Weekly reads 17/2/25

Week 4: This week, I focused on some pretty nifty studies in cancer research, each shedding light on different mechanisms that drive tumor progression and therapy resistance. From oncofetal reprogramming in colorectal cancer to the surprising role of electrical activity in small-cell lung cancer, these papers highlight the complexity and adaptability of cancer cells. The overarching theme that emerged was the concept of cellular plasticity—how cancer cells shift identities, evade differentiation constraints, and rewire their interactions with the surrounding environment to sustain growth. Whether through neuronal reprogramming in pancreatic cancer, stress-adaptive pathways in lung adenocarcinoma, or hijacked regenerative programs in mutant alveolar stem cells, these findings challenge traditional views of cancer progression and open up new avenues for therapeutic intervention.

Preprints/articles that i managed to read this week

Oncofetal Reprogramming Fuels Phenotypic Plasticity in WNT-Driven Colorectal Cancer

Mzoughi et al. (2025). Oncofetal reprogramming drives phenotypic plasticity in WNT-dependent colorectal cancer. Nature Genetics. https://doi.org/10.1038/s41588-024-02058-1​

The paper in one sentence

Colorectal cancer (CRC) cells evade targeted therapies by undergoing oncofetal (OnF) reprogramming, a process that expands their phenotypic plasticity and enables resistance to standard treatments.

Summary

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with WNT-driven CRC particularly resistant to treatment. This study identifies oncofetal (OnF) reprogramming as a key mechanism driving phenotypic plasticity in CRC cells, enabling them to transition between different cellular states and evade therapy.

Through transcriptomic and chromatin accessibility analysis, the authors show that mutant intestinal stem cells deviate from their normal identity after APC loss-of-function (LoF), entering a dynamic OnF state regulated by YAP and AP-1 transcription factors. This OnF state disrupts lineage fidelity, allowing cells to adopt features of fetal-like progenitors. Notably, tumors enriched for the OnF state show increased resistance to chemotherapy (FOLFIRI), suggesting that OnF reprogramming plays a critical role in therapy tolerance.

The study further reveals that retinoid X receptor (RXR) functions as a gatekeeper of OnF reprogramming, and its deregulation after APC loss creates a persistent OnF ‘memory’, reinforcing the plastic potential of tumor cells.

Personal highlights

• Oncofetal (OnF) reprogramming expands phenotypic plasticity: WNT-driven CRC cells lose stable lineage identity and gain a dynamic, fetal-like cellular state, increasing intratumoral heterogeneity.

• YAP and AP-1 act as core transcriptional regulators: YAP activation triggers OnF reprogramming, while AP-1 hyperactivation further enhances phenotypic flexibility in tumor cells.

• OnF state weakens the dependence on LGR5+ cancer stem cells: tumors with strong OnF signatures do not require LGR5+ stem cells for maintenance, indicating a shift away from a strictly hierarchical cancer stem cell model.

• Retinoid X receptor (RXR) suppresses OnF plasticity under normal conditions: RXR normally limits OnF reprogramming, but its deregulation after APC loss leads to a sustained OnF-like state that promotes cellular transitions.

• OnF cells maintain WNT activity independently of LGR5+ stem cells: unlike conventional cancer stem cells, OnF cells retain high WNT activity but do not express LGR5, indicating an alternative mechanism for WNT pathway activation in CRC progression.

Why should we care?

This study challenges the conventional view of cancer stem cell hierarchies by showing that colorectal cancer cells can dynamically shift their identity, making them more adaptable to therapy. The discovery that OnF reprogramming sustains tumor growth even when LGR5+ cells are depleted provides a major insight into why current treatments often fail. By identifying YAP, AP-1, and RXR as key regulators, the research opens up new therapeutic opportunities: targeting OnF reprogramming could enhance the effectiveness of existing treatments and reduce the likelihood of cancer recurrence.

Intrinsic electrical activity drives small-cell lung cancer progression

Peinado, P., Staż, M., Ballabio, C., et al. (2025). Intrinsic electrical activity drives small-cell lung cancer progression. Nature. https://doi.org/10.1038/s41586-024-08575-7

The paper in one sentence

This study reveals that intrinsic electrical activity in neuroendocrine cells drives the progression of small-cell lung cancer (SCLC)

Summary

The research explores the role of electrical activity in small-cell lung cancer (SCLC), a highly aggressive form of cancer. The study found that neuroendocrine (NE) cells within SCLC tumors are electrically active and capable of firing action potentials, unlike non-NE cells. This electrical activity increases the metabolic demands of NE cells, making them reliant on oxidative phosphorylation (OXPHOS) rather than glycolysis, which is typical for most cancer cells. The study also identified a metabolic support system where non-NE cells provide lactate to NE cells, akin to the astrocyte-neuron metabolite shuttle in the brain. This metabolic cooperation sustains the high ATP demand required for the electrical activity of NE cells, promoting their tumorigenic and metastatic potential. The findings suggest that targeting the electrical activity and metabolic vulnerabilities of NE cells could offer new therapeutic strategies for SCLC.

Personal highlights

• Electrical activity in NE cells: The study demonstrates that NE cells in SCLC are electrically active and capable of firing action potentials, which directly promotes cancer progression.

• Metabolic dependency: NE cells in SCLC exhibit a unique metabolic dependency on OXPHOS due to their high ATP demand, contrasting with the glycolytic metabolism typical of most cancer cells.

• Metabolic cooperation: Non-NE cells metabolically support NE cells by providing lactate, similar to the astrocyte-neuron lactate shuttle in the brain, which helps sustain the electrical activity of NE cells.

• Tumorigenic potential: The electrical activity of NE cells enhances their long-term tumorigenic and metastatic potential, highlighting a novel mechanism driving SCLC aggressiveness.

Why should we care?

This research provides groundbreaking insights into the mechanisms driving the progression of small-cell lung cancer, one of the most aggressive and deadly forms of cancer. By uncovering the role of electrical activity in cancer cells and the metabolic cooperation between different cell types within the tumor, the study opens new avenues for developing targeted therapies.

Neuronal Reprogramming in Pancreatic Cancer: A New Perspective on Tumor Progression

Thiel, V., et al. (2025). Characterization of single neurons reprogrammed by pancreatic cancer. Nature. DOI: 10.1038/s41586-025-08735-3

The paper in one sentence

Pancreatic cancer induces profound molecular and functional changes in innervating neurons, promoting tumor progression through complex neuron-cancer interactions.

Summary

This study explores the intricate relationship between pancreatic ductal adenocarcinoma (PDAC) and the peripheral nervous system, revealing how cancer reprograms neurons at a molecular level. Using Trace-n-Seq, a novel single-cell sequencing technique, the researchers mapped transcriptional changes in neurons infiltrating pancreatic tumors. They identified a distinct Pancreatic Cancer-Nerve (PCN) signature, characterized by metabolic rewiring, axon guidance shifts, and enhanced interactions with cancer-associated fibroblasts (CAFs). Functional experiments demonstrated that neurons actively drive PDAC proliferation, while denervation reduces tumor growth and enhances immune infiltration.

Personal highlights

• Cancer-induced neuronal reprogramming: PDAC alters gene expression in innervating neurons, creating a tumor-specific PCN signature distinct from inflammation or injury responses​

• Neuronal hyperinnervation: Tumors attract and rewire specific neuronal subtypes, particularly NEFM sensory neurons, promoting tumor proliferation and local relapse

• Neuron-cancer crosstalk: Neurons establish a strong interaction network with cancer-associated fibroblasts (CAFs), enhancing tumor growth through ligand-receptor signaling

• Denervation suppresses tumor growth: Sympathetic nerve ablation significantly reduces PDAC size and enhances immune responses.

• neuronal influence extends beyond the pancreas: Reprogrammed neurons affect immune cells in adjacent organs, suggesting a systemic impact of cancer-neural interactions

Why should we care?

This study shows that tumors do not just passively interact with nerves but actively reshape them to their advantage. Understanding this neuron-tumor crosstalk could unlock new treatment strategies, particularly for pancreatic cancer, which is notoriously resistant to therapy.

Lineage Plasticity of the Integrated Stress Response (ISR) as a Hallmark of Cancer Evolution

Diao et al. (2025). Lineage plasticity of the integrated stress response is a hallmark of cancer evolution. bioRxiv. https://doi.org/10.1101/2025.02.10.637516​

The paper in one sentence

The integrated stress response (ISR) drives lineage plasticity in lung adenocarcinoma (LUAD), enabling tumor evolution, therapy resistance, and metabolic adaptation.

Summary

Cancer cells face extreme stress conditions, including hypoxia, metabolic imbalances, and oncogenic signaling pressures. The integrated stress response (ISR), which regulates translation and stress adaptation, allows tumors to evade differentiation constraints, fostering stem-like, highly plastic cancer cell states that contribute to tumor heterogeneity and progression.

This study, using single-cell RNA sequencing (scRNA-seq) and lineage tracing in genetically engineered mouse models of LUAD, uncovers ISR-driven dedifferentiation as a key mechanism promoting epithelial-to-mesenchymal transition (EMT)-prone, stem-like tumor cell populations. The ISR transcription factor ATF4, in cooperation with MYC, activates gene programs that sustain tumor growth, while ISR inhibition disrupts mitochondrial integrity, impairing tumor evolution.

Personal highlights

• ISR promotes tumor cell dedifferentiation & plasticity: ISR activation (marked by phosphorylated eIF2α and ATF4) induces a stem-like, EMT-prone tumor state, enhancing lineage plasticity.

• MYC and ATF4 cooperate to sustain ISR-induced plasticity: ISR-driven MYC overexpression promotes mTOR signaling and stress-adaptive translation, reinforcing high-plasticity cell states.

• ISR Regulates Mitochondrial Integrity for Tumor Adaptation

  • ISR-activated genes support mitochondrial function; ISR inhibition results in a distinct Mito-Dysf (mitochondrial dysfunction) cell population, characterized by poor metabolic adaptation and impaired tumor growth.

• ISR-Driven High-Plasticity Cells Drive LUAD Progression

  • scRNA-seq reveals a unique cluster of ISR-activated, high-stemness cells, which serve as precursors for aggressive tumor states.

• ISR Controls the Transition from AT2-like Cells to Mesenchymal-like States

  • Tumor cells undergo a stepwise transition from alveolar type 2 (AT2)-like progenitors into high-stemness, EMT-prone states, bypassing normal differentiation programs.

• ISR-Mediated Lineage Transitions Are Predictive of Poor Prognosis

  • Analysis of human LUAD datasets (TCGA & patient samples) shows that high ISR activity correlates with worse survival and therapy resistance.

• KRAS-Mutant LUAD Exhibits ISR-Dependent Evolutionary Pathways

  • ISR-activated tumor cells in KRAS-driven LUAD display transcriptional similarities to neuroendocrine and mesenchymal-like lung cancer subtypes, revealing a shared stress-adaptation mechanism.

• ISR Upregulates Pre-EMT Gene Programs to Promote Tumor Dissemination

  • ISR-dependent genes, including Eif4ebp1 and Psph, drive mRNA translation and metabolic reprogramming, essential for maintaining tumor-initiating potential.

• Loss of ISR Results in a Developmental Dead-End for LUAD

• Genetic inhibition of ISR results in a lung transition cluster with high Nkx2-1 expression, indicating failure to complete dedifferentiation, effectively trapping cells in a non-progressing state.

Why should we care?

This study redefines tumor evolution by demonstrating that ISR-driven stress adaptation is not just a survival mechanism, but a fundamental driver of plasticity and heterogeneity in LUAD. By uncovering how stress-responsive pathways regulate lineage transitions, these findings provide new insights into why cancer cells can evade differentiation constraints and resist therapy.

Mutant Alveolar Stem Cells Hijack a Regeneration Program for Lung Tumor Initiation

England et al. (2025). Sustained NF-κB activation allows mutant alveolar stem cells to co-opt a regeneration program for tumor initiation. Cell Stem Cell. https://doi.org/10.1016/j.stem.2025.01.011

The paper in one sentence

Sustained NF-κB activation in Kras-mutant alveolar type II (AT2) stem cells hijacks a lung regeneration program, preventing differentiation and driving tumor initiation.

Summary

Lung adenocarcinoma (LUAD) frequently originates from alveolar type II (AT2) stem cells, but the mechanisms underlying their transformation into tumor-initiating cells remain unclear. This study shows that mutant AT2 cells co-opt a normal lung regeneration program, allowing them to expand without differentiating, a process driven by Il1r1-mediated NF-κB activation.

Using clonal lineage tracing and single-cell RNA sequencing (scRNA-seq) in genetically engineered mouse models, the authors identify two distinct AT2 subpopulations with differential tumorigenic capacities. They find that NF-κB activation blocks AT2-to-AT1 differentiation, enabling tumor-initiating cells to maintain plasticity. Interestingly, mutant AT2 cells also induce regenerative responses in surrounding wild-type cells, fueling tumor progression.

Personal highlights

• Kras-Mutant AT2 cells hijack a regeneration program to initiate tumors: AT2 cells typically contribute to lung repair after injury, but mutant cells exploit this process, failing to differentiate while expanding into tumor-initiating populations.

• Il1r1 signaling acts as a key trigger for AT2 reprogramming: The Il1r1 receptor is necessary for NF-κB activation, linking lung injury repair mechanisms to cancer initiation.

• NF-κB Sustains an Undifferentiated tumor state: Unlike transient activation during normal regeneration, NF-κB remains persistently active in tumor-initiating AT2 cells, blocking differentiation into alveolar type I (AT1) cells. Blocking NF-κB signaling forces mutant AT2 cells to differentiate, reducing their tumor-initiating potential.

• Lineage infidelity enables tumor cells to switch identities: Mutant AT2 cells do not commit to a stable cell fate, instead transitioning between proliferative and partially differentiated states, maintaining tumor plasticity.

• Mutant cells influence nearby wild-type AT2 cells: The presence of tumor-initiating AT2 cells induces proliferative responses in surrounding normal AT2 cells, altering the local lung microenvironment.

Why should we care?

This study challenges the traditional view of lung cancer initiation, showing that tumors do not arise simply through genetic mutations but by hijacking a normal regenerative program. By demonstrating how NF-κB activation prevents differentiation and sustains plasticity, the findings redefine tumor initiation as a process deeply linked to tissue repair mechanisms.

Other papers that peeked my interest and were added to the purgatory of my “to read” pile

• Nociceptive neurons promote gastric tumour progression via a CGRP–RAMP1 axis: https://www.nature.com/articles/s41586-025-08591-1

• Enhancer-driven cell type comparison reveals similarities between the mammalian and bird pallium: https://www.science.org/doi/10.1126/science.adp3957

• Amyloid-β precursor protein promotes tumor growth by establishing an immune-exclusive tumor microenvironment: https://www.biorxiv.org/content/10.1101/2025.02.10.637339v1

• Transcriptomic neuron types vary topographically in function and morphology: https://www.nature.com/articles/s41586-024-08518-2

• TabVI: Leveraging Lightweight Transformer Architectures to Learn Biologically Meaningful Cellular Representations: https://www.biorxiv.org/content/10.1101/2025.02.13.637984v1

• Single-molecule live-cell RNA imaging with CRISPR–Csm: https://www.nature.com/articles/s41587-024-02540-5

• TRIM28-dependent developmental heterogeneity determines cancer susceptibility through distinct epigenetic states: https://www.nature.com/articles/s43018-024-00900-3?utm_source=Live+Audience&utm_campaign=041552b1ff-nature-briefing-cancer-20250220&utm_medium=email&utm_term=0_b27a691814-041552b1ff-499210495

• Tumour-wide RNA splicing aberrations generate actionable public neoantigens: https://www.nature.com/articles/s41586-024-08552-0

• ImmuneLENS characterizes systemic immune dysregulation in aging and cancer: https://www.nature.com/articles/s41588-025-02086-5

• Joint imputation and deconvolution of gene expression across spatial transcriptomics platforms: https://www.biorxiv.org/content/10.1101/2025.02.17.638195v1

• Cooperative nutrient scavenging is an evolutionary advantage in cancer: https://www.nature.com/articles/s41586-025-08588-w

• Lactate controls cancer stemness and plasticity through epigenetic regulation: https://www.sciencedirect.com/science/article/pii/S1550413125000026?via%3Dihub

• Reducing batch effects in single cell chromatin accessibility measurements by pooled transposition with MULTI-ATAC: https://www.biorxiv.org/content/10.1101/2025.02.14.638353v1

Thanks for reading.

Cheers,

Seb.