Towards prevention of cancer relapse: Major strides from Japanese scientists

TOKYO – Cancer relapse after chemotherapy remains a major cause of cancer-related deaths. However, the exact mechanism of cancer reoccurrence has so far remained unclear. In this study, researchers from Japan developed a live imaging system and revealed that yes-associated protein (YAP) promotes the relapse of human colorectal cancer. Their study sheds light on the therapeutic potential of YAP inhibition in preventing cancer relapse among patients undergoing chemotherapy.

Recent developments in medical science have greatly improved the effectiveness and outcomes of cancer therapies. However, cancer relapse or the recurrence of cancer after chemotherapy remains a challenge and leads to many cancer-related deaths worldwide. Understanding how relapse occurs could hold the key to preventing it.

New evidence indicates that resident cancer stem cells that persevere and survive through chemotherapy may be the main culprits behind cancer recurrence. Unfortunately, current experimental systems are insufficient for testing this hypothesis, preventing targeted interventions against cancer recurrence.

To solve this problem, a group of scientists from Japan, led by Prof. Toshiro Sato of Keio University School of Medicine, developed a novel live imaging system. Using this system, they monitored human colorectal cancer organoids – 3D assemblies of cancer cells that mimic tumors – in real time.

More specifically, they looked at the dynamics of specific cancer cells during and after chemotherapy. Their findings, first published online July 7, 2022 in the journal "Nature," have been published in an article in the August 25, 2022 print issue of the journal. These findings shed light on the mechanisms that cause dormant cancer cells to reawaken and trigger cancer relapse after chemotherapy.

Prof. Sato explained "Cancerous tumors are made up of different types of cells. Each group of cells expresses a specific gene, which acts as a unique identifier and can be used to trace their lineage. Based on this principle, we traced the growth and proliferation of specific cancer cell types over time, before and after chemotherapy." Through this analysis, the researchers identified a group of cells marked by the gene LGR5, which remain dormant before chemotherapy. Interestingly, they found that LGR5-expressing cells that also express p27 – a key regulator of cell proliferation – can remain "asleep" or dormant and even tolerate chemotherapy. However, after chemotherapy, these cells "reawaken" and undergo rapid proliferation, leading to regrowth of the tumor and cancer relapse.

Encouraged by these findings, Prof. Sato and his team, which also comprised researcher Yuki Ohta and assistant professor Masayuki Fujii, both from Keio University School of Medicine, asked another important question: how do these cells remain dormant and tolerate chemotherapy?

To answer this question, they performed a large-scale analysis of gene expression in this specific group of cells. To their surprise, they found that these cells show an unusually high expression of the collagen protein COL17A1, which allows the cells to sleep through chemotherapy and survive. More intriguingly, chemotherapy disrupts COL17A1, reawakening these cells and causing them to proliferate. This leads to the recurrence of CRC.

"Chemotherapy is widely believed to kill cancer cells. However, we found that chemotherapy has the opposite effect on some dormant cancer cells and instead allows them to proliferate and make new tumors. This knowledge is very valuable for developing better anticancer treatments," commented Prof. Sato.

To enable more specific interventions against cancer relapse, the research team went on to examine how chemotherapy disrupts dormancy in cells with COL17A1. Through their investigations, they narrowed down on a special network of molecules called the FAK-YAP signaling pathway. When this YAP signally was inhibited, the dormant cells found it difficult to reawaken. As a result, tumor regrowth after chemotherapy – i.e., CRC relapse – was delayed.

Hailing these results, Prof. Sato said, "The networks controlling cancer are very intricate. Our findings offer a new piece of the puzzle, providing novel insights into what causes dormant cells to reawaken and make more tumors. They show that YAP inhibition could offer an effective treatment option for preventing cancer relapse."

The findings by Prof. Sato and his team bring researchers one step closer to solving the major problem of cancer relapse.

Reference

Title of original paper: "Cell-matrix interface regulates dormancy in human colon cancer stem cells"

Journal: "Nature"

DOI: https://doi.org/10.1038/s41586-022-05043-y

Dr. Toshiro Sato is a Professor in the Department of Organoid Medicine at Keio University School of Medicine, Japan. He received his MD and PhD from Keio University and developed an organoid culture system for adult intestinal stem cells during his postdoctoral research stint at Hubrecht Institute. In 2011, Prof. Sato set up his own laboratory at Keio University, with research focused on the modeling of human gastrointestinal diseases. Prof. Sato has published over 100 research papers and has also been honored with Japan's Inoue Research Award.

Submitted by Keio University School of Medicine, Japan..