Genetic remodeling in tumor formation
Scientists delineate process which drives tumor formation by Kras
oncogenes

Date:
February 7, 2022
Source:
Terasaki Institute for Biomedical Innovation
Summary:
A new study demonstrates the ability of the mutant Kras oncogene to
use genetic reprogramming to make cells more stem-like and plastic;
it resolves the long-standing debate over why Kras is so special in
tumor formation. They were also able to identify an effector complex
that can be targeted for therapeutic treatment against mutant Kras.



FULL STORY ========================================================================== Cancerous tumors are made up of rapidly growing, abnormally shaped,
cells that can infiltrate and destroy healthy tissues, travel to other
parts of the body, and form additional tumors. In part because of its
rapid and invasive nature, cancer remains the second leading cause of
death in the United States and a major cause of death worldwide.


========================================================================== Tumor formation is often driven by genes called oncogenes, which are
usually involved in the normal processes of cell growth, proliferation,
and death. But they can also mutate and be expressed at high levels,
which can drive the multiplication of cancerous cells.

Mutated oncogenes work in various ways, including on target cells'
chromatin, compact, dense structures of DNA and selected protein
molecules. Oncogenes also work with an extensive variety of protein
complexes that help turn specific genes "on" or "off" by binding to
certain regions of the DNA.

The most well-known oncogene is Kras. Mutant Kras is found in 20% of all
human cancers, including 97% of pancreatic ductal, 45% of colorectal,
and 30% of lung cancers.

Despite the attention focused on mutant Kras tumor formation, the question remains as to why Kras mutation is so essential for oncogenesis. The conventional wisdom is that Kras mutation simply promotes cell
proliferation.

However, as many genes can promote cell proliferation, what makes Kras
so deadly and difficult to treat? A collaborative team that includes researchers from the Terasaki Institute for Biomedical Innovation
(TIBI) and Duke University led by Dr. Xiling Shen, a professor and
the chief scientific officer of TIBI, has been able to shed light on
these processes. In a recent study, published in Developmental Cell,they discovered that Kras mutation causes rearrangements of chromatin inside
cells.

This rearrangement causes tissue cells to revert to an early
developmental, or "stem-like" state and erroneously start to regenerate
"new tissue," causing the onset of tumor formation.

The team revealed that Kras-induced chromatin remodeling was mediated by
a protein complex called AP-1, which binds and opens chromatins to rewire
the cell's fate. The AP-1 mediated chromatin accessibility mechanism
seems to be a common process in tumor initiation, including in the lung,
skin, and intestine.

The team demonstrated that small-molecule drugs inhibiting AP-1 deterred oncogenesis and cell proliferation, providing a promising way to treat
Kras- mutant tumors. This is especially significant because, currently,
the majority of Kras tumors are not treatable with drugs.

What is even more fascinating is that Kras/AP-1 induced chromatin
remodeling instills plasticity, or the ability to assume different
cellular characteristics in response to mutations. Hence, Kras-mutant
cells from different origins such as alveolar cells in the lungs and
club cells in the airway will start masking their cell identity and
become alike to one another.

This sheds new light on the question of how lung cancer originates.

According to Dr. Shen, "Our study demonstrates the ability of Kras to
use genetic reprogramming to make cells more stem-like and plastic;
it resolves the long-standing debate over why Kras is so special in
tumor formation. Our elucidation of the AP-1 complex as its effector for chromatin remodeling opens new therapeutic opportunities to target Kras,
a notoriously hard-to-drug target." "An understanding of the complex
processes involved in tumorigenesis is essential for designing drug
treatments and screening platforms for cancer," said TIBI Director and
CEO, Ali Khademhosseini, PhD. "Dr. Shen's work will prove invaluable
in meeting those needs and will dovetail with the drug delivery and physiological models platforms that we have here at the institute."
Authors are Preetish Kadur Lakshminarasimha Murthy, Rui Xi, Diana
Arguijo, Jeffrey I. Everitt, Dewran D. Kocak, Yoshihiko Kobayashi, Aline
Bozec, Silvestre Vicent, Shengli Ding, Gregory E. Crawford, David Hsu, Purushothama Rao Tata, Timothy Reddy, and Xiling Shen.

This work was funded by NIH U01 CA217514, U01 CA214300, and R35 GM122465
to XS and DFG-SPP microbone (BO3811-1/7) grant to AB.

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


========================================================================== Journal Reference:
1. Preetish Kadur Lakshminarasimha Murthy, Rui Xi, Diana Arguijo,
Jeffrey I.

Everitt, Dewran D. Kocak, Yoshihiko Kobayashi, Aline Bozec,
Silvestre Vicent, Shengli Ding, Gregory E. Crawford, David Hsu,
Purushothama Rao Tata, Timothy Reddy, Xiling Shen. Epigenetic basis
of oncogenic-Kras- mediated epithelial-cellular proliferation
and plasticity. Developmental Cell, 2022; 57 (3): 310 DOI:
10.1016/j.devcel.2022.01.006 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220207112650.htm

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