The Cantù Lab - Gene Regulation during Development and Disease

Claudio Cantu's research at WCMM

We study gene regulation during embryonic development, and how this leads to the formation of distinct cell types and organs.

Our body is made of more than ten trillion cells (a number that looks like this When we were conceived, however, we were a single cell!
Embryonic development is that process that drives the formation of this vast number of different cells, each one executing a diverse task: transmitting the electrical impulses (neurons in the brain), contracting (muscle and pumping heart cells), transporting oxygen (red blood cells), and many others.

The problem is that all the cells within an organism (with very rare exceptions) possess the same genetic material. How could a single “instruction manual” impose a different identity to each cell?

The Cantù Lab at LiU is focused on this important goal: to discover the mechanisms of genome regulation that drive specialization during embryonic development.

Our efforts are not only aimed at solving the incredible mechanisms that generate this complexity but might also impact our understanding of human disease. Several human pathological conditions, in fact, arise precisely when the mechanisms of cell-cell communication and genome-regulation are perturbed. For example, those mechanisms that drive extensive cell proliferation in a growing embryo might be aberrantly reactivated in an adult organism and can cause cancer.

Hence, the discovery of novel molecular details of embryonic development bears the potential of generating new marker for disease disagnosis and, perhaps in the future, novel therapeutic avenues for curing such diseases.

In the Cantù lab we make use of sophisticated tools, from mouse genetics to high-throughput state-of-the-art biochemical approaches, to discover the composition of signals and the protein “arsenal” that, in each cell type, allows the activation of the correct genes, while leaving silent many others.

Our experimental efforts are focused on the so-called ‘Wnt signalling pathway’, a molecular cascade important for virtually all aspects of development, and whose deregulation causes human malformations and several forms of aggressive cancers, among which colorectal cancer.

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Claudio Cantù's research group at BKV.
Claudio Cantù and the research group. John Karlsson

From top left:
Valeria Ghezzi (Master´s Student),
Naomi Yamada (Research Engineer),
Pritha Guha Mojumder (Master´s Student),
Anna Nordin (Master´s Student),
Mattias Pernebrink (Research Engineer),
Simon Söderholm (PhD Student),
Divia Solanki (Bachelor Student),
Gianluca Zambanini (Research Assistant).

From bottom left:
Pierfrancesco Pagella (Postdoctoral Scientist),
Claudio Cantù (Principal Investigator) ,
Amaya Jauregi Miguel (Postdoctoral Scientist).

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1. Tissue-Specific Wnt-Signalling

A protein called β-catenin orchestrates canonical Wnt target gene expression by recruiting a host of co-factors to Wnt-responsive elements on the DNA, occupied by TCF/LEF transcription factors. Our recent data indicate that the Wnt/β-catenin pathway can affect gene expression in a tissue-specific manner by the recruitment of tissue-specific co-factors. Several of our lines of investigations aim at discovering how cell-type-specific players contribute to the execution of the Wnt-mediated transcription in different cell types: a fundamental question in the field of Developmental Biology.

2. Finding a Therapeutic Window to Treat Colon Cancer

Colorectal cancer (CRC) is prominently caused by uncontrolled activation of the Wnt signalling pathway. However, a complete inhibition of this pathway would have devastating effects on normal tissue homeostasis. In vivo abrogation, in the mouse, of the interaction between β-catenin and BCL9 leads to the loss of metastatic traits without perturbing normal homeostasis. As BCL9 proteins serve as scaffold to a dynamic protein complex that represses and activates Wnt target genes, we are investigating the CRC-specific composition of the Wnt-dependent β-catenin/BCL9 transcriptional complex, as a fundamental first step to identify new players and protein-protein interaction surfaces that might constitute future therapeutic targets. This quest is tightly connected to our fundamental question of embryology: one of our current hypotheses is that one of the regulators of CRC metastasis is TBX3, previously identified by us as a Wnt player in limb development.

3. The Interface Between Transcriptional Regulation and Chromatin Landscape

A central theme of this research line is to understand the relation between the Wnt pathway-mediated transcription and the tissue-specific regulation of chromatin function. We are working hard to respond to the following question: does Wnt signaling impose a specific chromatin structure and function? Or, on the other hand, does the tissue-specific context (i.e. chromatin structure of individual cells) act as fundamental constrain defining how individual cells will respond to Wnt stimulation? This is an ambitious line of investigation that will bring together two fields of research: the study of developmental pathways and molecular epigenetics.

4.The role of Wnt/BCL9 in Congenital Heart Disease (CHD)

We have previously found that the Wnt regulator BCL9 is an important player of heart development. We now hypothesize that genetic variations in the genomic BCL9-regulated regulatory regions might contribute to the onset of congenital heart disorders.

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