Biology subjects

Pensa, S.

Publications and source records attributed to Pensa, S..

4 recordsLinked to original sources

bioRxiv2023

In the murine and bovine maternal mammary gland signal transducer and activator of transcription 3 is activated in clusters of epithelial cells around the day of birth

Signal Transducers and Activators of Transcription (STATs) regulate mammary gland development. Here we investigate the expression of pSTAT3 in the murine and bovine mammary gland around the day of birth. We identify polarisation of mammary alveoli towards either a low- or high-proportion of pSTAT3 positive alveolar epithelial cells. We present localised colocation analysis applicable to other mammary studies where identification, quantification and interrogation of significant, spatially congregated events is required. We demonstrate that pSTAT3-positive events are multifocally clustered in a non-random and statistically significant fashion. This finding represents a new facet of mammary STAT3 biology meriting further functional investigation.

cell biology↗

bioRxiv2023

A Human Breast Cell Atlas Mapping the Homeostatic Cellular Shifts in the Adult Breast

One of the barriers for breast cancer prevention and treatment is our poor understanding of the dynamic cellular shifts that naturally occur within the breast and how these changes contribute to tumour initiation. In this study we report the use of single cell RNA sequencing (scRNAseq) to compile a Human Breast Cell Atlas (HBCA) assembled from 55 donors that had undergone reduction mammoplasties or risk reduction mammoplasties. The data from more than 800,000 cells identified 41 cell subclusters distributed across the epithelial, immune, and stromal compartments. We found that the contribution of these different clusters varied according to the natural history of the tissue. Breast cancer risk modulating factors such as age, parity, and germline mutation affected the homeostatic cellular state of the breast in different ways however, none of the changes observed were restricted to any one cell type. Remarkably, we also found that immune cells from BRCA1/2 carriers had a distinct gene expression signature indicative of potential immune exhaustion. This suggests that immune escape mechanisms could manifest in non-cancerous tissues during very early stages of tumour initiation. Therefore, the Atlas presented here provides the research community with a rich resource that can be used as a reference for studies on the origins of breast cancer which could inform novel approaches for early detection and prevention.

cancer biology↗

bioRxiv2021

The generation of a Bcl11a lineage tracing mouse model

The transcription factor B-cell lymphoma/leukaemia 11A (BCL11A) has essential functions in physiological processes as well as haematological and solid malignancies, however, its contribution to tissue development and tumour progression is poorly understood. Here we show the generation of a Bcl11a lineage tracing mouse model to allow for in vivo tracking of Bcl11a-expressing cells and their progeny. We validate the model in the mammary gland by using flow cytometry and whole-tissue 3D imaging to locate labelled cells after induction of tracing in early development. We show that Bcl11a is predominantly expressed in long-lived luminal progenitors which populate mammary alveoli upon pregnancy, confirming bona fide labelling of Bcl11a cells. The Bcl11a lineage tracing mouse model therefore provides a powerful resource to study Bcl11a cells in development, homeostasis, and cancer.

developmental biology↗

bioRxiv2017

BCL11A interacts with SOX2 to control the expression of epigenetic regulators in lung squamous cell carcinoma

Patients diagnosed with lung squamous cell carcinoma (LUSC) have limited targeted therapeutic options. We report here the identification and characterisation of the transcriptional regulator, BCL11A, as a LUSC oncogene. Analysis of cancer genomics datasets revealed BCL11A to be upregulated in LUSC but not lung adenocarcinoma (LUAD). We demonstrated that knockdown of BCL11A in LUSC cell lines abolished xenograft tumour growth and its overexpression in vivo led to lung airway hyperplasia and the development of reserve cell hyperplastic lesions. In addition, deletion of Bcl11a in the tracheal basal cells abolished the development of tracheosphere organoids while its overexpression led to solid tracheospheres with a squamous phenotype. At the molecular level we found BCL11A to be a target of SOX2 and we show that it is required for the oncogenic role of SOX2 in LUSC. Furthermore, we showed that BCL11A and SOX2 interact at the protein level and that together they co-regulated the expression of several transcription factors. We demonstrate that pharmacological inhibition of SETD8, a gene co-regulated by BCL11A and SOX2, alone or in combination with cisplatin treatment, shows significant selectivity to LUSC in comparison to LUAD cells. Collectively, these results indicate that the disruption of the BCL11A-SOX2 transcriptional program provides a future framework for the development of targeted therapeutic intervention for LUSC patients.

cancer biology↗