Pancreatic tumors exploit several mechanisms to prevent starvation

In new findings published online March 18, 2021 in the journal Cancer Cell, an international team of researchers, led by scientists from the University of California San Diego School of Medicine and the Moores Cancer Center, describes how Pancreatic cancer cells are using an alternative method to deem necessary nutrients, defying current therapies, to help them grow and spread.

Pancreatic cancer accounts for about 3% of all cancers in the United States, but it is among the most aggressive and deadly, causing 7% of all cancer deaths each year. Pancreatic cancer is particularly deadly once it metastasizes, with the number of people alive five years later dropping from 37% to just 3%.

All cancer cells need a constant supply of nutrients. Some types of cancer do this by creating their own vascular networks to extract nutrients from the host’s blood supply. But other cancers, most notably pancreatic ductal adenocarcinoma, are surrounded by a thick layer of connective tissue and extracellular molecules (the so-called tumor stroma) that not only act as a kind of dividing line between malignant cells. and normal host tissue, but also as an obstacle to obtaining sufficient resources for cancer cells, including blood supply.

As a result, pancreatic and other nutritionally stressed cancers use a number of adaptive mechanisms to avoid starvation death, a risk particularly high in rapidly growing tumors. One of these mechanisms is autophagy or self-nourishment. Autophagy allows cancers under nutritional stress to digest intracellular proteins, especially denatured or damaged proteins, and use the released amino acid building blocks as an energy source to fuel their metabolism.

Previous research indicating that autophagy is high in pancreatic cancer has given rise to the idea that inhibition of self-nourishment could be used to starve tumors. Yet multiple clinical trials using compounds that inhibit autophagic protein degradation combined with traditional chemotherapy have produced no additional therapeutic benefit over chemotherapy alone, said Michael Karin, PhD, professor emeritus of pharmacology and pathology. at UC San Diego School of Medicine.

In the new study, Hua Su, PhD, a postdoctoral fellow in Karin’s lab and the study’s first author, and collaborators investigated why pancreatic cancers survive autophagy and, in fact, seem prosper. They found that inhibiting autophagy caused rapid upregulation or increased activity of another nutrient supply pathway called macropinocytosis, derived from the Greek for “large-scale drink or swallow.”

Macropinocytosis allows cancer cells compromised by autophagy and under nutritional stress to absorb exogenous proteins (found outside the cell), digest them, and use their amino acids for energy production. . “This explains why autophagy inhibitors fail to starve pancreatic cancer and cannot induce its regression,” Su said. “Once autophagy is inhibited, cancer cells simply use a different mechanism to feed themselves.”

In experiments using models of mouse cancer and human pancreatic cancers grown in mice, Su and colleagues found that a combination of inhibitors of autophagy and macropinocytosis caused rapid and almost complete tumor regression. .

“These results provide another example of the plastic nature of pancreatic cancer metabolism,” said lead author Karin. “It also shows that the combined inhibition of the two main nutrient supply pathways can result in successful blockage of energy supply leading to tumor starvation and consequent shrinkage.”

Study co-author Andrew Lowy, MD, chief of the surgical oncology division at UC San Diego Health’s Moores Cancer Center and professor of surgery at UC San Diego School of Medicine, said that the new data demonstrate the promise of targeting tumor metabolism as a treatment strategy and that success will likely require combining multiple agents for multiple targets.

“I think these findings are exciting and support the idea that we will have a significant impact against this very difficult disease in the near future,” Lowy said.

Reference: Su H, Yang F, Fu R et al. Cancer cells escape inhibition of autophagy via NRF2-induced macropinocytosis. Cancer cell. 2021; 0 (0). doi: 10.1016 / j.ccell.2021.02.016

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