An antibacterial protein, a new therapeutic target against pancreatic cancer

Immunotherapy represents new hope in the fight against cancer. However, not all tumors respond to this treatment. Pancreatic cancer, lethal for 9 out of 10 people diagnosed and which affects nearly half a million people in the world each year and more than 9,000 in Spain alone, according to the Spanish Society of Medical Oncology, does not respond to drugs. currently approved. For this reason, it is necessary, from biomedical research, to look for new targets that attack resistant cells, such as cancer stem cells that are mainly responsible for starting the tumor, forming metastasis and resisting treatments.

A recent study describes how pancreatic cancer stem cells take advantage of an antibacterial protein, PGLYRP1, to avoid the immune system and protect themselves from early elimination. When this protein is eliminated, the defenses are able to recognize tumor cells and kill them. Knowing this will allow us to design new immunotherapies that act against the root of pancreatic cancer and, in the future, obtain improvements in treatment.

The study has been co-directed by three researchers: Bruno Sainz, head of the Cancer Stem Cells and Fibroinflammatory Microenvironment group at the Sols-Morreale Biomedical Research Institute (IIBM) in Spain, which is a joint center of the Higher Council for Scientific Research (CSIC). ) and the Autonomous University of Madrid (UAM); Susana García Silva, scientist at the National Cancer Research Center (CNIO) in Spain; and Christopher Heeschen, from the IRCCS (Candiolo Cancer Institute) in Italy. Sainz also works in the Biomarkers and Personalized Approach to Cancer Group (BIOPAC) of the Ramón y Cajal Institute for Health Research (IRYCIS) in Spain.

Over the past ten years, the three scientists have led a collaborative project in which they identified a population of pancreatic cancer stem cells (CSCs) present in mouse models of this disease. These cells, known as the root of the tumor, are responsible for recurrences after treatment with chemotherapy or radiotherapy. Surprisingly, pancreatic cancer is also one of the tumors most resistant to immunotherapy. However, to date, nothing was known about the mechanisms by which CSCs manage to avoid elimination by the immune system.

As a result of this collaboration, Peptidoglycan Recognition Protein 1, PGLYRP1, was identified as one of the causes of immune evasion in CSCs, using animal models and patient samples. In this work, the role of this protein in pancreatic cancer, which is produced in excess in stem cells, has been described for the first time. The discovery lays the foundations for developing treatments against it.

Immunofluorescence of a pancreatic tumor. The PGLYRP1 protein appears in green. (Photo: Bruno Sainz / IIBM / CSIC / UAM)

A possible therapy against the root of pancreatic cancer

“When we eliminate PGLYRP1 from tumor cells, we observe that the immune system responds by attacking these cells, which prevents the primary tumor from forming and the tumor cells from spreading, forming metastases,” explains Bruno Sainz, group leader at the IIBM. “Now we are developing therapies that serve to block or eliminate this protein with the hope of being able to combine them with current treatments and attack stem cells in another way,” he adds.

Over the last four years, Juan Carlos López Gil, the first signatory of this work, has deciphered why CSCs produce this protein in pancreatic cancer: “We have observed that the cells of the immune system try to eliminate tumor cells by producing the tumor necrosis, but PGLYRP1 is very similar to this factor and interacts with the same receptor by blocking it,” he points out. For the researcher, this means that “CSCs protect themselves by using an incomplete key (PGLYRP1) to block the lock (the receptor) and thus avoid death caused by tumor necrosis factor (the complete key).”

What surprises researchers is that a protein used by our defenses to fight bacteria is used by pancreatic cancer to protect itself from those same defenses. “It will be a priority in the future to be able to understand the mechanisms by which tumor cells abuse physiological processes in order to ‘reeducate’ the environment surrounding the tumor so that it reacts against it,” says co-author García-Silva.

The study is titled “The Peptidoglycan Recognition Protein 1 confers immune evasive properties on pancreatic cancer stem cells.” And it has been published in the academic journal Gut. (Source: IIBM / CSIC)