Scientists at the University of Geneva (UNIGE) have discovered some of the mechanisms by which metastatic cells form in a primary tumor. Their findings pave the way for new therapeutic strategies.

The work was published in Cell Reports in a paper titled, “On the origin of metastases: Induction of pro-metastatic states after impending cell death via ER stress, reprogramming, and a cytokine storm.”

“How metastatic cells arise is unclear,” the researchers wrote. “Here, we search for the induction of recently characterized pro-metastatic states as a surrogate for the origin of metastasis. Since cell-death-inducing therapies can paradoxically promote metastasis, we ask if such treatments induce pro-metastatic states in human colon cancer cells. We find that post-near-death cells acquire pro-metastatic states (PAMEs) and form distant metastases in vivo.”

Previous studies have identified metastatic cells during migration. It is also known that certain treatments can induce them. However, the precise mechanisms of their development remain a mystery. “We don’t know why, at a given moment, certain cells separate from the primary tumor,” explained Ariel Ruiz i Altaba, a professor in the department of genetic medicine and development at the UNIGE Faculty of Medicine. “The phenomenon is difficult to analyze because, before they migrate, there is nothing to distinguish future metastatic cells, or pro-metastatic cells, from other cells within the tumor.”

Thanks to recent research, these UNIGE scientists have discovered that the experience of imminent death within the primary tumor pushes certain cells to acquire pro-metastatic states. The team observed that these cells, which should have died, reprogram themselves and then present a high metastatic risk.

The researchers used tumor samples taken from two colon cancer patients. These cells were subjected to an imminent death experience causing endoplasmic reticulum stress, which allowed the development of PAME cells.

The scientists also discovered that PAMEs trigger a storm of cytokines.

Their findings pave the way for new therapeutic strategies, including the prevention of the development of pro-metastatic fields generated by certain treatments. “Currently, one of the main criteria when defining a treatment is tumor shrinkage. Thanks to our study, PAME cells now appear as potential therapeutic and metastasis prevention targets to be taken into account,” concluded Ruiz i Altaba.

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