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30/05/2022 - Press release

Researchers Discover a Set of Poor Prognosis Markers in Patients with Colon and Rectal Cancer

A group of genes has been identified in cancerous cells that survive chemotherapy treatment. The activity of these genes leads to treatment resistance and increased capacity for metastasis.

This breakthrough opens the door to studying targeted treatments using drug inhibitors of these genes combined with chemotherapy, potentially providing alternatives for patients with a worse prognosis in this type of tumor, accounting for 30% of cases.

The research, led by scientists from the Hospital del Mar Medical Research Institute, highlights that this type of tumor cell reverts to an embryonic state. Identifying the factor that triggers this change could aid in designing new treatments for high-risk patients.

The primary treatment for colon and rectal cancer, chemotherapy, is not effective for all patients. In a significant group, around 30%, resistance develops and tumors lead to metastasis. These patients face a poor prognosis. Now, a team of researchers led by the Hospital del Mar Medical Research Institute has uncovered the chain of events causing this phenomenon. They have identified a set of poor prognosis markers and a potential therapeutic target for these patients. The findings are published in the journal Nature Communications.

In some cases, due to various reasons, chemotherapy treatment fails to eliminate all tumor cells, leaving a portion of them to survive and transition into an embryonic state. From here, the tumor can resurge with greater strength, becoming resistant to treatment and capable of generating metastasis. The researchers replicated this process in organoids created from patient cells and confirmed that cells in this embryonic state express a specific group of genes - eight genes, to be precise - that are characteristic of these aggressive tumor cells. Dr. Laura Solé and Dr. Teresa Lobo, lead authors of the study and researchers at IMIM-Hospital del Mar and CIBER Cancer (CIBERONC), state that "this embryonic signature could serve as a tool to predict patient prognosis and consider specific treatments for them." The results were validated through in vivo tests with human tumors implanted in mice.

Image: Tumor of colon cancer patient expressing the embryonic signature (YAP1 in green and S100A4 in red).

Potential Therapeutic Target

The researchers believe that understanding the factors involved in the embryonic conversion process of tumors will help assess the risk of recurrence in colon and rectal cancer patients. Dr. Lluís Espinosa, lead author of the study, coordinator of the Molecular Mechanisms of Cancer and Stemness Research Group at IMIM-Hospital del Mar, and CIBERONC investigator, explains, "We've observed that cells resistant to chemotherapy undergo this embryonic conversion. We believe that this also happens to a portion of tumors even before treatment in patients - the cells that chemotherapy doesn't kill develop this embryonic phenotype."

Efforts are now focused on leveraging this discovery not only for patient prognosis but also for determining new treatments and personalize the approach for high-risk patients. Identifying the specific regulator of this embryonic cell conversion will facilitate a new approach to treating these cases, combining chemotherapy with targeted gene inhibitors. Currently, there are already drugs available that can act on tumors displaying embryonic characteristics.

In fact, the authors' intention is to develop a kit that can determine the presence of these genes based on patient samples. According to Dr. Espinosa, "Once the factor triggering the conversion in these patients is identified, this signature could be detected to determine who is eligible for a specific treatment targeted at these genes."

Dr. Marta Guix, another co-author of the study and attending physician at the Medical Oncology Service of Hospital del Mar, notes, "When treating patients with colon and rectal cancer, one of the first lessons you learn is that each case is different, not only because each person is unique but also because the tumors they have behave very heterogeneously. Research like this allows us to understand why there are so many differences and what the best way to treat each case might be. There's still much to do, but undoubtedly an exciting path lies ahead."

The study involved collaboration from Dr. Anna Bigas, coordinator of the Cancer and Stem Cell Research Group at IMIM-Hospital del Mar and director of CIBERONC; Dr. Toni Celià-Terrassa, coordinator of the Cancer Stem Cells and Metastasis Dynamics Research Group at IMIM-Hospital del Mar; Dr. Alberto Villanueva from the Biomedical Research Institute of Bellvitge (IDIBELL) and the Catalan Institute of Oncology (ICO); and Drs. Antonio Barbachano and Alberto Muñoz from the 'Alberto Sols' Biomedical Research Institute (IIBM) and CIBERONC investigators. Medical professionals from the Oncology and Pathology Services of Hospital del Mar also participated in the study. The research received support from the Spanish Association Against Cancer (AECC).

Image: From left to right - Anna Bigas, Mar Iglesias, Lluís Espinosa, Teresa Lobo, and Laura Solé.

Reference Article

Solé, L., Lobo-Jarne, T., Álvarez-Villanueva, D. et al. p53 wild-type colorectal cancer cells that express a fetal gene signature are associated with metastasis and poor prognosis. Nat Commun 13, 2866 (2022). https://doi.org/10.1038/s41467-022-30382-9

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