Organoid study uncovers key to colorectal cancer recurrence after chemotherapy
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Nature Cancer: Organoid study uncovers key to colorectal cancer recurrence after chemotherapy.
Colorectal cancer is the third most common cancer in the world, with nearly 2 million new cases every year, second only to breast cancer and lung cancer, and nearly 1 million deaths every year, second only to lung cancer. About 1 in 25 people will develop colorectal cancer in their lifetime.
Chemotherapy is commonly used to treat colorectal cancer and is effective in the initial treatment, but most patients experience recurrence after chemotherapy.
Recently, researchers from the Barcelona Institute of Science and Technology in Spain published a research paper entitled: Mex3a marks drug-tolerant persister colorectal cancer cells that mediate relapse after chemotherapy in Nature Cancer.
The study constructed organoids ( Organoids ) using tumor samples from colorectal cancer patients .
Through organoid research, it was found that tumor stem cells with Mex3a protein activity were in a latent state during chemotherapy, so they were resistant to chemotherapy.
After chemotherapy When the environment is favorable, these latent cancer stem cells are reactivated and regenerate tumors.
These latent tumor stem cells are the key to the recurrence of colorectal cancer after chemotherapy.
Professor Eduard Batlle , the corresponding author of the study, said that chemotherapy is clearly effective in the treatment of colorectal cancer, killing most but not all tumor cells.
The study revealed a population of chemotherapy-resistant cancer stem cells that continue to regenerate tumors after chemotherapy.
The discovery paves the way for the development of true-toxic drugs that clear these cells, which could further enhance the efficacy of chemotherapy and improve the survival rate of colorectal cancer patients.
The study was mainly conducted using organoids (Organoids) constructed from tumor samples from patients .
By observing the organoids, the research team was able to track changes in tumor cells throughout the course of chemotherapy and observe their response to chemotherapy.
The research team also used a colorectal cancer mouse model to further observe and reproduce the behavior of these cells in vivo, and compared the results obtained in patient colorectal cancer cell-derived organoids and colorectal cancer mouse models with those of patient tumor samples. Transcriptome analysis for comparison.
A study of colorectal cancer cell-derived organoids from patients showed that cells highly expressing Mex3a were resistant to chemotherapy and regenerated after chemotherapy ended.
A mouse model study of colorectal cancer showed that Mex3a-positive cells contributed little to metastatic growth, however, after chemotherapy, Mex3a-positive cells gave rise to large cell clones that regenerated the disease.
Lineage tracing analysis showed that persistent Mex3a-positive cells downregulate the WNT/stem cell gene program immediately after chemotherapy, transitioning to a transient state similar to YAP-positive fetal intestinal progenitor cells, and then regenerating into tumor cells after chemotherapy. In contrast, Mex3a- deficient cells differentiated into a goblet cell-like phenotype and were unable to resist chemotherapy.
The research team knocked out the Mex3a gene by gene editing, which made colorectal cancer cells highly sensitive to chemotherapy again.
Mex3a-deficient cancer metastases can be completely eliminated by chemotherapy.
Although the function of the Mex3a gene remains unknown, this finding suggests that drugs targeting Mex3a can work synergistically with chemotherapy and prevent cancer recurrence.
These findings demonstrate that adaptation of cancer stem cells to adversity protects them from chemotherapy and identify candidate cells responsible for relapse after chemotherapy in colorectal cancer.
Follow-up work will focus on analyzing the molecular mechanisms behind, specifically how the Mex3a protein maintains cancer stem cells in this dormant state, the team said.
Paper link :
https://www.nature.com/articles/s43018-022-00402-0
Organoid study uncovers key to colorectal cancer recurrence after chemotherapy
(source:internet, reference only)
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