Have we found a solution to cure pancreatic cancer, one of our most formidable foes?

Pancreatic malignancies exhibit a multifaceted microenvironment, governing metabolic shifts and fostering a dynamic interplay among diverse cell populations residing in this specialised area. Despite the decade-long endeavours to predominantly elucidate the most lethal pancreatic malignancy, Pancreatic ductal adenocarcinoma (PDAC) continues to stand as one of the most lethal forms of cancer. Adding more concerns, it has been hypothesised that PDAC will overtake colorectal cancer before 2040, moving only behind lung cancer as a leading cause of cancer-related mortality. With almost 97% of oncology trials failing to reach the clinical stage, the dreadful question arises, “Was a solution ever there?”. Cut back through the decades, a hope amidst all odds can be seen, where the culprit cells driving the spread of pancreatic cancer have been identified. Maybe it could be premature enthusiasm to say that we have now found the weakness to target, but a hope is always a hope, and we can be cheerful about that, with all thanks to the study done by Moreno et al., published in Science Advances on 18 October 2023. 

An amoeboid property of a cell is defined as a type of movement in which the cell changes its shape and moves by extending and retracting pseudopods. To reach distant organs, cancer cells disseminate using different migration modes, including collective, mesenchymal-elongated, and rounded-amoeboid strategies. The tumour microenvironment is the mediating factor in determining the type of cell migration and, consequently, the progression of tumour malignancy. To disseminate and successfully metastasise, cancer cells need not only to become migratory but also to evade immunity. The amoeboid melanoma cells reprogram the immune microenvironment via secretion of immunosuppressive factors. Pancreatic tumors are characterised by a highly immunosuppressive microenvironment. However, the presence of amoeboid cells in pancreatic cancer and their potential role in immunosuppressive checkpoint control remained rather enigmatic, at least till the study done by Moreno et al.

The primary aim of this study was to investigate whether amoeboid behaviour is a feature of pancreatic cancers and how they interact with their tumour microenvironment to support their aggressive behaviour. The preliminary results of the study proved the first part of this hypothesis when it was found that invasive and metastatic behaviours in PDAC are related to amoeboid transcriptional and cytoskeletal features. Again, To reach distant organs, cancer cells need not only to invade but also to survive immune system attack. The invasive amoeboid cancer cells were found to create an “immune protective niche” for themselves while they escape the primary tumor. The study further found that the amoeboid pancreatic cancer cells could also communicate more avidly with normal cells, particularly with immune cells, and corrupt them while they leave the primary tumor.  

 

Getting this information was quite interesting as not all cells show this property. The primary reason behind this immune-modulatory property could be a different gene expression profile of amoeboid PDAC cells as compared to the epithelial PDAC cells. Investigating this, the group found the upregulation of CD73, a cell surface receptor that can exert immunosuppressive functions in the tumor microenvironment. By inhibiting the activity of this particular molecule, the researchers managed to curtail the cancer's dissemination to the liver and diminish the population of immune cells that provided sustenance to the tumour. 

The study involved examining mice subjected to short-term (3 weeks) and long-term anti-CD73 treatment, with clinical endpoints indicating direct clinical benefits such as increased survival, reduced pain, or the absence of disease. In the long-term treatment group, anti-CD73 therapy decreased the occurrence of liver metastasis of cancerous tumors from 66.6% to 36.4%. Although more research is needed before these findings can move from the bench to the bedside, the study hints at the potential efficacy of inhibiting CD73 as a promising strategy for addressing pancreatic cancer and its metastasis. This is particularly noteworthy given that CD73-blocking drugs are already in development and undergoing clinical trials for various cancer types. 

Moreover, given that amoeboid cells were observed in both early and late-stage pancreatic cancer, it would not be an exaggeration to propose that this unveils a potential novel approach to intervene by targeting CD73 at an early stage of the disease. This could help mitigate the aggressiveness of these cells and their detrimental impact on the body. 

Thus, when the growing number of pancreatic cancer cases started to hit a global alarm, the study, with its unique approach and investigation, provided a glimpse of hope. At this phase, a question again arises, “Could this be the last ever promising effort in the fight against PDAC?”. The loud answer is a clear, resolute, and resounding no since, despite promising, the efficacy of the aforementioned target has yet to be claimed in clinical trials, and secondly, even, if it does, the quest to identify a better successful target will never be stopped.  Because in the ever-evolving journey of scientific discovery, the constant pursuit is to improve, advance our understanding, and remain committed to the relentless quest for knowledge and the continuous hunger to be better. 

 

References: 

Samain, R., Maiques, O., Monger, J., Lam, H., Candido, J., George, S., ... & Sanz-Moreno, V. (2023). CD73 controls Myosin II–driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells. Science Advances, 9(42), eadi0244.

Queen Mary University of London. "New study suggests promising approach for treating pancreatic cancer." ScienceDaily. ScienceDaily, 18 October 2023.