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Susanna F. Greer: Pancreatic ductal adenocarcinoma – The party crasher
May 8, 2024, 18:00

Susanna F. Greer: Pancreatic ductal adenocarcinoma – The party crasher

Susanna F. Greer, Chief Scientific Officer at the V Foundation, published the following newsletter on LinkedIn:

“Imagine you’re at a big party where most people seem likeable and fun, but there’s this one guest who goes unnoticed, hangs out in dark corners, and suddenly out of nowhere, causes complete chaos. That’s pancreatic ductal adenocarcinoma (PDA), a type of pancreatic cancer with a reputation for being sneaky and very hard to treat. PDA has a low survival rate, partly because it tends to be diagnosed late when the cancer already spread to other parts of the body. It’s like a terrible party crasher who blends in until it’s too late to stop them.

Researchers know that an ‘accomplice party crasher’ in Pancreatic ductal adenocarcinoma or PDA is a gene called KRAS, which is mutated in over 90% of cases. Think of KRAS as the lead of a rebellious gang of genes. Other members of this gang include genes called CDKN2A, TP53, and SMAD4/DPC4-genes often involved in regulating cell growth and death. When they go rogue, they help PDA cancer cells grow out of control and spread.

To understand more about what makes PDA so good at spreading, The V Foundation grantee Dr. Christine Chio and colleagues Columbia University Irving Medical Center are looking deeper into these DNA and RNA ‘playbooks’ that cancer cells use. These playbooks are like blueprints and instructions for building and operating cells. But we also need to understand the ‘protein factory’ because proteins are the actual workers and machines that make cells function. Ie, we know the party crashers involved, but we don’t know the disguises they are wearing, how many are showing up, or when they are going to arrive.

One tool Dr. Chio and colleagues use is a technique called ‘dynamic stable-isotope labeling by amino acids in cell culture’ or dSILAC. It’s a VERY long name for a relatively simple technique for adding invisible trackers to these protein-building materials to see how quickly the proteins are made and, in turn used up, in cells. The researchers are also using organoids, (which are incredible!), like mini-tumors grown in labs. The team takes cells from PDA tumors and grows them into organoids to study their behavior.

I love this paper for a lot of reasons, some of which are the cool techniques the researchers use. From their organoids and dSILAC, Dr. Chio and team found that metastatic PDA tumors (the ones that have spread) have a faster protein turnover rate than primary tumors (the original ones). This means their protein factories run faster, turning over proteins at a higher rate. Think of it as a factory working overtime to keep up with demand. This rapid turnover is particularly noticeable in mitochondrial proteins, which are essential for energy production in cells.

The researchers found that the mitochondrial proteins have a shorter lifespan in metastatic tumors, suggesting they are getting replaced more often. This could be because metastatic tumors need more energy to spread and grow. The finding that metastatic PDA has a faster protein turnover rate, especially in mitochondria, offers new insights into why this cancer spreads so aggressively. Their findings help identify targets for future treatments by focusing on the mechanisms that control protein stability and mitochondrial function. These are incredible findings! Congratulations to all involved and keep up the great progress-cancer patients need you.

Read Dr. Choi’s paper here, and find her lab here.”

Source: Susanna F. Greer/LinkedIn