Researchers Examine Autophagy’s Regulatory Role in Cancer Cells

Cell competition is a dynamic process by which unhealthy, often cancerous cells, are surrounded and destroyed by healthy cells. Autophagy is one of the many cellular mechanisms allowing this process to occur, and its dysregulation has been increasingly noted in various diseases and cancers. A team of researchers from the Tokyo University of Science investigated these patterns in more detail to answer the question – Does autophagy regulate the early destruction of cancer cells through cell competition?

The team, whose work was published in the journal Cell Reports, began generating cell lines in which cell competition is triggered via RasV12, a cancer-causing protein. “We have previously shown that when a small number of mutant cells are produced in the normal epithelial layer by activating the cancer-causing gene Ras, the mutant cells are eliminated into the lumen as loser cells,” says lead author Dr. Shunsuke Kon, junior associate professor at Tokyo University of Science. “This happens as a result of cell competition between the normal epithelial cells and the Ras mutant cells.”

Using the RasV12-induced mosaic of healthy and cancer cells, plus fluorescent protein labeling, allowed the team to discover a variety of results. First, they noted that the RasV12 cells had an increased number of autophagosomes, or structures containing degradable cytoplasmic contents. Additionally, the researchers noted that lysosomes also appeared impaired, which likely caused the autophagosome increase. In turn, this altered the “autophagic flux,” or the measurement of autophagic degradation, in RasV12-transformed cells.

The team also revealed that the autophagosomes and impaired lysosomes acted together in apical elimination of the cancerous cells via cell competition. However, when the team removed the autophagy gene ATG-5 in RasV12-induced cells, they noted impairments to autophagy-mediated cell competition. The autophagy impaired cells also showed resistance to elimination within mouse models, eventually leading to chronic pancreatitis or inflammation in pancreatic ducts.

These findings highlight autophagy’s role in cell competition and subsequent elimination of mutant cancer cells, plus their crucial role in tissue homeostasis. Future work could investigate the role of autophagy in cancer prevention during early stages, plus potential avenues for anti-cancer therapeutics.

“The development of anti-cancer drugs targeting autophagy is being intensely pursued worldwide,” says Dr. Kon. “Since the role of autophagy has been found to differ depending on the stage of cancer progression, anti-cancer strategies that take into account the stage of cancer progression can enhance treatment efficacy.”