Cancer: Sialylation of the epidermal growth factor receptor modulates
cell mechanics and enhances invasion

Date:
April 22, 2022
Source:
University of Alabama at Birmingham
Summary:
In a study that included tests of three types of human cancer
cells, researchers report that ST6Gal-I--mediated sialylation of
the epidermal growth factor receptor modulates cell mechanics and
enhances invasion by the cancer cells.



FULL STORY ==========================================================================
For more than two decades, University of Alabama at Birmingham researcher
Susan Bellis, Ph.D., has studied how the addition of sialic acid to
various proteins increases cancer resistance and oncogenicity.


==========================================================================
One of the enzymes that transfers sialic acid to target glycoproteins is ST6Gal-I, and it has attracted increased attention in the cancer field
in recent years. ST6Gal-I is upregulated in breast cancer, gliomas,
pancreatic cancer, prostate cancer and ovarian cancer, and it plays a
key role in tumor progression and metastasis.

Metastasis is the spread of a tumor to other parts of the body, through
the migration of tumor cells. Cells move themselves through cell adhesion mechanics -- integrins at the cell membrane can attach themselves to
a surface, acting as tiny anchors. The cell's cytoskeleton then pushes
the front of the cell forward to establish new anchors, and the now-rear anchors let go. Such cell mobility is vital in embryogenesis, development
and wound healing. However, in cancer, cell migration can be deadly.

UAB researcher Alexa Mattheyses, Ph.D., is able to study cell adhesion mechanics directly, using DNA tension-gauge tether probes displaying an integrin ligand and attached to a coverslip surface. When a cell binds to
the tension probe and exerts force, the DNA duplex separates, generating
a fluorescent signal whose changes are monitored by sophisticated
fluorescence microscopy. Two years ago, the Mattheyses lab showed that activation of the epidermal growth factor receptor, or EGFR, by its ligand
-- epidermal growth factor, or EGF -- modulated integrin forces and
attenuated the mechanical threshold for integrin tension and formation
of focal adhesions. Focal adhesions are the mechanical linkages, the
anchors, to the extracellular matrix outside the cell. They are also the
place where mechanical force and regulatory signals are transmitted. A cell-surface receptor like EGFR transfers a signal from its external
ligand to the interior of the cell.

The Mattheyses and Bellis labs collaborated to expand their EGFR
work by looking at the effect of adding sialic acid to EGFR on cell
mechanics. In a study published in theJournal of Biological Chemistry
that included tests of three types of human cancer cells, they report
that ST6Gal-I-mediated sialylation of the EGFR modulates cell mechanics
and enhances invasion by the cancer cells.

"Given the widespread impact of sialylation and the prognostic
value of ST6Gal- I expression, an improved understanding of how ST6Gal-I-mediated sialylation alters cell mechanics may open the door
to a new range of cancer therapeutics," Mattheyses said. "Our results
help bridge the mechanistic gap in the field, while demonstrating the
potential value in oncogenic mechanosignaling as a therapeutic target." "Clinically, increased glycoprotein sialylation has been associated with carcinogenesis, and ST6Gal-I promotes vital cancer hallmarks such as self- renewal, invasiveness, proliferative potential and resistance to cell
death," Mattheyses said. "While mechanical changes in cells and tissues
also contribute to malignancy and metastasis, the underlying mechanisms
by which these changes promote cancer have remained understudied."


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The UAB researchers used primate kidney cells as a test-bed system,
and three types of human cancer cells. In cells with little or no
ST6Gal-I, they introduced and overexpressed the enzyme. In cells that
expressed ST6Gal-I, they knocked down expression. They then compared overexpressing and poorly expressing cells, using DNA tension-gauge
tethers and fluorescence microscopy.

They found that ST6Gal-I overexpression promoted cell spreading and focal adhesion maturation in an activated EGFR-dependent manner. The cells'
force histories, as reported by the DNA tethers, showed that ST6Gal-I overexpression led to increased tension generation by integrins. Classical cancer biology assays showed that ST6Gal-I overexpression enhanced mechanosignaling-increased migration, invasion, proliferation and
survival.

The researchers also examined the downstream EGFR-signaling cascades that
might regulate mechanical outcomes or alterations in cell morphometrics,
which is the quantitative analysis of form. They found that changes in
cell mechanical properties -- such as integrin tension, focal adhesion nucleation and promotion of cell spread area -- depended on the extracellular-signal-regulated kinase, or ERK, pathway. In contrast,
increases in cellular migration, invasion, proliferation and survival
were controlled via the phosphoinositide 3-kinase- Akt serine/threonine
kinase, or AKT, cascade.

They also found that high ST6Gal-I activity led to sustained EGFR membrane retention, making it a key regulator of cell mechanics.

"Our findings suggest a novel sialylation-dependent mechanism
orchestrating cellular mechanics and enhancing cell motility via EGFR signaling," Mattheyses said.

Mattheyses and Bellis are associate professor and professor, respectively,
in the UAB Department of Cell, Developmental and Integrative Biology,
in the Marnix E. Heersink School of Medicine. At UAB, Bellis holds the
Alma B.

Maxwell-UAHSF Endowed Chair in Biomedical Research. Bellis is a senior scientist and Mattheyses a scientist in the O'Neal Comprehensive Cancer
Center at UAB, and Mattheyses also directs the center's Microscopy
Shared Resource.

Co-authors with Mattheyses and Bellis are Tejeshwar C. Rao, Reena
R. Beggs, Katherine E. Ankenbauer and Jihye Hwang, UAB Department of Cell, Developmental and Integrative Biology; and Victor Pui-Yan Ma and Khalid Salaita, Emory University, Atlanta, Georgia.

Support came from National Science Foundation CAREER grant 1832100; and
from National Institutes of Health grants GM131099, CA233581, CA225177, CA223074 and CA013148.


========================================================================== Story Source: Materials provided by
University_of_Alabama_at_Birmingham. Original written by Jeff
Hansen. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Tejeshwar C. Rao, Reena R. Beggs, Katherine E. Ankenbauer,
Jihye Hwang,
Victor Pui-Yan Ma, Khalid Salaita, Susan L. Bellis, Alexa
L. Mattheyses.

ST6Gal-I-mediated sialylation of the epidermal growth factor
receptor modulates cell mechanics and enhances invasion. Journal
of Biological Chemistry, 2022; 298 (4): 101726 DOI:
10.1016/j.jbc.2022.101726 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220422114737.htm

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