Colon cancer: How mutation of the APC gene disrupts lymphocyte migration


Date:
April 14, 2022
Source:
Institut Pasteur
Summary:
In patients with familial adenomatous polyposis, a genetic disease
predisposing to colon cancer, mutations of the APC gene induce
the formation of intestinal polyps, but also reduce immune system
activity.

In a new study, researchers describe the mechanisms that modify the
structure of T lymphocytes and hinder their migration towards the
tumors to be destroyed. This discovery provides new perspectives
on the migration of immune cells, a key process in antitumor
immune defense.



FULL STORY ==========================================================================
In patients with familial adenomatous polyposis, a genetic disease
predisposing to colon cancer, mutations of the APC gene induce the
formation of intestinal polyps, but also reduce immune system activity. In
a new study, researchers from the Institut Pasteur, INSERM(1) and
Universite' Paris Cite' describe the mechanisms that modify the structure
of T lymphocytes and hinder their migration towards the tumors to be
destroyed. This discovery, published in the journal Science Advances
on April 13, 2022, provides new perspectives on the migration of immune
cells, a key process in antitumor immune defense.


==========================================================================
As its name suggests, familial adenomatous polyposis is transmitted from generation to generation. The cause: mutations of the tumor suppressor
gene APC (adenomatous polyposis coli). People who inherit these mutations develop hundreds, possibly thousands, of polyps in their colon from adolescence, then colorectal cancer(2) in adulthood if the polyps
are not surgically removed. "As it's a hereditary disease, all of the
body's cells carry the mutation and can be affected in different ways," explains Andre's Alcover, Head of the Lymphocyte Cell Biology Unit at
the Institut Pasteur and joint senior author of the study. "Today we
know that these mutations disrupt the functioning of colon cells but
also cells of the immune system." In previous studies, the team of
researchers from the Institut Pasteur, CNRS and Inserm -- funded by the
French Cancer League since 2018(3) -- demonstrated the dual impact of
APC mutations. Not only do these mutations prevent intestinal epithelial
cells from differentiating correctly and cause them to form tissue growths (polyps), they also adversely affect the functioning of immune cells,
thereby preventing them from effectively combating polyps and tumors. Two mechanisms that together promote the growth of tumors.

In order to better understand what prevents immune cells from fulfilling
their role, the researchers this time decided to take a closer look
at the T lymphocytes whose mission is to detect and destroy tumors by infiltrating them.

To this end, biologists and clinical research physicians of the Institut Pasteur's ICAReB platform, Dr. He'le`ne Laude and Dr. Marie-Noe"lle
Ungeheuer, approached the patient association POLYPOSES FAMILIALES
France. A new clinical research project involving the association
recruited patient volunteers for the collection of blood samples. "Thanks
to the association, we met patients and also clinicians specialized in polyposis. We learned a lot about this complex pathological condition,
the experience of patients and families, and the different levels
of disease severity. We recognize the valuable role of the patients,
who were highly motivated to take part in the study, and the input of specialists," pointed out Andre's Alcover.

The naturally mutated T lymphocytes present in the blood of these patients
were cultured then subjected to several in vitro experiments. Using
several microdevices -- filters, channels, protein substrates and layers
of vascular endothelial cells -- the researchers could compare the
behavior of diseased lymphocytes with that of lymphocytes from healthy volunteers. They studied how lymphocytes moved along biological surfaces similar to blood vessel walls, but also how easily they could separate
cells and cross tightly packed cell layers.

"In order to move along blood vessel walls, cross them and reach the tumor
to be infiltrated, healthy lymphocytes change their morphology. Something
akin to a large adhesive foot, supported by the lymphocyte's cytoskeleton, grows longer in the direction of migration. This polarization is essential
for movement in the right direction," explains Marta Mastrogiovanni,
researcher in the Institut Pasteur's Lymphocyte Cell Biology Unit
and lead author of the study. In mutated lymphocytes, the microtubules
making up the cytoskeleton are disorganized and there are fewer adhesion proteins. The cells lose their polarity and their 'muscles'." Although
the mutated T lymphocytes are not necessarily moving more slowly than
healthy lymphocytes, they adhere less well to the walls and have more difficulty moving in a given direction and passing through the walls. In
short, this research showed their migration to be less effective. "This discovery is important because the motility of immune cells is a key
process in antitumor immune defense. "We know that the immune system
is very important in combating pathogens but we sometimes forget that
it also contributes to combating cancer cells," concludes Vincenzo Di
Bartolo, researcher in the Institut Pasteur's Lymphocyte Cell Biology
Unit and joint senior author of the study.

(1) Collaborative project: Institut Pasteur, Department of Immunology
and Center for Translational Science (CRT, ICAReB), and Institut Pasteur, Institut Cochin, Institut Curie, and Institut Pierre-Gilles de Gennes.

(2) Familial adenomatous polyposis accounts for 1% of all colorectal
cancers.

(3) Funding via the French Cancer League (La Ligue Contre Le Cancer),
2018-2022 "E'quipe Labellise'e" program, the Institut Pasteur and
Inserm. Marta Mastrogiovanni was funded by the Pasteur-Paris University International Doctoral Program and the European Union Horizon 2020
Research and Innovation Programme under Marie Sklodowska-Curie grant
agreement 665807 and La Ligue Contre Le Cancer, doctoral grant 4th year
of PhD.


========================================================================== Story Source: Materials provided by Institut_Pasteur. Note: Content may
be edited for style and length.


========================================================================== Journal Reference:
1. Marta Mastrogiovanni, Pablo Vargas, Thierry Rose, Ce'line Cuche,
Elric
Esposito, Marie Juzans, He'le`ne Laude, Amandine Schneider, Mathilde
Bernard, Sophie Goyard, Charlotte Renaudat, Marie-Noe"lle Ungeheuer,
Je'ro^me Delon, Andre's Alcover, Vincenzo Di Bartolo. The tumor
suppressor adenomatous polyposis coli regulates T lymphocyte
migration.

Science Advances, 2022; 8 (15) DOI: 10.1126/sciadv.abl5942 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220414110750.htm

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