Mechanisms help pancreatic cancer cells avert starvation

December 11, 2019

A new study reveals the mechanism that helps pancreatic cancer cells avoid starvation within dense tumors by hijacking a process that pulls nutrients in from their surroundings.

Led by researchers at NYU Grossman School of Medicine, the study explains how changes in the gene RAS -- known to encourage the abnormal growth seen in 90 percent of pancreatic cancer patients - also accelerate a process that supplies the building blocks required for that growth.

Called macropinocytosis, the process engulfs proteins and fats, which can be broken down into amino acids and metabolites used to build new proteins, DNA strands, and cell membranes. Cancer cells cannot multiply without these resources on hand, say the study authors.

Published online December 11 in the journal Nature, the new work identifies the key molecular steps that are marshalled by the cancer cells to boost micropinocytosis.

"We found a mechanism related to nutrient supply that we believe could be used to deny RAS mutant tumor cells of a key survival mechanism," says first study author Craig Ramirez, PhD, a postdoctoral fellow in the Department of Biochemistry and Molecular Pharmacology at NYU School of Medicine.

Theater of Operations

Specifically, the research team found that RAS mutations further activate the protein SLC4A7, which enables the protein called bicarbonate-dependent soluble adenylate cyclase to activate the enzyme protein kinase A. This in turn was found to change the location of a protein called v-ATPase.

By shifting where v-ATPase operates from the depths of cells to areas near their outer membranes, the reaction positions the enzyme to deliver the cholesterol needed by RAC1 to attach to cell membranes, the researchers say. Build-up of v-ATPase near outer membranes, and the related positioning of Rac1, enable membranes to temporarily bulge, roll over on themselves, and form nutrient-engulfing pockets (vesicles) during macropinocytosis.

In cell culture studies, treatment of mutant RAS cells with the SLC4 family inhibitor S0859 led to a significant reduction in RAS-dependent v- ATPase localization to outer membranes, as well as to the inhibition of micropinocytosis.

Furthermore, analysis of molecular data from human pancreatic ductal adenocarcinoma (PDAC) tissue revealed that the gene for SLC4A7 is expressed four-fold higher in tumors than in normal nearby pancreatic tissue.

The study team also showed that silencing the gene for SLC4A7 in pancreatic cancer cells slowed down or shrunk tumors in mice. After 14 days, 62 percent of tumors with silenced SLC4A7 showed reduced growth in mice compared with tumors with the active gene, and 31 percent of tumors showed shrinkage.

"We are now searching for drug candidates that might inhibit the action of SLC4A7 or v-ATPase as potential future treatments that block macropinocytosis," says study senior author Dafna Bar-Sagi, PhD, senior vice president, vice dean for science, and chief scientific officer at NYU Langone Health. "Both of these proteins are in principle good targets because they're linked to cancer growth and operate near the cancer cell surfaces, where a drug delivered through the bloodstream could reach them."
-end-
Along with Ramirez and Bar-Sagi, authors of the study in the Department of Biochemistry and Molecular Pharmacology at NYU Grossman School of Medicine were Andrew Hauser and Emily Vucic.

This work was supported by a grant from The Lustgarten Foundation, a Canadian Institutes of Health Research Fellowship (146792), and by National Institutes of Health grants CA210263, CA055360, T32 GM007238, and T32CA009161.

NYU Langone Health / NYU School of Medicine

Related Cancer Cells Articles from Brightsurf:

Cancer researchers train white blood cells to attacks tumor cells
Scientists at the National Center for Tumor Diseases Dresden (NCT/UCC) and Dresden University Medicine, together with an international team of researchers, were able to demonstrate that certain white blood cells, so-called neutrophil granulocytes, can potentially - after completing a special training program -- be utilized for the treatment of tumors.

New way to target some rapidly dividing cancer cells, leaving healthy cells unharmed
Scientists at Johns Hopkins Medicine and the University of Oxford say they have found a new way to kill some multiplying human breast cancer cells by selectively attacking the core of their cell division machinery.

Breast cancer cells use message-carrying vesicles to send oncogenic stimuli to normal cells
According to a Wistar study, breast cancer cells starved for oxygen send out messages that induce oncogenic changes in surrounding normal epithelial cells.

Breast cancer cells turn killer immune cells into allies
Researchers at Johns Hopkins University School of Medicine have discovered that breast cancer cells can alter the function of immune cells known as Natural killer (NK) cells so that instead of killing the cancer cells, they facilitate their spread to other parts of the body.

Breast cancer cells can reprogram immune cells to assist in metastasis
Johns Hopkins Kimmel Cancer Center investigators report they have uncovered a new mechanism by which invasive breast cancer cells evade the immune system to metastasize, or spread, to other areas of the body.

Engineered immune cells recognize, attack human and mouse solid-tumor cancer cells
CAR-T therapy has been used successfully in patients with blood cancers such as lymphoma and leukemia.

Drug that keeps surface receptors on cancer cells makes them more visible to immune cells
A drug that is already clinically available for the treatment of nausea and psychosis, called prochlorperazine (PCZ), inhibits the internalization of receptors on the surface of tumor cells, thereby increasing the ability of anticancer antibodies to bind to the receptors and mount more effective immune responses.

Engineered bone marrow cells slow growth of prostate and pancreatic cancer cells
In experiments with mice, researchers at the Johns Hopkins Kimmel Cancer Center say they have slowed the growth of transplanted human prostate and pancreatic cancer cells by introducing bone marrow cells with a specific gene deletion to induce a novel immune response.

First phase i clinical trial of CRISPR-edited cells for cancer shows cells safe and durable
Following the first US test of CRISPR gene editing in patients with advanced cancer, researchers report these patients experienced no negative side effects and that the engineered T cells persisted in their bodies -- for months.

Zika virus' key into brain cells ID'd, leveraged to block infection and kill cancer cells
Two different UC San Diego research teams identified the same molecule -- αvβ5 integrin -- as Zika virus' key to brain cell entry.

Read More: Cancer Cells News and Cancer Cells Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.