Episode Transcript
[00:00:00] Speaker A: Foreign.
Welcome to Base by Bass, the papercast that brings genomics to you wherever you are. Thanks for listening and don't forget to follow and rate us in your podcast app.
So today we are diving deep into a really fundamental question in cancer biology.
Why doesn't every single cell with a cancer driving mutation actually become a tumor?
[00:00:34] Speaker B: It's a huge puzzle, right? I mean, the simple answer is that our tissues have these incredible, robust ways of protecting themselves.
[00:00:40] Speaker A: And nowhere is that protection and the paradox that comes with it more confusing than in the liver.
We know that these oncogenic mutations, you know, the main molecular triggers for cancer, are actually pretty common in many tissues, but they don't immediately cause disease.
[00:00:55] Speaker B: And in the liver, the entire organ is structured by this massive cell signaling highway, the WNT or Pikmin pathway.
[00:01:02] Speaker A: Right. And that pathway controls what's called zonation. It's basically an internal map that tells all the cells where they are and what their specific job is.
[00:01:10] Speaker B: And here is the monumental paradox that researchers have been really struggling with for years. WNNT signaling is absolutely essential for a healthy liver cell to mature, to do its job.
[00:01:23] Speaker A: Okay.
[00:01:24] Speaker B: And yet it's also one of the most prominent drivers of hepatocellular carcinoma, or HCC.
[00:01:29] Speaker A: It's the ultimate biological catch 22. I mean, how can the exact same signal that makes a liver cell grow up and do its job also be the thing that pushes it toward cancer?
[00:01:40] Speaker B: Exactly. And if we can figure out what that pre cancerous cell has to hijack to break free, we might find new ways to stop liver cancer before it even gets started.
[00:01:49] Speaker A: And this deep dive really shows that this highly specialized geography of the liver acts as a critical protective shield that has to be actively dismantled for cancer to thrive.
[00:01:59] Speaker B: It's such complex work. And, you know, we really have to celebrate the collaborative research that went into this. Today we're focusing on findings led by Alexander Raven and Owen J. Sansom from the Cancer Research UK Scotland Institute, along with colleagues from Harvard and other institutions all over the world. Their work published in Nature, it really redefines how we think about these WNT driven tumors.
[00:02:20] Speaker A: Okay, so let's start by mapping out the terrain.
[00:02:22] Speaker B: Yeah. Yeah.
[00:02:23] Speaker A: You can't understand the liver paradox without first understanding hepatic zonation. Right. Think of the liver lobule as a tiny city block functionally divided along an axis that runs from the portal node to the central vein.
[00:02:35] Speaker B: Exactly. And this little block is split into three functional zones. You have zone one, the periportal area. That's where the blood comes in. Then you have zone three, the pericentral area Right around the central vein. And zone two is just that transitional bit in the middle.
[00:02:49] Speaker A: And wnt signaling is what creates this whole order in the first place.
[00:02:53] Speaker B: That's right. In a healthy liver, the wnt pathway is most active near that central vein in zone three, and it drops off as you move away.
[00:03:01] Speaker A: So the active molecule, nuclear catenin Is basically pinned into zone three almost entirely.
[00:03:06] Speaker B: And this really high wnt activity Is what drives that final maturation step. It compartmentalizes all the gene expression.
[00:03:13] Speaker A: Can you give us an example? Like, What's a classic Zone 3 job?
[00:03:16] Speaker B: The textbook example is the gene glul.
It's involved in ammonia detoxification.
So when a hepatocyte in zone 3 turns on glul and other markers like LGR5, it's terminally differentiated.
[00:03:29] Speaker A: So it's mature, it's doing its job, and it's quiet, not dividing much precisely.
[00:03:34] Speaker B: It's settled down.
[00:03:35] Speaker A: Okay, so now let's bring in the cancer. HCC frequently has mutations in the gene CTNNB1, which is the gene that encodes ocacatinin.
[00:03:43] Speaker B: Right. But the researchers noticed this critical pattern. The mutations you see in human hcc are almost always these specific point mutations, Usually in a place called ex.
[00:03:54] Speaker A: The first major clue.
[00:03:55] Speaker B: It's a huge clue because these azon pre mutations Give you a moderate sort of specific level of wnt activation. They're selected for over other mutations, like ones that just delete the APC gene.
[00:04:05] Speaker A: Which would give you what? Just a massive out of control wnt signal.
[00:04:10] Speaker B: Catastrophically high total overdrive.
[00:04:12] Speaker A: So cancer seems to prefer a dimmer switch, not just flipping the lights all the way on. Yeah, that kind of goes against the idea that more oncogene always equals more cancer.
[00:04:20] Speaker B: It totally does. It hints that there's an upper limit, A ceiling to wnt signaling. If you push it too hard, you just force the cell into that mature, non dividing zone 3 state.
[00:04:32] Speaker A: So too much wnt is actually protective?
[00:04:34] Speaker B: In a way, yes. It drives maturity, not proliferation.
[00:04:38] Speaker A: And to make things even more dangerous for the patient, this bitkentinin mutation, it's actually pretty weak on its own in mice. The real threat is when it cooperates with another oncogene.
[00:04:48] Speaker B: And we see that in people. A staggering 81% of these CTNNB1 mutated tumors also have extra copies of MYC. So to get that aggressive growth, WNT needs a copilot.
[00:04:59] Speaker A: Okay, so to figure out how this all Happens how a single mutant cell escapes its environment. The researchers used these really clever mosaic mouse models.
[00:05:07] Speaker B: Yeah, this part is brilliant. They sporadically activated the CTNMB1 and MyC genes at a very low density. So you just get these rare scattered mutant cells.
[00:05:15] Speaker A: Which lets you watch the very beginning of the story.
[00:05:17] Speaker B: Exactly. You can see which cells manage which ones just fizzle out.
[00:05:21] Speaker A: And to compare the successful cells to their neighbors that failed, they needed some really advanced tools.
[00:05:26] Speaker B: Oh, yeah. This is where the methodology gets really powerful. They used spatial transcriptomics, which is like.
[00:05:33] Speaker A: Having a microscope that can also read the genetic fingerprint of every cell it sees. Right.
[00:05:37] Speaker B: Purr fect analogy. It let them compare the gene expression of tiny little precancerous lesions. We're talking clusters of just five or more cells Right next to the single dormant mutant cells. It answers the question, what's different right here that let this one grow?
[00:05:52] Speaker A: But they went even deeper than just which genes were on.
[00:05:56] Speaker B: They used ribosome profiling, which is a functional test. It doesn't just tell you what instructions the cell has. It tells you which instructions are actively being fed into the protein factories. The ribosomes. Right.
[00:06:07] Speaker A: Now, the oncogenic translate tone.
[00:06:09] Speaker B: Yes. It's a snapshot of what the cell is actually building. It's the difference between having a blueprint and actually running the assembly line.
[00:06:16] Speaker A: And then they confir thing with functional tests Using drugs like rapamycin, which blocks a major growth regulator called mtor.
[00:06:24] Speaker B: They didn't just find correlations. They proved cause and effect.
[00:06:28] Speaker A: Okay, so let's get to the core discovery, the big insight. The highly differentiated Zone 3 acts as an ultimate tumor suppressor.
[00:06:36] Speaker B: That's the headline. When they tracked those CTNNB1MYC mutant cells, they found that the zone 3 hepatocytes, the ones with those GLUL and LGR5 markers, were almost completely refractory to tumors.
They were safe. Their mature differentiated state Is like a powerful bright on cell division. And it's a direct consequence of that really high wnt signal.
[00:07:00] Speaker A: So if differentiation is the shield, Then the cancer cell's first mission has to be escaping it.
[00:07:06] Speaker B: This is where it all comes together. That just right. Wnt signal is a survival strategy.
[00:07:10] Speaker A: What did they see in the cells that actually started to grow?
[00:07:13] Speaker B: They saw that the successful mutant souls, the ones that progressed into little lesions, Were characterized by a significantly reduced wnt pathway innovation. Lower nuclear catenin.
[00:07:24] Speaker A: Wait, hold on. Let me make sure I'm getting this. The cells that failed to become tumors had more of the oncogenic WNT signal. While the cells that actually started a tumor had to dial the WNT signal down.
[00:07:34] Speaker B: Precisely. They are deliberately dampening that differentiating signal just enough to avoid that protective zone 3 fate. The mutation gives them a growth advantage for sure, but they have to stop it from pushing them over the cliff into maturity.
[00:07:49] Speaker A: So they're literally running away from the protective high WNT zone 3 identity. Where do they go? What do they use for growth instead?
[00:07:55] Speaker B: That's what they found. By shedding that high WNT identity, they switched on pathways linked to active MAPK signaling, A major proliferation switch, and that massive protein synthesis program. The oncogenic translatome.
[00:08:08] Speaker A: And they weren't inventing a new way to grow, were they? They were hijacking something that was already there.
[00:08:13] Speaker B: Exactly. They were co opting the exact same molecular axis that's used for normal everyday growth in the mid lobule in z, the IGFBP2 MTOR cyclin D1 axis.
[00:08:24] Speaker A: And MTOR is that master regulator of cell growth you mentioned. It's like the central gas pedal.
[00:08:29] Speaker B: It is. And they showed that IGFBP2, which helps control this whole process, was way upregulated in both their mouse tumors and in human HCC samples with the same WNT NYC mutations. It's the new vulnerability.
[00:08:41] Speaker A: So the B catenin mutation unlocks the door, but it's the NYC CO pilot and hijacking this IG FBP2 mtor engine that actually lets them hit the gas.
[00:08:50] Speaker B: Yes.
And the MAPK signaling pathway is what helps them tear down the shield. They proved this using BRFV 600e, which is a really powerful MAKK activator.
[00:09:00] Speaker A: So if you combine that BRAF mutation with the WNT mutation, Specifically in Those normally safe zone 3 cells, what happens?
[00:09:08] Speaker B: Rapid and dramatic tumor genesis. The MAQK activation was like an escape hatch. It just switched the cell's identity away from the protective zone 3 markers like GLUL and forced it toward proliferative markers you'd see in zone one or two.
[00:09:21] Speaker A: So MAK dismantling the liver's architecture?
[00:09:24] Speaker B: It is. And the ribosome profiling timeline backs this all up perfectly. At day four, the CTNB1 MYC combo drives this huge burst of protein synthesis for division. But by day 10, that whole program is shut down as the cells mature into their Zone 3 fate.
[00:09:39] Speaker A: So the successful cancer cells are the ones that divide before that 10 day deadline hits.
[00:09:42] Speaker B: They have to escape before they get locked down. That's why the just right WNT signal from those exon3 mutations is so critical, it's just enough to start the process, but not so much that they commit suicide by maturing too quickly.
[00:09:55] Speaker A: This is a huge shift in thinking, and it offers real hope for treatment. Because W and a itself is famously very difficult to target with drugs.
[00:10:04] Speaker B: Exactly. But now we know the vulnerabilities that the tumor relies on after the wnt mutation. We're not just looking at the starting gun anymore.
[00:10:12] Speaker A: And what did the drug test show Targeting those downstream pathways?
[00:10:15] Speaker B: It is profound.
Briefly, inhibiting mtor with rapamycin Resulted in a huge reduction in tumor number and extended survival in the mice. You're hitting the gas pedal that the cancer cell hijacked.
[00:10:26] Speaker A: And what about the MPK pathway? Could they target that too?
[00:10:29] Speaker B: Yep. In the tumors driven by the wnt and brf combination, Inhibiting braf with a drug called dobrofenib successfully suppress tumor growth. It confirms that you can either interrupt the identity switch or you can interrupt the proliferative engine. Both are viable strategies.
[00:10:44] Speaker A: So this research really opens up a new, highly druggable target space, maybe for stopping early liver cancer or even for prevention in high risk patients.
[00:10:53] Speaker B: Absolutely. It moves the focus away from just the mutation itself and towards the entire environmental context that allows that mutation to actually cause a problem.
[00:11:01] Speaker A: Okay, so what's the big take home message here for our overall understanding of cancer? What does this all mean?
[00:11:06] Speaker B: At the end of the day, it means liver zonation acts as this incredibly powerful physical barrier against wnt driven cancer.
[00:11:13] Speaker A: And for a cell with a beta mutation progress, it has to pull off a great escape.
[00:11:18] Speaker B: It has to. It must dampen that differentiating WNT signal to avoid the zone 3 fate. And at the same time co opt the zone 2 specific IGFBP2 mtor growth pathway. That's what lets it fire up the machinery to divide before the liver's protective architecture forces it into retirement.
[00:11:36] Speaker A: Which raises a really important question for all of us to think about.
What does this insight that tumor cells co opt these localized homeostatic growth mechanisms to evade their specialized job.
What does that mean for how we understand cancer starting in other structured organs like the gut or the kidney? This episode was based on an open access article under the CCBY 4.0 license. You can find a direct link to the paper and the license in our episode description. If you enjoyed this, follow or subscribe in your podcast app and leave a five star rating.
If you'd like to support our work, use the donation link in the description now. Stay with us for an original track created especially for this episode and inspired by the article you've just heard about. Thanks for listening and join us next time as we explore more science Base by Bass.
[00:12:54] Speaker C: Three rings In a quiet field of light Slow tides run running from the dark too bright signals falling like a coated rain Drawing borders round a living vein Some lines hold a storm outside Some lines let the fire inside when the current bends the guide you can feel the switch collide where souls decide who breaks, who stays when hidden wise we ride the waves turn up the poles the sails ignite or lock the gate and hold the night on the edge of loss and light where zones decide the spark to rise.
New voices riding on the ancient wave Second engines looking for a place to crave Silent helpers feed the growing flame Translation turning whispers into aim turn the dial on every side make sparks across the line Mentor drums begin to climb as the rhythm steals the time where songs decide to break who stays when hidden wise Rewrite the waves turn up the poles the sails ignite or lock the gate and hold the night on the edge of loss and light where zones descend Rise in a wall Singles fall back to a softer shore and the map remembers what it's for when zones decide who breaks, who stays we learn the patterns, change the ways Turn down the fire, restore the light let's leave sleeping field Survive the night on the fragile borderline where songs descend.
We rewrite the sound.
