How alike are the cancer cells from a single patient?

Date:
November 11, 2021
Source:
Keck School of Medicine of USC
Summary:
Using an experimental system involving new genetic technology,
researchers analyzed the gene expression signatures of a
representative sample of barcoded leukemia cells. After implanting
some of the leukemia cells in mice, they discovered that distinct
gene expression signatures correlated with the various organs
where the cancer cells ended up. They were also able to identify
previously unknown genes that are involved in disease progression
and chemotherapy resistance, which may offer new targets for
treatment.



FULL STORY ==========================================================================
Even within a single patient with cancer, there is a vast diversity
of individual tumor cells, which display distinct behaviors related to
growth, metastasis, and responses to chemotherapy. To carry out these behaviors, each cancer cell uses its genes to make the needed molecules
in a unique way known as its "gene expression signature." To correlate
gene expression signatures with cancer progression and chemotherapy
resistance, a team of scientists led by Rong Lu from USC and Akil
A. Merchant from Cedars-Sinai have introduced a new genetic technology
in a study published in Nature Communications.


==========================================================================
To develop the experimental system, first author Humberto
Contreras-Trujillo from USC and his colleagues combined two existing technologies. The first enabled the researchers to read the gene
expression signatures of individual cancer cells from patients with
leukemia. The second technology, developed by the Lu Lab, allowed the scientists to label individual leukemia cells with heritable, DNA-based "barcodes," offering a way to track not only the cells but also their
progeny during disease progression.

Using this experimental system, the team analyzed the gene expression signatures of a representative sample of barcoded leukemia cells, and
then transplanted the remainder of the cells into mice.

Distinct gene expression signatures correlated with the various organs
where the cancer cells ended up in the mice. For example, cancer cells
with high expression of a gene called CMC2 tended to colonize the ovaries, while cells with low levels of CMC2 expression established colonies in
the blood and spleen.

Other cancer cells with elevated expression of the genes BTK, DNAJC,
and LRIF1 tended to generate progeny in discrete pockets of bone
marrow. When the scientists deactivated these genes, leukemia cells
accelerated migration, losing their ability to adhere to other cells in
the bone marrow.

"In our study, we were able to identify previously unknown genes that are involved in disease progression and chemotherapy resistance. These genes
may provide new targets for future therapies," said Lu, who is a Richard
N. Merkin Assistant Professor of Stem Cell Biology and Regenerative
Medicine, Biomedical Engineering, Medicine, and Gerontology at USC,
and a Leukemia & Lymphoma Society Scholar.



==========================================================================
By demonstrating that cancer cells with distinct gene expression
signatures tend to grow in different organs and bone marrow pockets,
the study also underscored a major problem facing cancer researchers:
studying non- representative samples of patient cells. For instance,
if a physician collects patient cells via a standard blood draw, the
sample would not include the non- circulating leukemia cells localized
to pockets of the bone marrow. Even more concerning, since these pockets
of cancer cells are not uniformly distributed, standard bone marrow
biopsies may not accurately diagnose disease in the patient.

There are similar challenges when patient cells are transplanted into laboratory mice in order to conduct pre-clinical cancer research. Less
than one percent of the patient cells grow and multiply in mice.

These problems are compounded if patient cells are collected from one
mouse, and subsequently transplanted into another mouse. This practice,
known as serial transplantation, is a standard technique for allowing
small samples of patient cells to expand into the larger quantities
needed for research.

However, the new Nature Communicationsstudy shows that serial
transplantations also favor the survival of cancer cells with particular
gene expression signatures.

In addition, cells from relapsed patients seemed less likely to survive
when transplanted into mice, compared to the cells derived from the
same patients prior to any therapeutic treatments. In most cases, the
progeny of one or two leukemia cells from the relapsed phase dominated
in transplanted mice.

"Our new system laid bare glaring limitations in the leukemia models
that are currently used to carry out the final stages of testing before potential therapeutic treatments advance to human clinical trials,"
said Merchant, who is a physician-scientist at Cedars-Sinai. "These
leukemia models do not capture the full diversity of individual tumor
cells within a single patient, let alone within the broader population of patients affected by this disease." The researchers also exposed their
mice to different variations of the standard leukemia treatment regimen: short-term intensive chemotherapy, followed by long-term maintenance
therapy. There were distinct gene expression signatures in leukemia
cells that eventually died from intensive treatment, ceased growing due
to maintenance therapy, or only responded to a combination of both.

Accordingly, in actual clinical practice, combination therapy has proven
to be the best overall approach for patients.

"By using our experimental system, we learned a lot about how
the gene expression of individual leukemia cells influence
their progression and treatment resistance," said Lu. "The same
system can provide similar insights about many other types
of cancer, and help identify and characterize the particular
cells that drive the disease and underlie treatment resistance." ========================================================================== Story Source: Materials provided by
Keck_School_of_Medicine_of_USC. Original written by Cristy Lytal. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Humberto Contreras-Trujillo, Jiya Eerdeng, Samir Akre, Du Jiang,
Jorge
Contreras, Basia Gala, Mary C. Vergel-Rodriguez, Yeachan Lee, Aparna
Jorapur, Areen Andreasian, Lisa Harton, Charles S. Bramlett, Anna
Nogalska, Gang Xiao, Jae-Woong Lee, Lai N. Chan, Markus Mu"schen,
Akil A.

Merchant, Rong Lu. Deciphering intratumoral heterogeneity using
integrated clonal tracking and single-cell transcriptome
analyses. Nature Communications, 2021; 12 (1) DOI:
10.1038/s41467-021-26771-1 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211111080401.htm

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