Flash from the Lab 2023

Eureka Discovery!

“It’s the most amazing thing to see something for the first time – baby’s first steps, sunrise on the water. And then there’s being the first person on the planet to see something for the first time – staring in a microscope. When that happens, the caffeine-fueled chronic sleep deprivation is all worth it.” -Dr. Bill Stanford

Recent exciting data shows that Bill’s team may have discovered the source of the LAM cell. This is a question that researchers have been asking for decades.

• Myelin is a vital insulating layer around the peripheral nerves of the lungs.
• LAM nodules are full of disorganized myelin.
• In healthy lungs, myelin is in neat bundles of nerves but in LAM patients it is a disorganized mess.
• Peripheral nerve cells may thus be the source of LAM cells!
• One of the components of myelin is encoded on the X chromosome, which could explain why only women get LAM.
• Bill’s team is engineering mice to test the contribution of peripheral nerve cells to LAM.

And in other breaking news….

Breakthrough!

We have grown LAM cells directly from a lung.

The next critical step is to see if we can transplant the cells into mice and test anti-LAM drugs!

A New Model for LAM’s Associated Kidney Disease

LAM patients often have abnormal kidney lesions that share many features with LAM lung nodules. We used our stem cell models to grow TSC kidney tissues in a dish.

LAM cells need SPAG4:

We identified SPAG4 as a potential key protein in LAM and its associated kidney disease.

We produced an RNA inhibitor of SPAG4, which shuts down our stem cell model of LAM: some cells die, others stop growing. Amazingly, blocking SPAG4 in normal cells seems to do absolutely nothing to them. Thus, our SPAG4 inhibitor should have few side effects. No spaghetti for you LAM cells!

Got to TWIST1 and Shout!

We identified TWIST1 as a cancer gene found in LAM cells and discovered two types of drugs that target TWIST1.

Both are effective in killing our stem cell models of LAM by themselves and in combination with Sirolimus (also known as Rapamycin), the only drug currently approved to treat LAM.

HDAC Inhibitors March On!

Using Dr. Molly Shoichet’s lung-like hydrogel, we discovered drugs called HDAC inhibitors that kill LAM cells and prevent LAM cells from invading tissues.

Two of these are FDA and Health Canada approved anti-cancer drugs called Vorinostat and Pracinostat. Molly’s team has now validated these results using more LAM cell models.

What’s the Role of the Immune System in LAM Progression?

Molly’s lab has been investigating the role of T-cells in LAM by co-culturing the iPSC-derived cells from Bill’s lab with T-cells isolated from donated human blood of women.

By comparing LAM patient tissue collected over the past 20 years at UHN with healthy tissue, they have identified some key immune markers that we will investigate in their co-culture systems.

What’s the Role of the Vascular System in LAM Progression?

Molly’s lab has also begun to investigate the co-culture of endothelial and LAM cells in terms of invasion – something that can only be achieved using 3-dimensional culture. Their 3D hydrogels provide a great opportunity to better understand the interplay between these two cell types.