Researchers discover new options to treat pancreatic cancer

Solution proposed by researchers aims to “stop tumor progression and minimize therapeutic resistance” in patients with pancreatic cancer

A team from the Institute for Research and Innovation in Health at the University of Porto (i3S), led by researcher Sónia Melo, discovered that, in pancreatic tumors, cancer stem cells communicate with other tumor cells through extracellular vesicles, giving orders them to grow the tumor and resist chemotherapy. The study also demonstrates that, by preventing this communication between cells, the tumor does not grow. These data reveal new therapeutic possibilities for treating pancreatic cancer.

Pancreatic tumors are composed of different populations of cells (cancer stem cells and non-stem cancer cells) that communicate with each other through the secretion of extracellular vesicles (EVs). The i3S team discovered that in these tumors there is an organized communication network with a defined hierarchy called EVNet. The researchers also discovered that, despite being in much smaller numbers, it is the stem cells that communicate the most with other cells. In fact, they are the ones who command and transmit the guidelines for the tumor to survive.

In view of this, the team analyzed what this communication consists of and found that, inside the extracellular vesicles (EVs) secreted by cancer stem cells, there is a protein called Agrin and it is this protein that, when sent to other cells, drives the tumor to grow and overcome adversity, namely chemotherapy.

During this work, “we also realized that when we cut off this communication between cancer stem cells and other cancer cells, we prevent the tumor from growing”, explains Sónia Melo. For this, adds the researcher, “we used samples of pancreatic tumors from patients at the Centro Hospitalar Universitário de S. João that were introduced into mice and, using molecules that inhibit cell-to-cell communication, we managed to stop the progression of the tumor”.

Additionally, adds the team leader, “we used antibodies to block the Agrin protein and we also saw a slowdown in tumor growth”.

The most frequent communication route in the PDAC EVNet occurs from CSC to NSCC

(A) Schematics of the methodological approach: MIA PaCa-2 clones expressing different fluorescently labelled markers are cultured at the percentages found in the parental cell line and are analysed through flow cytometry in order to trace the flow of EVs among subpopulations. A total of seven intermix of colour-coded subpopulations was analysed, corresponding to five distinct intermixes.  (B) Representative confocal microscopy live images of 72-hour culture MIA PaCa-2 colour-coded subpopulations. Right panel: representative images of a cell where EVs uptake was not detected (single positive), a cell that received EVs from one different subpopulation (double positive), a cell that received from two other subpopulations (triple positive) or from all four subpopulations (quadruple positive). Scale bars from left to right: 20, 10 and 10 µm. (C) Dot plot representing the percentage of single-positive, double-positive, triple-positive and quadruple-positive cells found in the cocultures (n=7, Mann-Whitney test ***p<0.001). (D) Quantification of the percentage of cells that received EVs from CD133+, CD24+CD44+, CD2444+ and 4N subpopulations (n=7, one-way analysis of variance (ANOVA) *p<0.05, **p<0.01, ****p<0.0001). (E) Quantification of cells of different subpopulations that receive EVs from CSC or NSCC (highlighted on top). The fold change was calculated against the minimum percentage of communication found in each coculture (n=7). (F) Quantification of the percentage of cells that received EVs (left) and schematic representation of the most frequent communication route in the EVNet, from CSC to NSCC (right, comparison of CSC positive for NSCC EVs and NSCC positive for CSC EVs; n=7, Mann-Whitney test, *p=0.0379).

New solutions to “stop tumor progression”

These results, underlines Sónia Melo, indicate that these two options – drugs to prevent communication between cancer cells and antibodies to block the Agrin protein – “have potential as therapeutic solutions to be applied by clinicians to patients with pancreatic cancer with the aim of halt tumor progression and minimize therapeutic resistance”.

In collaboration with Hospitals da Luz and Beatriz Ângelo, “we analyzed the blood of patients with pancreatic cancer and found that those with a greater number of extracellular vesicles positive for the Agrin protein circulating in the blood have a three times greater risk of disease progression ”. This means, according to the i3S researcher, that “the circulating agrin-positive EVs are potential biomarkers to determine the response to therapy and the risk of pancreatic tumor progression”.

This work took place in part within the scope of the Porto Comprehensive Cancer Center and reflects one of its main lines of action: the development of pre-clinical research to accelerate early-phase clinical trials driven by investigators.

About pancreatic cancer

Pancreatic cancer is a silent disease, usually detected in advanced stages. It is one of the deadliest cancers, with a 5-year survival rate of less than 10%, that is, in 100 people diagnosed with pancreatic cancer, less than 10 will be alive after 5 years. In Portugal, around 1800 cases arise annually and estimates suggest that, by 2030, pancreatic cancer will be the second leading cause of cancer death.

These tumors are generally resistant to chemotherapy and there are still no other effective therapeutic options for these patients. Knowing the biology of these tumors is, therefore, essential to find new therapeutic targets that improve the quality of life of these patients.

SourceUniversity of Porto

Ruivo CF, Bastos N, Adem B, Batista I, Duraes C, Melo CA, Castaldo SA, Campos-Laborie F, Moutinho-Ribeiro P, Morão B, Costa-Pinto A, Silva S, Osorio H, Ciordia S, Costa JL, Goodrich D, Cavadas B, Pereira L, Kouzarides T, Macedo G, Maio R, Carneiro F, Cravo M, Kalluri R, Machado JC, Melo SA. (2022) Extracellular Vesicles from Pancreatic Cancer Stem Cells Lead an Intratumor Communication Network (EVNet) to fuel tumour progression. Gut [Epub ahead of print]. [article]

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