Nature: Identification of cells associated with colon cancer recurrence

Colorectal cancer organoids, edited to express the tdTomato reporter gene in cells with high expression of epithelial membrane protein 1 (Emp1), were implanted into the cecum of mice to produce primary tumors
.
After a few weeks, we sliced the whole liver and stained tdTomato (red) and E-Cadherin (gray) to look for metastatic initiating cells
.
In the figure, it can be observed how CRC disseminated tumor cells express high levels of Emp1, a marker gene
for the high relapse cell (HRC) population we describe.

Colon cancer is the third most common cancer in the world, with about 2 million new cases
each year.
Most patients are diagnosed while the tumor is still in the colon or rectum
.
These tumors are removed surgically and, in many cases, chemotherapy to prevent recurrence
.
However, in 20 to 35 percent of patients, the cancer reappears
in the form of metastases from other vital organs.
This is caused
by tumor cells left over from surgery.
Metastasis is the leading cause
of death for almost all types of cancer, including colon cancer.

Most colorectal cancer research focuses on the primary disease
.
In recent years, important progress
has also been made in characterizing metastatic diseases after the emergence of metastatic diseases.
However, until now, it has not been possible to study this small group of scattered tumor cells because diagnostic techniques used in clinical practice are invisible
.
This lack of knowledge has led to the lack of effective therapies to eliminate residual disease and prevent metastatic relapse, which has a poor
prognosis.
Scientists at IRB Barcelona, led by ICREA researcher and CIBER Network (CIBERONC) group leader Dr.
Eduard Batlle, have for the first time identified residual tumor cells hidden in the liver and lungs and described how they evolved to cause metastasis in these organs
.

"Understanding and avoiding the phenomenon of recurrence after surgery is an unaddressed medical need
.
After many years of colon cancer research, we have taken the first steps to prevent metastasis in patients with localized disease," explains
Dr.
Eduard Batlle, Director of the Colorectal Cancer Laboratory at IRB Barcelona.

How does colon cancer return?

The scientists developed a new experimental mouse model that can recreate the process
experienced by relapsed patients.
This usually goes through a phase
of diagnosis, therapeutic surgery, and subsequent recurrence.
At the same time, they devised a technique that can isolate tiny fractions
of diffuse tumor cells hidden in the liver.

"This model is very similar to the progression of patients with metastatic colon cancer, and it allows us to describe in detail the dynamics of
residual disease.
" We have studied metastasis from 3 or 4 tiny cells to medium or even larger cells and described in detail how they evolve during disease development
.
”

Define highly recurrent cells

Scientists have known for years that colon cancer is made up of different types of tumor cells that perform different functions
during the development of the disease.
In a mixture of various cell types that cause colon cancer, researchers led by Dr.
Batlle found a population
they called HRCs (high recurrence cells).
These cells have little proliferative activity and do not promote the growth
of the primary tumor.
However, the aggregated HRCs are able to separate from the main tumor, migrate into the bloodstream, reach the liver, and hide for a while
after surgery.
In samples from colon cancer patients, the researchers have been able to confirm that the same cells
are present in those individuals who are most at risk of recurrence after treatment.

The researchers also confirmed that eliminating these cells by genetic technology was enough to prevent the formation of metastases; That is, mice with colon cancer remained disease-free after the primary tumor was removed and did not recur.

Dr.
Batlle's team has also developed a therapeutic strategy that specifically eradicates residual disease and prevents relapse
.
They have shown that early metastases, which are not yet visible, can be eliminated
by immunotherapy before surgery.

"Our findings shed light on the behavior of the population of tumor cells responsible for recurrence, as well as the genes
that define them.
" In addition, it represents a proof of concept that paves the way for the development of new therapies, in particular aimed at eliminating residual disease, as well as new diagnostic tools to identify those patients
who are most at risk of relapse.
Finally, our study points to the need to revise clinical treatment guidelines for this type of cancer, as in many cases immunotherapy is recommended before surgery," concludes
Dr.
Batlle.

These findings open up the possibility of
developing new research directions.
Dr.
Batlle's lab is now focused on studying when HRCs that reach the liver are "activated" to regenerate tumors, with the goal of interfering with this process and preventing the formation
of metastases.
They also sought to identify the factors that influence the appearance of these cells, and why the number of these cells varies
between each patient.

Metastatic recurrence in colorectal cancer arises from residual EMP1+ cells