Researchers discover remaining tumor cells responsible for colon cancer relapse

Researchers discover remaining tumor cells responsible for colon cancer relapse

Colorectal cancer is the third most common type of cancer in the world, with around 2 million new cases per year. Most patients are diagnosed when the tumor is still in the colon or rectum. These tumors are surgically removed and, in many cases, treated with chemotherapy to prevent recurrence. However, in 20% to 35% of patients, the cancer recurs as metastases to other vital organs. These are caused by residual tumor cells that remain hidden at the time of surgery. Metastases are the leading cause of death in almost all cancers, including colon cancer.

Most colorectal cancer research has focused on the primary disease. In recent years there have also been important advances in characterizing metastases as they manifest. However, until now it has not been possible to study this small population of disseminated tumor cells, which is invisible to the diagnostic techniques used in the clinic. This lack of knowledge has resulted in a lack of effective therapies to eliminate residual disease and prevent recurrence of metastases, which carry a poor prognosis. Scientists from IRB Barcelona led by Dr. Eduard Batlle, ICREA researcher and group leader within the Cancer CIBER Network (CIBERONC), have for the first time identified residual tumor cells hidden in the liver and lungs and described how they develop leading to the appearance of metastases in these organs.

Understanding and preventing the phenomenon of relapse after surgery is an unmet medical need. After many years of research into colon cancer, we have taken the first step toward preventing metastasis in patients with localized disease.”

Dr. Eduard Batlle, Head of the Colorectal Cancer Laboratory, IRB Barcelona

How does colon cancer come back?

Scientists have developed a new experimental mouse model that recreates the process that relapse patients go through. This typically progresses through the stages of diagnosis, curative surgery and subsequent relapse. In parallel, they have developed a technique that makes it possible to isolate the tiny fraction of disseminated tumor cells hidden in the liver.

"The model, which is very similar to the progression of metastatic colon cancer in patients, has allowed us to describe in detail the dynamics of residual disease. We have studied metastases in the micro range from 3 or 4 cells to medium-sized or even larger and have described in detail how each of them evolves during disease progression," comments Dr. Adrià Cañellas-Socias, a researcher from Dr. Batlle led the laboratories and was the first author of the study.

Definition of highly recurrent cells

Scientists have known for years that colon cancer is made up of different types of tumor cells that perform different functions as the disease progresses. Within the mix of cell types that drive colon cancer, researchers led by Dr. Batlle identified a population that they called HRCs (High Relapse Cells). These cells have low proliferative activity and do not contribute to the growth of the primary tumor. However, clusters of HRCs are capable of detaching from the main tumor, migrating into the bloodstream, reaching the liver and remaining hidden for some time after surgery. In samples from patients with colon cancer, researchers were able to verify the presence of the same cells in people at greatest risk of recurrence after treatment.

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The researchers have also confirmed that eliminating these cells through genetic techniques is sufficient to prevent the formation of metastases; that is, mice with colon cancer remain disease-free after removal of the primary tumor and do not suffer subsequent relapses. The team of Dr. Batlle has also developed a therapeutic strategy to specifically eliminate residual disease and prevent recurrence. They have shown that incipient metastases that are not yet visible can be eliminated by treatment with immunotherapy before surgery.

"Our discovery reveals how the group of tumor cells responsible for relapse behaves, as well as the genes that define them. Furthermore, it represents a proof of concept that paves the way for the development of new therapies specifically aimed at eliminating residual disease." as well as new diagnostic tools to identify the patients at greatest risk of recurrence. “Finally, our study points to the need for a revision of clinical guidelines for the treatment of this type of cancer, since in many cases it would be advisable to prescribe immunotherapy before surgery,” concludes Dr. Batlle.

These discoveries open up the possibility of developing new research directions. The laboratory of Dr. Batlle is now focused on studying when HRCs that have reached the liver become “activated” to regenerate a tumor, with the goal of disrupting this process and preventing metastasis formation. They are also trying to identify the factors that influence the appearance of these cells and why the number of these cells varies from patient to patient.

This work involved scientists from the Department of Biostatistics and Bioinformatics of the IRB Barcelona, ​​led by Dr. Camile Stephan-Otto and the Advanced Digital Microscopy Core Facility led by Julien Colombelli. Researchers from the laboratories led by the following PIs also worked on the study: Dr. Simon Leedham, at Oxford University (UK), Dr. Sabine Tejpar, at the Katholieke Universiteit de Leuven (Belgium), Dr. Holger Heyn, at the Centro Nacional de Análisis Genómico (CNAG-CRG) and Dr. Xavier Trepat at the Institute of Bioengineering of Catalonia.

The project was funded by the La Caixa Foundation, the Marató de TV3, the Asociación Española Contra el Cáncer, Cancer Research UK, the Spanish Ministerio de Ciencia e Innovación and the European Research Council.

Source:

Institute of Biomedical Research (IRB Barcelona)

Reference:

Cañellas-Socias, A., et al. (2022) Metastatic recurrence in colorectal cancer arises from residual EMP1+ cells. Nature. doi.org/10.1038/s41586-022-05402-9.

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