Control of gene expression in inflammation
In response to inflammatory stimuli, such as microbial components, macrophages and other cells of the innate immune system rapidly activate the expression of genes that encode for anti-microbial molecules or organize the subsequent inflammatory and immune response. The regulatory information required for gene expression changes is contained in hundreds of thousands of DNA sequences (enhancers and promoters) associated with genes. We work at understanding the molecular mechanisms of activation and usage of such genomic regulatory elements.
Deregulated inflammatory responses are involved in a large number of diseases with a huge societal impact including sepsis, auto-inflammatory diseases, metabolic disorders and cancer. Inflammatory responses are associated with massive changes in gene expression. The coordinated and accurate expression of such a large amount of genes depends on the many thousands of regulatory DNA sequences harbored in metazoan genomes that serve as platforms for the recruitment of transcription factors (TFs). Such regulatory sequences include promoters, which are associated with the gene transcription start sites, and enhancers, which regulate expression of genes located at variable distances in the genome thanks to the physical proximity enabled by the 3-dimensional folding of chromatin and the looping out of the intervening sequences. Enhancers and promoters have a similar organization based on the clustering of short DNA sequences (6-12 base pairs) recognized by multiple TFs, thus enabling their cooperative binding. It is the specific combination of TF binding sites characteristic of individual enhancers and promoters that determines their responsiveness to distinct TFs, whose activity or expression is in turn controlled by upstream signal transduction pathways. Therefore, genomic regulatory sequences act as essential integration hubs at the interface between the afferent (signal-transduction pathways) and the efferent (changes in gene expression) arms of any response to environmental changes.
A central focus of our lab is the molecular understanding of these mechanisms critical for the regulation of inflammation and immunity in normal conditions and in disease.
Control of cellular diversity in human pancreatic cancer
In about ten years, pancreatic cancer will represent the first cause of cancer deaths in the western world. The very poor prognosis of this tumor has complex causes, including the coexistence in the same tumor of cancer cells with very different properties, so that no therapy is sufficient to control all of them. Our work aims at understanding the bases for cellular diversity in pancreatic cancer, with the objective of identifying the rational bases for novel therapies.
Pancreatic ductal adenocarcinoma (PDAC) is projected to become the first cause of cancer deaths by 2030. The causes of the aggressive behavior and the incurability of PDACs are both the indolent clinical presentation (with a locally advanced or metastatic disease in 80% of cases at diagnosis) and the peculiar biology of the disease. A typical biological feature of human PDAC is the coexistence of well-differentiated glandular ducts and poorly differentiated groups of cancer cells with different gene expression programs and biological properties. Large scale genomic analyses indicate that such heterogeneity may be generated at the beginning of tumorigenesis by a rapid series of catastrophic mitotic errors, rather than resulting from mutational changes that slowly accumulate over time. Mechanistically, normal or tumor cell differentiation is determined by the coordinated activity of transcription factors that enforce lineage specification and cell identity by binding and activating genomic regulatory elements (enhancers and promoters) that control the expression of genes maintaining the differentiated state. While well differentiated tumor cells retain gene expression profiles that resemble those of their normal counterpart, the poorly differentiated ones deviate to a various extent from the normal tissue and often gain transcriptional and functional properties of stem cells. Therefore, understanding heterogeneity of human PDACs requires a complete understanding of the transcriptional mechanisms that enforce differentiation of pancreatic tumor cells. Our lab works at deconvoluting the transcriptional bases for the extreme cellular heterogeneity in human PDACs, their interplay with genetic changes and eventually their impact on response to different therapies.