. Indeed, RRM2B upregulation in chemotherapy-treated HB cells promoted cell survival and subsequent relapse, during which RRM2B was gradually replaced back by RRM2. Combining an RRM2 inhibitor with chemotherapy showed an effective delaying of HB tumor relapse in vivo. Overall, our study revealed the distinct roles of the two RNR M2 subunits and their dynamic switching during HB cell proliferation and stress response.

cancer biology↗

bioRxiv2021

Deciphering Tumour Tissue Organization by 3D Electron Microscopy and machine learning

Despite recent progress in the characterization of tumour components, the tri-dimensional (3D) organization of this pathological tissue and the parameters determining its internal architecture remain elusive. Here, we analysed the spatial organization of patient-derived xenograft tissues generated from hepatoblastoma, the most frequent childhood liver tumour, by serial block-face scanning electron microscopy using an integrated workflow combining 3D imaging, manual and machine learning-based semi-automatic segmentations, mathematics and infographics. By digitally reconstituting an entire hepatoblastoma sample with a blood capillary, a bile canaliculus-like structure, hundreds of tumour cells and their main organelles (e.g. cytoplasm, nucleus, mitochondria), we report unique 3D ultrastructural data about the organization of tumoral tissue. We found that the size of hepatoblastoma cells correlates with the size of their nucleus, cytoplasm and mitochondrial mass. We also discovered that the blood capillary controls the planar alignment and size of tumour cells in their 3D milieu. Finally, a set of tumour cells polarized in the direction of a hot spot corresponding to a bile canaliculus-like structure. In conclusion, this pilot study allowed the identification of bioarchitectural parameters that shape the internal and spatial organization of tumours, thus paving the way for new investigations in an emerging field that we call onconanotomy.

cancer biology↗