How cancer cells escape crowded tumors

Date:
October 19, 2020
Source:
St. Anna Children's Cancer Research Institute
Summary:
When trapped in a crowded environment, cells of the human body try
to escape. Scientists now discovered that it is the cell nucleus,
which triggers the 'evasion reflex'. This reflex is activated once
cell compression exceeds the size of the nucleus. This unexpected
finding could help to predict treatment response and metastatic
spreading of tumors.



FULL STORY ==========================================================================
Like people, cells in the human body protect their personal space. They
seem to know how much space they need, and if it gets too tight,
most cells prefer to break free. The mechanism enabling cells to evade
crowded environments appears to involve an unusual player -- the cell
nucleus. This is what researchers from St. Anna Children's Cancer Research Institute Vienna, King's College London, Institute Curie Paris, and ETH
Zu"rich in Basel showed in their recent work.


========================================================================== Tissue cells protect their "personal space" The human body consists of trillions of cells growing in confined volumes, which often leads to
cell crowding. The crowding effect is exacerbated when cell growth and proliferation are out of control during tumor formation. This creates
a compressive microenvironment for the constituent cells. How do tumor
cells cope with the lack of space and compressive stresses? Answering
this question, the investigators found that the cells are able to sense environmental compression.

To do so, they utilize their largest and stiffest internal compartment,
the nucleus. Squeezing cells to the degree that physically deforms
the nucleus causes the nuclear membranes to unfold and stretch. These
changes are detected by specialized proteins, activating cellular contractility. The ability to develop contractile forces helps squeezing
the cell out of its compressive microenvironment in an "evasion reflex" mechanism. Therefore, the study proposes that the nucleus operates as
a ruler (see the accompanying illustration). It allows living cells to
measure their personal space and trigger specific responses once the
space becomes violated.

Fat restrictions to target metabolic vulnerability in cancer? As the scientists describe in the paper, Ca2+-dependent phospholipase cPLA2 is a protein, which senses nuclear membrane stretch upon cell compression. The
lead author Alexis Lomakin, PhD, emphasizes that cPLA2 represents a
druggable target. "Pharmaceutical companies are currently testing small molecule inhibitors of cPLA2. Based on our data, downregulating the
activity of cPLA2 in tumor cells might interfere with their ability to
escape the primary tumor and metastasize to distant locations," explains
Dr. Lomakin.

cPLA2-inhibitors prevent the production of arachidonic acid (ARA), which subsequently affects cell migration, growth, and survival. However,
ARA can also be obtained by cells from their environment. The Western
diet, for instance, is a potent source of omega-6 fatty acids, such as
ARA. Dietary fat restriction and consumption of omega-3 instead of omega-6 fatty acids could synergize with cPLA2 inhibitors to effectively attenuate tumor cell escape from overcrowded areas. "Testing these hypotheses is
an exciting direction for future research," concludes Dr. Lomakin.

Potential predictive marker for chemo-resistance Identifying the cell
nucleus as an active player that rapidly converts mechanical inputs into signaling or metabolic outputs is surprising. Until today, the nucleus
was considered as a passive storehouse for genetic material.

"We are very excited about what comes next," says Dr. Lomakin. According
to him, high degrees of nuclear deformation could be predictive of
metastatic potential and resistance to chemotherapy and immunotherapy.

"For many years, pathologists have been evaluating changes in the shape
of the nucleus to discriminate between different stages of tumor growth; however, how these structural-mechanical alterations of the nucleus functionally impact cancer cells remained completely unexplored," says
Dr. Lomakin.


========================================================================== Story Source: Materials provided by St._Anna_Children's_Cancer_Research_Institute. Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. A. J. Lomakin, C. J. Cattin, D. Cuvelier, Z. Alraies, M. Molina,
G. P. F.

Nader, N. Srivastava, P. J. Saez, J. M. Garcia-Arcos,
I. Y. Zhitnyak, A.

Bhargava, M. K. Driscoll, E. S. Welf, R. Fiolka, R. J. Petrie,
N. S. De Silva, J. M. Gonza'lez-Granado, N. Manel,
A. M. Lennon-Dume'nil, D. J.

Mu"ller, M. Piel. The nucleus acts as a ruler tailoring
cell responses to spatial constraints. Science, 2020 DOI:
10.1126/science.aba2894 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201019090121.htm

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