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 10.000.000.000.000). 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.

Resarch group Show/Hide content

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).

PI - Claudio Cantù Show/Hide content

Claudio Cantù - Bio sketch

I obtained PhD training at the University of Milano-Bicocca in the lab of Prof. Antonella Ronchi and Prof. Sergio Ottolenghi, focusing on the factors that drive the regulation of human globin genes transcription in erythroid cells, and how fetal genes are replaced by adult ones, a process known as “globin switching”. A summer stay in Oxford (UK) in the lab or Prof. Tariq Enver at the Weatherall Institute of Molecular Medicine, working 24/7 with Dr. Cristina Fugazza, allowed me to identify and focus on one specific protein, the transcription factor SOX6. In 2011 I changed field and joined the developmental genetics lab of Prof. Dr. Konrad Basler, at the University of Zurich, Switzerland, and started an ambitious research program in which I applied the genetic knowledge obtained in Drosophila melanogaster to study mammalian genetics.

I generated a series or mutant mouse strains that allowed me to dissect several aspects of how the Wnt pathway is transduced in different cell types during development. Here, many persons shaped my scientific growth in addition to Koni Basler, from George Hausmann, to Tomas Valenta, Dario Zimmerli, Nick Doumpas, Christian Mosimann and Erich Brunner – to mention a few.

My efforts generated a series of scientific discoveries that not only revealed how little was known about signaling pathways, but also shown how these mechanisms are employed or hijacked by cancer cells. In February 2018, I moved from Switzerland to Sweden, when I was awarded a generous research starting grant from the Knut och Alice Wallenberg Foundation. This allowed me to build a research group focused on the mechanisms via which cells influence each other´s genomes during development.

Pierfrancesco Pagella Show/Hide content

Pierfrancesco Pagella - Bio sketch

Pierfrancesco was born in Alessandria, Italy. He studied Biology at the University of Milano-Bicocca from 2005 to 2011, and then moved to Zurich, Switzerland. During his PhD and his postdoc at the University of Zurich, he focused on the study of teeth, an incredibly powerful model for the study of developmental and evolutionary biology. In this system, he identified and characterized non-canonical functions of several molecules – including the neurotrophin Nerve Growth Factor, the neurite growth inhibitor Nogo-A, and the Wnt/β-catenin transcriptional coactivators Bcl9/9L and Pygo1/2. As Oberassistant/Junior Group Leader at the University of Zurich, he set up microfluidic culture systems to emulate complex organs in vitro, with the aim of modeling and imaging developmental processes. With these microfluidic devices, he could faithfully recapitulate the in vivo tooth innervation patterns.

He exploited these culture systems to compare the neurotrophic properties of dental pulp and bone marrow stromal cells, cell populations currently studied in the context of hard tissue regeneration, as well as cancer cells. In a parallel line of research, he applied single cell RNA sequencing to determine the cellular composition of human teeth, realizing a comprehensive single cell atlas of human teeth.
In April 2021, he joined the lab of Prof. Claudio Cantù at Linkoping University, to gain expertise in the study of chromatin structure, protein / DNA interactions, and how these events affect major developmental and pathological processes.

Pierfrancesco Pagella, postdoctoral fellow, works in the lab with Pritha Guha Mojumder (center) and Valeria Ghezzi (left).Pierfrancesco Pagella, postdoctoral fellow, works in the lab with Pritha Guha Mojumder (center) and Valeria Ghezzi (left). Pierfrancesco is an expert in organogenesis, tissue dissection and ex vivo culture. Photo credit John Karlsson

Simon Söderholm Show/Hide content

Simon Söderholm - Bio sketch

Simon is from a smaller town called Söderköping located in Östergötland County, Sweden. He started his academic journey studying environmental science at Linköping University, Campus Norrköping. After receiving a bachelor’s degree, Simon then worked in the industry as an environment- and quality technician. After a number of years, he moved to Linköping and decided to start studying again, this time Chemical Biology, which was more in line with his interest in the molecular aspects of biology. During his Master’s he also went into the world of computational biology and bioinformatics, which was – he feels – a natural step giving his strong interest and experience in programming. After that, he worked as a research assistant until he started his doctoral training in the Claudio Cantù lab. 
The overall aim of his work, common to the aim of the group as a whole, revolves around studying tissue-specific properties of Wnt signaling, using genome-wide sequencing technologies and computational methods.

The long-term goal is to better understand how this seemingly linear process is able to act in such a versatile manner, knowledge that could improve our ability to treat diseases such as cancer.

Outside of work, Simon´s hobbies include writing novels, programming games and taking care of collections of coins and fossils/minerals.

Claudio Cantú and Simon Söderholm discuss the results.Claudio Cantù (left) and Simon Söderholm (right) discuss the implications of a new discovery. Simon Söderholm points to the identification of a small region, within the vast genome, that contains the small group of genes identified in the new study, which is important for the ability of embryonic stem cells to decide whether to divide or become specialized cells. Simon combined experimentation with sophisticated informatic analyses to identify the behaviour of these genes. Photo credit John Karlsson

Anna Nordin Show/Hide content

Anna Nordin - Bio sketch

Anna grew up in the United States and has a bachelor's degree in Biomedicine from the University of Skövde. Currently she is doing a master's degree at Linköping's University in the Experimental and Medical Biosciences program. Anna is interested in how chromatin and epigenetics are involved in cell behavior, and how this can be implicated in disease. In the lab her project involves looking into how the Wnt signaling pathway affects the three-dimensional structure of the genome, using both wet-lab and bioinformatic methods.

Anna Nordin, Master's student at BKV and connected to Claudio Cantù's research group, works in the lab.Anna Nordin, member of the Cantù Lab. Anna is an expert in Transcription Factors profiling and Genomic 3D organization. Photo credit John Karlsson

 

Gianluca Zambanini Show/Hide content

Gianluca Zambanini - Bio sketch

Originally from Riva del Garda (Italy), Gianluca moved to Milan in 2015 to study Biological Science. After 3 years he obtained a bachelor’s degree and started a master´s program at the University of Milano- Bicocca. During the second year of that master´s, Gianluca moved to Linköping to work on a master´s project. During this project, Gianluca focused on the DNA binding detection of β-catenin, a critical component of the WNT signaling pathway. To do so, Gianluca tried to develop a new and improved version of the CUT&RUN protocol first described by the Henikoff Lab in 2017.
After the thesis´ defense, Gianluca was awarded a 6-month scholarship by LiU to proceed with his project, aimed at improving the CUT&RUN technology.

At the moment, Gianluca is working in the Lab as a research assistant using CUT&RUN to study limb development in addition to the differential binding pattern of β-catenin in different tissue and phases of mouse development.

Gianluca Zambanini, member of Claudio Cantù's research group.Gianluca Zambanini, member of Claudio Cantù's research group. Photo credit John Karlsson

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Previous members of The Cantù Lab

Mattias Jonasson Show/Hide content

Mattias Jonasson is a previous member of the Cantù Lab.Mattias Jonasson.

Mattias Jonasson - Bio sketch

Mattias was awarded his MSc in Molecular Biology by Umeå University. Drawn to the field of developmental biology, he joined the Cantù lab as a research engineer in 2018. Chromatin biology soon caught his interest, leading him to set up CUT&RUN to study transcription factor occupancy in development and cancer. Apart from hands-on lab work, he also found fulfillment in supervising undergraduate students; all of whom he remembers with great pride. In 2021, Mattias left to join the lab of Dr. Elly Tanaka (IMP, Vienna) as a PhD student. He now studies how fibroblast plasticity determines wound healing outcomes and regenerative potential of different species.

Mattias Jonasson, previous member of the Cantù Lab.Mattias Jonasson in the lab.

Michael Gerstorfer Show/Hide content

Michael Gerstorfer, previous member of the Cantù Lab.Michael Gerstorfer.

Michael Gerstorfer - Bio sketch

Michael is a cellular biologist who has focused his academic studies and work towards investigating highly spatially organized in vitro cellular constructs, like gastruloids and organoids, and their potential to act as medical screening, research and eventually treatment tools. Michael received a Bachelor’s degree in Biomedical Engineering from the UAS Technikum Vienna.
Later, he went on to do a double Master’s degree in Cell and Tissue Engineering from the UAS Technikum Vienna and Medical Sciences from Linköping University. During his thesis, Michael used gastruloids as research device to investigate the role of Wnt signalling in early embryonic development in the group of Claudio Cantù. Michael is currently working at the CeMM Research Institute in Vienna investigating gastric organoids as a screening tool for esophageal and gastric diseases in the lab of Georg Busslinger.

Vittorio Monticelli Show/Hide content

Vittorio Monticelli, previous member in the Cantù Lab.Vittorio Monticelli.

Vittorio Monticelli - Bio sketch

Vittorio studied Biomedical Laboratory Techniques at the University of Foggia, Italy, and he received his Degree of Master of Medical Science at Linköping University. Here he defended his thesis “Uncovering the regulatory machinery required for the transcription of the Wnt target gene AXIN2” after attending Claudio Cantù’s Lab for a period of 6 months in June 2020. Following a post-degree research course in the Cantù Lab, Vittorio started his Ph.D. at the University of Liège where he studies the tumor evolution of a virus-induced type of leukaemia by means of microfluidics single-cell approaches.

Patricia Johansson Show/Hide content

Patricia Johansson, alumnus of Claudio Cantù's research group.Patricia Johansson.

Patricia Johansson - Bio sketch

Patricia started her career in the Cantù lab as a Master´s student in January 2019, and stayed for about 2 years as a Research Assistant after her studies. In the group, she got a lot of freedom to explore new and fascinating techniques and help establish them in the lab. This ranged from stem cell work and proteomics with Mass Spectrometry. Currently, she has chosen to set her eyes on research connected to product development and is working at Fujirebio Diagnostic AB with development of in vitro-diagnostic products.

Ongoing Projects Show/Hide content

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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