Episodio 21: Metabolic and genetic alterations in disease

00:00:00: Welcome to another episode of Ph.D.

00:00:09: Dibinem, Beyond the Lab!

00:00:11: Today we'll explore the fascinating world of metabolic and genetic alterations in disease.

00:00:17: Let's begin!

00:00:21: Cellular metabolism is a foundation for life.

00:00:24: It fuels our cells, regulates their growth And allows them respond to environmental changes.

00:00:31: When metabolic pathways are tightly regulated, they sustain health and cellular balance.

00:00:37: However when these processes become disregulated often in connection with genetic alterations the consequences can be profound In cancer for tumor cells frequently harbor gene mutations that drive metabolic reprogramming enabling rapid growth and survival.

00:00:56: But these alterations are not limited to oncology.

00:01:00: Growing evidence shows that changes in gene expression and metabolic functions also play a crucial role in many other diseases, including neurological disorders.

00:01:11: In this episode we will examine the role of several metabolism and genetic alterations in disease from different perspectives offering an overlook on how metabolic and genetic reprogramming shapes human health.

00:01:26: Okay, let's start.

00:01:31: Hello everyone!

00:01:33: I'm Serena Mazzone and i would talk about cellular metabolism.

00:01:40: I won't focus on neurodegenerative disease because cellular metabolism plays a key role.

00:01:48: Because neurons are high energy demanding cells and they're extremely sensitive to metabolic imbalance, in this context my research focuses on neuro-degenative diseases called laffaradisease.

00:02:04: Laffaradease is rare genetic neurodegenerative disorder with onset tp occur during adolescence.

00:02:12: It's characterized by progressive epilepsy, cognitive decline and over time an increasingly severe motor and psychological deterioration.

00:02:22: From

00:02:23: a biological perspective, what makes this disease particularly interesting?

00:02:28: It's the direct link to glycogen metabolism.

00:02:33: Glycogen is the storage form of glucose in cells mainly found in liver and muscles but also present in smaller amounts in the brain.

00:02:46: Under normal conditions, glycogen acts has a well-controlled energy reserve.

00:02:54: It's constantly made and broken down so it can provide energy without accumulating in a harmful way.

00:03:02: In Lafrae disease this regulatory system is disrupted And the diseases usually manifest healthy adolescents and death commonly occur within ten years of the symptom onset.

00:03:19: Laffara disease is caused by a loss-of-function.

00:03:22: mutations in APM to A or NHLRC one genes, which encode for protein lafarin and malin and the absence of aether protein leads to deformation of poorly branched hyperphosphory-related glycogen which precipitates, aggregates and accumulates in structures known as laforabodies.

00:03:55: These accumulations are particularly toxic for neurons and in the brain they build up of abnormal glycogen interferes with how cells normally work, disrupts communication between neurons.

00:04:14: In this way, lafroid disease clearly shows how a problem in the basic metabolic process can have severe consequences for their nervous system.

00:04:30: Behind

00:04:31: the biological aspects one of the most dramatic features of Lafroid Disease involves its cognitive and psychological consequences, which appear early and progressively worsen over the course of disease.

00:04:49: Patients gradually develop cognitive impairments that often begin with learning difficulties and deficits in attention and executive function.

00:05:01: has the disease progresses, visospatial deficit and memory impairments emerge leading to global cognitive deterioration.

00:05:10: This cognitive decline is closely linked.

00:05:17: Neurons, as posited to chronic metabolic stress due the accumulation of abnormal glycogen progressively lose their ability to sustain efficient synaptic activity with direct consequences for information processing and transmissions.

00:05:36: From a psychological perspective mood disorders anxiety depression specific phobias are frequently observed and these symptoms are not secondary reactions to the disease but an integral part of neurodegenerative process.

00:05:56: The gradual loss of autonomy, together with awareness and progressive nature of the disease has a profound impact not only on patients but also on families and caregivers making LaFra disease a condition within extremely significant human and social burden.

00:06:17: Studying cellular metabolism and in particular glycogen metabolism in lafora disease therefore means not only understanding the molecular mechanism underlying neurodegeneration but also paving their way for new therapeutic strategies aimed at slowing down or preventing disease progression.

00:06:43: Thank you Serena, for talking about this rare and not well known disease.

00:06:47: I'm Lucia Romagnoli

00:06:48: and i would like to take you a very different clinical setting, cancer.

00:06:53: In particular will introduce you to chronic maloid leukemia

00:06:57: Chronic

00:06:57: malaria leukemia, or CML is often described as one of the greatest success stories in modern oncology.

00:07:04: It was first-ever cancer to be clearly linked with a single genetic event.

00:07:09: that is DBCA Eboone Fusion gene That encodes a constitutively active tyrosine kinase which drives uncontrolled cell proliferation.

00:07:18: The development of Tyrosine Kinase inhibitors, or TKIs completely transformed this disease.

00:07:25: What was once fat leukemia become for most patients a manageable chronic condition?

00:07:31: Today many people with chronic maloedukemia can live four decades within your normal life

00:07:37: expectancy.

00:07:39: So problem solved,

00:07:40: right?!

00:07:41: Not quite!

00:07:42: Despite these extraordinary therapeutic success, CLML therapy is still largely one size fits all.

00:07:49: Risk stratification relies mostly on clinical parameters such as age, spleen size and platelet counts.

00:07:57: But this scores us very little about what is happening inside the leukaemic cells And clinically we see consequences of these limitations.

00:08:07: Most patients respond well to TKI's but some don't.

00:08:11: Some fail to achieve deep molecular responses and others progress towards advanced disease phases despite optimal therapy.

00:08:19: This tells us something very important, BCL Able-I is not the whole story.

00:08:25: My research group become interested in one particular player that is SET DII.

00:08:30: SETD II is a tumor suppressor gene encoding a high stone material transferase responsible for the addition of third material group to Lysin-XXVI of Eastern HIII obtaining so detrimental form of Eastern III at Lysing XXVI.

00:08:46: This epigenetic mark is crucial for proper transcription, RNA splicing, DNA repair and overall genetic and genomic stability.

00:08:54: In many cancers, Ceddi-II is lost through genetic mutations but in CML, CEDDI-II protein is actively degradated by the aprotosome leading to reduced level of histone.

00:09:05: III applies in thirty six in its remitillated form.

00:09:09: Importantly, sedidudeficiency is enriched in blast-phase CML where it correlates with genomic instability resistance to therapy and aggressive disease behavior.

00:09:21: The hypothesis of my research group that when sedidoof function is lost the chemic cells undergo a profound metabolic rewiring.

00:09:29: And now here's where metabolism comes back into picture.

00:09:33: We think that instead of balancing mitochondrial respiration and glycolysis, leochemic cells become strongly bioset toward glycolysis even when oxygen is available.

00:09:43: This shift is marked by the upregulation of key glycolic enzymes such as exokinases, phosphor fructokinase, and lactate dehydrogenase effectively pushing glucose through the glicolytic pathway at high speed.

00:09:59: This metabolic state provides fast energy and biosynthetic intermediates, supporting cell proliferation.

00:10:07: But at a cost.

00:10:08: high glycolytic flux leads to increased reactive oxygen species mitocondial stress and genomic instability features that favor cancer evolution and resistance to

00:10:18: therapy.

00:10:19: in this context metabolism is not just fooling with growth it's shaping the evolutionary trajectory of disease.

00:10:27: Our

00:10:27: experiments recently showed that when sedidue expression is restored, the metabolic advantages are lost.

00:10:34: This tells us that metabolic reprogramming in chronic myeloid leukemia is stable and functionally relevant.

00:10:42: CME may be clinically manageable but biologically it remains complex.

00:10:47: by integrating metabolism into risk stratification and therapeutic design we move beyond standardized treatment toward precision medicine targeting not only the oncogenic signaling, but also metabolic states that allows leukemia to survive.

00:11:07: Thank you Lucia for this interesting insight and hello everyone.

00:11:11: I'm Letitia Bukki And i will talk about lipid metabolism in cancer.

00:11:16: So, when we talk about tumor metabolism.

00:11:18: We usually think first about glucose glycolysis and the Warburg effect.

00:11:23: over the last few years it has become increasingly clear that lipids are also key players in cancer.

00:11:30: Lipid's not just an energy reserve.

00:11:34: they're building blocks of cellular membranes.

00:11:37: They regulate membrane fluidity They participate in cell signaling And influence processes such as proliferation migration and survival.

00:11:45: cells which grow rapidly and often live under stressful conditions deeply reprogram their lipid metabolism.

00:11:52: In particular, they increase the novel fatty acid synthesis lipid uptake from the extracellular environment.

00:12:05: This leads to membranes that are richer in saturated fatty acids and lipids, making cancer cells more resistant to oxidative stress.

00:12:14: And also to anti-cancer drugs.

00:12:17: In practical terms, Lipid metabolism becomes both a protective shield and a growth engine for tumor cells.

00:12:24: This metabolic reprogramming provides several advantages.

00:12:29: First it supports proliferation So every dividing cells needs to build new membranes and lipids are essential for that.

00:12:37: Second, it modulates cell signaling so some lipid acts as a real signal in molecules that activate oncogenic pathways promoting growth migration and invasiveness.

00:12:47: Third is increases survival.

00:12:49: More saturated membranes are less susceptible to lipid peroxidation making cancer cells more resistant to oxidative stress And therapy induce damage.

00:12:59: This is exactly why lipid metabolism is emerging as a therapeutic vulnerability.

00:13:05: Many cancer cells become highly dependent on these pathways, much more than normal cells.

00:13:11: If we narrow the focus to prostate cancer Lipid metabolism becomes even more intriguing.

00:13:17: The prostate is an organ with unique metabolic profile under physiological conditions and process.

00:13:23: cancer cells exploits and amplifies this features.

00:13:26: In prostate cancer we observe increased lipogenesis, greater use of fatty acids as an energy source and a strong dependence on specific lipid metabolic pathways.

00:13:38: When the tumor metastasizes to the bone this scenario becomes even more complex.

00:13:43: The bone microenvironment is rich in lipids largely due to the presence of bone marrow deposites which release fatty acids and other metabolize.

00:13:52: Metastatic cancer cells are not passive, they engage in a metabolic dialogue with the bone exploiting these lipids to sustain growth adaptation and resistance to therapy.

00:14:03: In this context metabolized such as citrate and fatty acids become central nodes connecting bone metabolism with tumor progression.

00:14:12: it is a clear example of how cancer.

00:14:18: In conclusion, deep metabolism is not a secondary aspect of cancer but one of its core pillars.

00:14:25: Understanding it means not only better explaining how tumors grow and survive but also identifying new therapeutic strategies especially in complex settings such as bone metastasis from prostate cancer.

00:14:36: This is also the perspective behind my own research, where I look at how lipid metabolism is shaped by the interaction between prostate cancer cells and the bone microenvironment.

00:14:46: And our metabolites like citrate and fatty acids contribute to disease progression.

00:14:57: Thank you Letitza for this introduction to Lipid Metabolism in Cancer.

00:15:02: Hi everyone, I'm Elizabeth Alieva and now would like to narrow the focus specifically to osteosarcoma And two one key aspect of its lipid remodeling The accumulation and function of lipid droplets especially in response to tumor acidity and oxidative stress.

00:15:20: Osteo sarcoma is the most prevalent bone cancer market.

00:15:23: by an aggressive clinical course with a high tendency to metastasize It grows within a metabolically challenging niche, it usually develops acidic areas as a result of higher glycolytic metabolism that increases the build-up of protons in the extracellular space.

00:15:42: This acidic environment is not just byproducts of altered metabolism – it profoundly challenges and shapes tumor cells' behavior.

00:15:51: When osteosarcoma cells are exposed to acidic conditions, one of the earliest and most striking adaptations is the accumulation of lipid droplets.

00:16:02: Lipid droplets are intracellular organelles composed by a hydrophobic core of neutral lipids mainly triglycerides and cholesterol esters surrounded by single phospholipid monolayer.

00:16:17: Embedded in this monolayer are specific proteins, including member of the perilipine family which regulates lipid storage and mobilization.

00:16:27: In many cancers, lipid droplets are often described as energy reservoirs that store fatty acids that can later be mobilized and oxidizing mitochondria to produce energy.

00:16:40: However, in osteosarcoma particularly under acidic conditions this rule appears to be very different and immediately protective.

00:16:50: Acidosis is tightly linked to oxidative stress.

00:16:54: Low pH conditions disrupt mitochondrial function and increase the production of reactive oxygen species.

00:17:01: This highly Reactive molecules can damage proteins, DNA and especially membrane lipids through lipid peroxidation.

00:17:11: If not controlled oxidative stress can trigger cell death.

00:17:15: Here is where lipid droplets become crucial.

00:17:18: By converting free fatty acids into neutral triglycerides and sequestering them inside the lipid droplet, osteosarcoma cells reduce the pool of free fatty acid available for peroxadation.

00:17:32: Free fatty acids, particularly polyunsaturated ones are highly susceptible to oxidative damage.

00:17:39: So when stored safely inside lipid droplets they're less exposed to reactive oxygen species.

00:17:46: When lipid droplet formation is experimentally impaired, we've seen that osteosarcoma cells exposed to acidic condition show increased oxidative damage and reduced survival.

00:18:00: So this demonstrates that lipid droplets accumulation is not a passive consequence of metabolic imbalance but an active survival mechanism that allows

00:18:09: cells

00:18:10: tolerate acid-induced oxidative stress.

00:18:14: In conclusion, lipid droplets in osteosarcoma should not be viewed simply as fat-store structures.

00:18:21: There are integral components of a stress adaptation program that enables tumor cells to survive in an acidic and oxidative microenvironment.

00:18:31: So targeting lipid droplet biogenesis or lip handling pathways represents a promising strategy in combating aggressive osteosacoma cells resistant to conventional therapies.

00:18:47: Okay, welcome back.

00:18:49: Thank you for the sharing.

00:18:50: I'm Jiayin Liu.

00:18:52: Today i will talk about TP-Fifty Three mutation from accelerating gelocal genesis and wildly consuming glucose to synthesizing large amount of lipids.

00:19:04: What is the master switch behind this series of cypress metabolic transformation?

00:19:11: Increasing evidence point two acute genetic evident The mutated of tp-fifty three.

00:19:17: It's not just a guiding guide force, it becomes an active shift energy of metabolic reprogramming.

00:19:26: The mutation flips a deep cellular switch rebuilding the cell inter-metabolic system to support rapid growth evidence in mule systems and recessed drugs.

00:19:39: Beyond changes we have previously discussed, TP-FVIII mutations drive several other key metabolic adaptations.

00:19:48: Let's walk through three of them.

00:19:50: The first one is glutamine addiction.

00:19:54: TP-FVIII mutation increased the production called GLS I and GLS II, which helps cells take in and break down glutamine an amino acid that becomes a white hopeful source.

00:20:11: This glutamine is fed into the TCA circle.

00:20:17: Here, it serves two critical roles.

00:20:20: On one side, provide carbon and nitrogen building blocks to make protein lipids and other molecules needed for growths.

00:20:29: on the other side It supplied raw materials to produce globesin a manager anti-oxidants that helps cancer cell cope with oxidative stress.

00:20:42: second about mitochondrial damage.

00:20:45: TP-FVIII mutation disrupts cell energy factory, the mitochondrial.

00:20:51: It leads to a key protein called T-farm which controls mitochondrial DNA.

00:20:58: Its interaction hampers production of proteins for energy generating weakens respiratory chain and

00:21:06: at same

00:21:06: time MUTATION P-FIVIII lost ability to protect against occidental damage.

00:21:13: The result is dysfunctional mitochondria.

00:21:16: for cells to rely on gelucolysis, a faster but less evidence way to make energy.

00:21:22: This shifts the risk levels of reaction-oxygen specie or ROS.

00:21:28: But cancer cells can't adapt.

00:21:31: The activate backup pathway like the PANTO pass fade pathway to produce anti-oxidant and manage the ROS When interesting thing Increase the hours can also act as a growth signal furthering driving proliferation.

00:21:49: Third, boosting DNA building blocks to replicate their DNA.

00:21:54: replicated cancer cells need huge supply of nucleotides.

00:22:00: TP-Fifteen-Three mutation means this damage by activating CAD A key estimate in pacmanting synthesize and boosting pure work production.

00:22:12: This ensures that the innumerable requirements for DNA building blocks during the un-controlling growths.

00:22:20: In summary, those changes are not just a passive breakdown in function.

00:22:25: TP-Fifteen-Three mutate take active control driving or metabolic reprogramming.

00:22:31: It serves energy supplied building blocks manage stress and turn on gross signal.

00:22:38: So those adaptations create a self-reinforcing cycle that secures the aggressive behavior of cancer.

00:22:46: This deep metabolic recrogramming is why tp-fifteen-three mutation tumors are so challenging to treat and while understanding these pathways opens up new opportunities for smarter, more targeted therapies.

00:23:07: And with that, we wrap up today's episode.

00:23:10: Thank you for joining us on this journey and stay tuned to more episodes of PHDBNM.

00:23:16: Beyond the Love!

00:23:18: Until next time...