Cancer's origin story features predictable plot line, researchers find
Predictable mutations chart cancer's path

Date:
July 7, 2023
Source:
Stanford Medicine
Summary:
Human cells evolving in the laboratory undergo a series
of predictable, sequential genetic changes that lead to
pre-cancer. Blocking these changes may allow intervention before
cancer occurs.


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FULL STORY ========================================================================== Cancer cells-to-be accumulate a series of specific genetic changes in
a predictable and sequential way years before they are identifiable as
pre- malignancies, researchers at Stanford Medicine have found. Many of
these changes affect pathways that control cell division, structure and internal messaging -- leaving the cells poised to go bad long before
any visible signs or symptoms occur.

The study is the first to exhaustively observe the natural evolution of
the earliest stages of human cancers, starting with cells that have a
single cancer-priming mutation and culminating with a panel of descendants harboring a galaxy of genetic abnormalities.

Identifying the first steps associated with future cancer development
could not only facilitate earlier-than-ever diagnosis -- when a deadly
outcome is but a twinkle in a rogue cell's eye -- but may also highlight
novel interventions that could stop the disease in its tracks, the
researchers say.

"Ideally, we would find ways to intercept this progression before the
cells become truly cancerous," said Christina Curtis, PhD, professor of medicine, of genetics and of biomedical data science. "Can we identify
a minimal constellation of genetic alterations that imply the cell will progress? And, if so, can we intervene? The striking reproducibility
in the genetic changes we observed from multiple donors suggests it's possible." Curtis is the senior author of the research, which was
published on May 31 in Nature. The lead authors of the study are former postdoctoral scholar Kasper Karlsson, PhD, and visiting graduate student
Moritz Przybilla.

Cells of nefarious beginnings The research builds on previous work in
Curtis's laboratory indicating that some colon cancer cells are seemingly
born to be bad -- they acquire the ability to metastasize long before
the disease is detectable.

"Our studies of established tumors showed us that early genomic
alterations seem to dictate what happens later, and that many of these
changes seem to happen before tumor formation," Curtis said. "We wanted
to know what happens at the very earliest stages. How does a cancer
cell evolve, and is this evolutionary path repeatable? If we start with
a given set of conditions, will we get the same result in every case?"
The researchers studied tiny, three-dimensional clumps of human stomach
cells called gastric organoids. The cells were obtained from patients undergoing gastric bypass surgery to treat obesity. At the beginning
of the study, the researchers nudged the cells toward cancers by
disabling the production of a key cancer-associated protein called p53
that regulates when and how often a cell divides. Mutations in p53 are
known to be an early event in many human cancers, and they trigger the accumulation of additional genetic changes including mutations and copy
number alterations -- in which repetitive regions of the genome are lost
or gained during cell division.

Then they waited.

Every two weeks, for two years, Karlsson cataloged the genetic changes occurring in the dividing cells. When Karlsson and Przybilla analyzed
the data they found that, although changes occurred randomly, those that conferred greater fitness gave their host cells an evolutionary advantage
over other cells in the organoid. As the cells continued to divide and
the cycle of mutation and competition repeated over many iterations,
the researchers saw some common themes.

Predictable pathways "There are reproducible patterns," Curtis
said. "Certain regions of the genome are consistently lost very early
after the initial inactivation of p53. This was repeatedly seen in cells
from independent experiments with the same donor and across donors. This indicates that these changes are cell-intrinsic, that they are hardwired
into tumor evolution. At the same time, these cells and organoids appear
mostly normal under the microscope. They have not yet progressed to a
cancer." The researchers found that these early changes usually occur in biological pathways that control when and how often a cell divides, that interfere with a cell's intricate internal signaling network coordinating
the thousands of steps necessary to keep it running smoothly, or that
control cell structure and polarity -- its ability to know what is "up"
and "down" and to situate itself with respect to neighboring cells to
form a functioning tissue.

The researchers saw similar patterns occur again and again in cells
from different donors. Like water flowing downhill into dry creek beds,
the cells traced tried-and-true paths, gaining momentum with each new
genetic change.

Several of these changes mirror mutations previously observed in stomach
cancer and in Barrett's esophagus, a pre-cancerous condition arising
from cells that line the colon and stomach.

"These changes occur in a stereotyped manner that suggest constraints
in the system," Curtis said. "There's a degree of predictability at the
genomic level and even more so at the transcriptomic level -- in the
biological pathways that are affected -- that gives insights into how
these cancers arise." Curtis and her colleagues plan to repeat the study
in different cell types and initiating events other than p53 mutation.

"We're trying to understand exactly what malignant transformation is,"
Curtis said. "What does it mean to catch these cells in the act, about
to topple over the edge? We'd like to repeat this study with other
tissue types and initiating mutations so we can understand the early
genetic events that occur in different organs. And we'd like to study
the interplay between the host and the environment. Do inflammatory
factors play a role in promoting progression? We know that it matters
that the cells in these organoids are communicating with each other, and
that is important to understanding progression and treatment response." Researchers from Karolinska Institutet, the University College London
and the Chan Zuckerberg Biohub also contributed to the study.

The research was supported by the National Institutes of Health (grants
DP1- CA238296 and U01-CA217851) and the Swedish Research Council.

* RELATED_TOPICS
o Health_&_Medicine
# Cancer # Stem_Cells # Lymphoma # Brain_Tumor
# Lung_Cancer # Colon_Cancer # Skin_Cancer #
Diseases_and_Conditions
* RELATED_TERMS
o Prostate_cancer o Cervical_cancer o Colorectal_cancer o
Breast_cancer o Chemotherapy o Carcinogen o Cancer o Metastasis

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========================================================================== Journal Reference:
1. Karlsson, K., Przybilla, M.J., Kotler, E. et al. Deterministic
evolution
and stringent selection during preneoplasia. Nature, 2023 DOI:
10.1038/ s41586-023-06102-8 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/07/230707153834.htm

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