Biology subjects

Tavernari, D.

Publications and source records attributed to Tavernari, D..

4 recordsLinked to original sources

bioRxiv2024

Patient-derived lymphomoids preserve the tumor architecture and allow to assess response to therapies in lymphoma

The efficacy of anti-cancer therapies depends on the genomic composition of the tumor, its microenvironment, spatial organization, and intra-tumor heterogeneity. B cell lymphomas are a heterogeneous group of tumors emerging from B cells at different stages of differentiation and exhibiting tumor-specific interactions with the tumor microenvironment. Thus, to measure response to therapy in lymphoma, it is critical to preserve the tumor composition and functional interactions among immune cells. Here, we developed a platform to maintain small fragments of human lymphoma tissue in culture for several days and use them to test response to therapies. We collected 25 patient samples representative of different lymphoma subtypes and established ex vivo tissue fragments that retained histological, cellular, and molecular characteristics of the original tissue, here referred to as lymphomoids. Using lymphomoids, we tested sensitivity to several clinically approved small molecule inhibitors in parallel and examined tissue remodeling upon treatment. Importantly, when this information was available, we showed that sensitivity to therapy observed in lymphomoids was consistent with patients response in the clinic. Lymphomoids are an innovative tool to assess treatment efficacy in clinically relevant contexts and could be used to uncover novel aspects of lymphoma biology.

cancer biology↗

bioRxiv2023

CellCharter: a scalable framework to chart and compare cell niches across multiple samples and spatial -omics technologies.

Tissues are organized in cellular niches, the composition and interactions of which can be investigated using spatial omics technologies. However, systematic analyses of tissue composition are challenged by the scale and diversity of the data. Here we present CellCharter, an algorithmic framework to identify, characterize, and compare cellular niches in spatially resolved datasets. CellCharter outperformed existing approaches and effectively identified cellular niches across datasets generated using different technologies, and comprising hundreds of samples and millions of cells. In multiple human lung cancer cohorts, CellCharter uncovered a cellular niche composed of tumor-associated neutrophils and cancer cells expressing markers of hypoxia and cell migration. This cancer cell state was spatially segregated from more proliferative tumor cell clusters and was associated with tumor-associated neutrophil infiltration and poor prognosis in independent patient cohorts. Overall, CellCharter enables systematic analyses across data types and technologies to decode the link between spatial tissue architectures and cell plasticity.

bioinformatics↗

bioRxiv2022

Cis-regulatory effect of HPV integration is constrained by host chromatin architecture in cervical cancers

Human papillomavirus (HPV) infections are the primary drivers of cervical cancers, and often the HPV DNA gets integrated into the host genome. Although the oncogenic impact of HPV encoded genes (such as E6/E7) is well known, the cis-regulatory effect of integrated HPV DNA on host chromatin structure and gene regulation remains less understood. Here, we investigate the genome-wide patterns of HPV integrations and associated host gene expression changes in the context of chromatin states and topologically associating domains (TADs). We find that HPV integrations are significantly enriched and depleted in active and inactive chromatin regions, respectively. Interestingly, regardless of the chromatin state, the genomic regions flanking HPV integrations showed transcriptional upregulation. Nevertheless, the upregulation (both local and long-range) is mostly confined to the TADs with integration and does not affect the adjacent TADs. Few TADs showed recurrent integrations associated with overexpression of oncogenes within them (such as MYC, PVT1, TP63 and ERBB2), regardless of the proximity. To further understand the long-range effect, we performed HiC and 4C-seq analyses in HeLa and observed chromatin looping interaction between the integrated HPV and MYC/PVT1 regions (situated [~]500 kb apart), leading to allele-specific overexpression of these genes. Again, these chromatin interactions involving integrated HPV are mostly observed within the same TAD. Together, these results suggest the cis-regulatory potential of integrated HPV DNA that drives host gene upregulation at intra-TAD level in cervical cancer. Based on this, we propose HPV integrations can trigger multimodal oncogenic activation to promote cancer progression.

genomics↗

bioRxiv2020

Sustained Androgen Receptor signaling is a determinant of melanoma cell growth potential and tumorigenesis

Melanoma is a benchmark of major clinical significance for cancer development with greater aggressiveness in the male than the female population. Surprisingly little is known on the role of androgen receptor (AR) signaling in the disease. Irrespectively of expression levels, genetic and pharmacological suppression of AR activity in a large panel of melanoma cells, derived from both male and female patients, suppresses proliferation and self-renewal potential while, conversely, increased AR expression or ligand stimulation enhance proliferation. AR gene silencing in multiple melanoma lines elicits a shared gene expression signature related to interferon- and inflammatory cytokines signaling with an inverse association with DNA repair-associated genes, which is significantly linked with better patients survival. AR plays an essential function in maintenance of genome integrity: in both cultured melanoma cells and tumors, loss of AR activity leads to chromosomal DNA breakage, leakage into the cytoplasm, and stimulator of interferon genes (STING) activation. In vivo, reduced tumorigenesis resulting from AR gene silencing or pharmacological inhibition is associated with intratumor macrophage infiltration and, in an immune competent mouse model, cytotoxic T cell activation. Although at different levels, androgens are produced in both male and female individuals and AR targeting provides an attractive therapy approach for improved management of melanoma irrespective of patients sex and gender. SignificanceThe study uncovers an essential role of androgen receptor (AR) signaling in melanoma cell expansion and tumorigenesis, with loss of AR activity inducing cellular senescence, genomic DNA breakage, a STING dependent inflammatory cascade and immune cells recruitment. Use of AR inhibitors as growth inhibitory and DNA damaging agents in melanoma cells can provide an attractive venue for new combination approaches for management of the disease.

cancer biology↗