Hippo Pathway Cancer Explained: Your Guide to a Key Discovery

Hey there. If you've landed here, maybe you're digging into something deeply personallike a diagnosis for you or someone you love. Or maybe you just heard the term "Hippo pathway" on a podcast and thought, "Wait what? Is this about animals?"

It's not about the hippo at the zoo. But what it is about? Could be one of the most important frontiers in cancer research today.

Let's be honest: cancer biology can feel like trying to read a foreign language. So instead of throwing jargon at you, I'll walk you through this like we're sitting at a quiet coffee shop, catching up over lattes. Because this isn't just lab talkit's real science with real hope, especially for tough cancers like mesothelioma.

And guess what? Scientists in Melbourne recently used advanced microscopy to watch the Hippo pathway in actionlike a live feed from inside a cancer cell. What they saw? A system running wild when it should be in control. But also, a system we might finally be able to fix.

Let's start at the beginning.

What Is It?

So, the Hippo pathway is a network of proteins in your cells that acts like a brake pedal for cell growth. When it's working properly, it steps on the brakes before cells divide too muchpreventing tumors before they start.

Think of it like a team of tiny traffic cops inside each cell. When everything's calm, they wave traffic through smoothly. But when there's dangera signal that something's wrongthey slam on the brakes.

The big players? Proteins called MST1/2, LATS1/2, and the two main "engines" of the system: YAP and TAZ.

When Hippo is "on," it tags YAP and TAZ with phosphates (a chemical signal), trapping them in the outer part of the cell where they can't do much. No damage done.

But when the pathway failswhen the brake failsYAP and TAZ slip into the nucleus, team up with TEAD proteins, and turn on genes that tell the cell: "Grow. Survive. Spread."

Suddenly, that traffic cop is asleep at the wheel. And cancer takes the wheel.

This system is ancientfound in fruit flies, mice, and yes, us. It's that important. And when it goes wrong, it's not just a small glitch. It's a full system override.

Why It Fails

So what flips the switch? Why does the Hippo pathway stop working in cancer?

Turns out, it's rarely just one broken part. It's like a car with multiple systems failing at onceelectrical, fuel, mechanical. Let's break down the main culprits.

Genetic Glitches

In many cancers, especially mesothelioma, the gene NF2 is lost or silenced. NF2 makes a protein called Merlin, which acts like a scaffold for the Hippo pathway. No Merlin? The signal can't get through. The brake fails. YAP goes rogue.

And it's not rare: about 40% of mesothelioma cases have this NF2 loss. Another 45% have mutations in LATS2, the kinase that's supposed to shut down YAP. So both the starter and the brake are broken.

There are also rare fusionslike YAP-TFE3 or TAZ-CAMTA1that literally fuse the gas pedal to the ignition. These drive cancers like epithelioid hemangioendothelioma. Not common, but powerful proof that YAP/TAZ aren't just passengersthey're drivers.

And here's something wild: in mouse models, deleting YAP stops tumors even when NF2 is gone. That's huge. It means YAP is the final messengerthe point where everything converges.

Environment Matters

But it's not just genes. Your body's environment can hijack this system too.

Stiff tissue? Like scarred lung tissue after asbestos exposure? That mechanical stress activates YAP. Low cell densitylike after an injury? YAP says, "Time to grow!" Hypoxia, or low oxygen? That shuts off LATS, unleashing TAZ.

Even your metabolism plays a role. High glucose levels trigger a process called O-GlcNAcylation, which stabilizes YAP so it doesn't get broken down. So yesyour blood sugar can quietly feed this cancer pathway.

It's wild to think that something as simple as tissue stiffness or oxygen levels can flip a molecular switch that leads to cancer. But it does.

It Talks to Others

Here's the kicker: Hippo doesn't work alone. It's deeply connected to other cancer pathways.

YAP teams up with Wnt/-catenin to help cancer cells act like stem cellsavoiding treatment and regenerating. It partners with TGF- to drive metastasis. In resistant lung cancers, YAP turns on PD-L1, helping tumors hide from the immune system.

And with KRAS or mTOR? YAP ramps up amino acid transport so fast-growing cells get the building blocks they crave.

This is why so many targeted therapies fail. You block one road, but cancer takes a detour through Hippo. That's also why targeting Hippo might be so powerfulit sits at the crossroads.

Protein	Role	Cancer Relevance
MST1/2	Start the kinase cascade	Mutated or silenced in some cancers
LATS1/2	Activate YAP/TAZ phosphorylation	Lost in mesothelioma, lung cancer
SAV1, MOB1	Adaptors help signal flow	Reduced in aggressive tumors
YAP & TAZ	Main effectors drive gene expression	Overactive in 70%+ solid tumors
TEAD	Partners with YAP/TAZ	Target of new drugs like VT3989
VGLL4	Competes with YAP for TEAD	Natural tumor suppressor

Hippo & Mesothelioma

If you're reading this because of mesothelioma, I want you to know: this topic matters. Deeply.

Mesothelioma is rare. Aggressive. Often tied to asbestos. And tragically, treatment options have gone nowhere fast for decades. Chemo helps some. Immunotherapy helps others. But many people run out of road.

And yethere's a glimmer: in nearly every mesothelioma case, the Hippo pathway is broken. NF2 loss. LATS mutations. YAP/TAZ running wild. It's not a side effect. It's central.

Which means, for the first time, we might have a real shot at a targeted therapy.

What's in the Pipeline?

There are actual drugs being tested right now. Not theoryreal clinical trials.

VT3989, for example, blocks TEAD palmitoylationa key step for YAP/TAZ to activate genes. Early results from the phase I trial show antitumor activity and good tolerability. Not a cure, but a signal. Hope.

IK-930, another TEAD inhibitor, is also in phase I for mesothelioma and other NF2-deficient tumors. IAG933 is focusing on the YAP/TAZ-TEAD interaction. And researchers are even looking at older drugs like verteporfina medication once used for eye conditionsthat can disrupt YAP-TEAD binding.

Then there's "dropwort," a natural plant extract that, in preclinical studies induces metabolic changes in mesothelioma cells by reactivating Hippo signaling. Nature, it turns out, might have been ahead of us all along.

Drug	Target	Stage	Tumor Type	Source
VT3989	TEAD palmitoylation	Phase I	Mesothelioma	NCT04665206
IK-930	TEAD palmitoylation	Phase I	Mesothelioma, NF2-deficient	NCT05228015
IAG933	YAP/TAZ-TEAD PPI	Phase I	Mesothelioma	NCT04857372
Verteporfin	YAP-TEAD interaction	Preclinical	Multiple, including mesothelioma	PMC study
Dropwort	Metabolic reprogramming	Preclinical	Mesothelioma	PMC10547939

This isn't science fiction. It's science in motion.

Hidden Powers

But it gets deeper. This pathway doesn't just control growth. It reprograms how cancer eats, breathes, and remembers itself.

Metabolic Mayhem

YAP doesn't just say "grow"it says "fuel up." It turns on genes like GLUT1 and HK2 to pull in more glucose. It boosts amino acid transporters so cells can make proteins faster. It even drives fatty acid oxidation and cholesterol production.

In liver cancer, for example, losing LATS2 leads to cholesterol buildupfeeding tumor growth.

Block YAP, and you don't just stop growth. You starve the tumor.

Epigenetic Hijack

And here's something even more fascinating: YAP changes the epigenomethe chemical tags that control which genes are on or off.

It helps silence RASSF1A, a tumor suppressor gene, through DNA methylation. It recruits TET1 to open up chromatin and activate growth genes. And microRNAs like miR-135b block proteins that would normally inhibit YAP.

So not only does YAP turn on bad genesit helps make sure they stay on. It's a self-reinforcing loop. Dangerous. But also, potentially breakable.

What's Ahead?

You might be asking: "Can we really target this?"

Yesbut carefully.

YAP and TAZ aren't all bad. They're vital for wound healing, liver regeneration, even gut repair. Block them completely, and you might slow down healing. TEAD proteins are everywherein the heart, brain, skin. Toxicity is a real concern.

And not all cancers react the same. In a few rare cases, YAP actually suppresses tumors. Context is everything.

So researchers are being smart. They're not going for a sledgehammer. They're crafting precision tools: drugs that block YAP-TEAD binding, that stop TEAD palmitoylation, or that silence YAP at the RNA level with antisense drugs like ION537.

Natural compoundsursolic acid from apples, liquiritigenin from licorice, curcumin derivativesare also being studied for their ability to gently reactivate the Hippo brake.

Is this a magic bullet? No. But it's a breakthrough in understanding.

Hope Realistic

Let's be honest: we're not handing out cures tomorrow.

Most of these drugs are in phase I trialstesting safety, not effectiveness. A phase III trial, if all goes well, is five to seven years away.

But for mesothelioma patients, this could be the first targeted therapy in decades. That's not small.

If you or a loved one is facing a diagnosis with Hippo pathway dysfunctionespecially NF2 loss or mesotheliomahere's something practical: ask your oncologist, "Is there a clinical trial targeting YAP, TAZ, or TEAD?"

Trials like VT3989 or IK-930 might be available. You don't have to go through this blindly. There's movement. There's momentum.

We're not there yet.

But we're moving.

And sometimes? That's everything.

If you've made it this far, I want to say: thank you. This topic is heavy. But you're not alone. Scientists, doctors, patients, familiesthey're all in this together, pushing forward, one discovery at a time.

And if you have questions, or just want to share your story, I'm here. Because knowledge shared? That's power. And healing. And hope.

Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always consult with a healthcare professional before starting any new treatment regimen.