"One recipe for growth for different cancers": how scientists found common "nodes" - from MYC to ribosome assembly

A study published in Science Advances showed, using a huge data set, that a variety of oncogenic pathways, from WNT/β-catenin and GLI to RAS/RTK/PI3K, converge on the same “nodes” of cell growth control. The authors assembled a multiomic puzzle (ChIP-seq, single-cell transcriptomics, phosphoproteomics, chemical proteomics, metabolomics, functional tests) and reached two main target blocks: the MYC transcriptional program and ribosome biogenesis/translation. Moreover, they identified specific proteins, the “forks of signal distribution” - NOLC1 and TCOF1 - whose work and phosphorylation are critical for tumor cell proliferation.

Background of the study

Tumors are incredibly heterogeneous in their "upper" breakdowns - some are accelerated by RAS/RTK/PI3K, others are held by WNT/β-catenin, hormonal receptors or transcription factors of the lineage. But they all have a common phenotype: cells begin to grow and divide without brakes. Therefore, oncologists have long been maturing the idea of searching for convergent "lower" nodes where different oncogenic pathways converge - such targets are potentially wider in applicability and more resistant to resistance than a pinpoint strike only on the "upper" driver. More and more data indicate that such nodes often become ribosome biogenesis and translation control, that is, the "protein factory" itself that feeds growth, and the signaling cascades associated with it.

In this picture, MYC, one of the main regulators of ribosome gene transcription and components of the translational apparatus, occupies a special place. MYC accelerates rRNA transcription, ribosome assembly and switches cellular metabolism to "growth mode", while oncogenic kinase cascades (mTORC1, etc.) fine-tune the same processes post-translationally. This duet - "MYC + kinases" - provides a well-coordinated boost of the ribosome factory and protein synthesis, which is observed in a wide variety of tumors and is increasingly considered as a therapeutic vulnerability.

The key "bolts" of this factory are the nucleolar proteins NOLC1 and TCOF1 (treacle). They serve as assembly sites and adapters for polymerase I and modifying complexes, coordinating rRNA synthesis and maturation of ribosomal particles. Their levels and phosphorylation change under oncogenic stimuli; TCOF1 mutations are known from ribosomopathy (Treacher Collins syndrome), and TCOF1 and NOLC1 expression is increased in many tumors - from triple-negative breast cancer to head and neck tumors. This is why these proteins are increasingly being looked at both as proliferation markers and as intervention points.

A new study in Science Advances takes this “common nodes” hypothesis head-on: the authors assembled a multiomic puzzle - from ChIP-seq and single-cell transcriptomics to phospho- and chemoproteomics - and showed that a variety of oncogenic programs converge on MYC and the ribosomal circuit, with early events passing through post-translational switches and the nucleolar regulators NOLC1/TCOF1. This shift in focus - from the “upstream” drivers to the final nodes of growth - sets a practical agenda: testing combinations that hit both the driver and the ribosomal axis (Pol I/translation initiation/nucleolar factors) to more broadly cover tumor bypasses.

Why is this important?

There are hundreds of "cancer genes" in genomic catalogs, and each tumor type loves "its own" mutations. But the phenotype is surprisingly similar for all of them: unlimited growth and longevity of cells. The work provides a plausible answer to this paradox: different drivers press the same pedals of biosynthesis, increasing the power of the ribosome factory and the launch of translation, and also cooperatively spinning up MYC. This means that instead of chasing dozens of "upper" drivers, you can target common downstream nodes that are potentially relevant for many tumors at once.

How was this tested?

The team compared direct targets of oncogenic transcription factors (ER, AR/ERG, TCF4/β-catenin, GLI/PAX3, FLI1, etc.) with expression data and GWAS associations. In parallel lines, they:

• treated cells with cytostatic kinase inhibitors and used scRNA-seq to filter out changes that occur before cell cycle arrest;
• performed phosphoproteomics at early time points (≤2 h) to capture rapid post-translational events;
• PISA (protein solubility assay) was used to document the rearrangement of the complexes;
• confirmed the functionality of key sites and promoters by competitive genomic editing (CGE). The result was the same everywhere: the common thing is the MYC program + ribosomes/translation, and the phosphorylation of a number of regulators is ahead of transcriptional waves.

The main findings in one list

• MYC is a common transcriptional 'hub'. Different oncogenic TFs converge to activate MYC and CDK4/6; this is evident from both ChIP-seq and GWAS signals (MYC, CDKN2A/B).
• Early signals go through ribosomes. Already after 2 hours, phosphorylation of ribosome biogenesis and splicing proteins changes; transcriptional effects in "sensitive" cells come later.
• NOLC1 and TCOF1 are markers and regulators of proliferation. Their levels and phosphorylation "mark" proliferating zones in real tumors (squamous cell carcinoma of the tongue), and mutations of regulatory sites in these proteins and in their MYC binding sites spoil the fitness of cells.
• The cooperation of oncogenes has a biochemical explanation: optimal growth activation requires both increased expression (via MYC) and precise post-translational tuning (via kinase cascades) - on the same ribosomal nodes.

What's new about NOLC1/TCOF1 "nodes"

Traditionally, these nucleolar proteins are known for their participation in rRNA synthesis and ribosome assembly. Here, it is shown that they are not just markers of factory activity, but signal convergence points:

• their transcription is among the first-line MYC targets;
• their phosphorylation changes rapidly and in a coordinated manner when oncogenic kinases are blocked;
• mutations in phosphorylation sites break the proliferative advantage in CGE assays;
• in tumor tissue, it is they that “delineate” the proliferating compartment. All this makes NOLC1/TCOF1 candidates for universal biomarkers of growth activity and potential therapeutic targets.

Ribosomes, Metabolism, and Growth: A Common Scenario

In addition to the ribosomal branch, the authors found early phosphosignals in metabolic enzymes (for example, in hexokinase HK2, where the criticality of Y461 for growth was confirmed by point editing). The idea is that growth is a synchronous acceleration of both the ribosome "hardware" and the fuel supply of metabolism, and coordination occurs through the "MYC + kinase" link.

Why does the clinic and the pharma need this?

If different oncogenes are drawn to the same downstream processes, this opens up three practical directions:

• Combined strategies: target the “upstream” driver (EGFR/MEK/PI3K) and the ribosome/translational junction where pathways converge (e.g. via regulation of translation initiation, Pol I/ribosome biogenesis, NOLC1/TCOF1 junctions).
• Proliferation biomarkers: NOLC1/TCOF1 as indicators of an active tumor “factory” in histo- and proteomic panels.
• Explanation of resistance: even when one driver is inhibited, cells can “switch” to a parallel kinase branch, but the point of departure remains the same - ribosomes/translation → target for an “additional” hit.

Where are the boundaries and what's next?

This is a powerful but preclinical study with human tissue validation in one representative cancer type. The next steps are obvious: (1) validate the nodes in other primary tumors and PDX models, (2) test which drug interventions (Pol I, eIF nodes, rRNA regulators) synergize with targeted therapy, (3) expand NOLC1/TCOF1 into clinical panels and observe the association with treatment response and survival.

Briefly - three theses to remember

• Different oncogenes - common "downstream" targets: MYC program, ribosome assembly and translation.
• NOLC1/TCOF1 are key nodes of proliferation: both transcriptionally and by phosphorylation, and in tumor tissue.
• Oncogenic cooperation is explainable: expression (MYC) + phosphorylation (kinases) on the same ribosomal circuit.

Source: Kauko O. et al. Diverse oncogenes use common mechanisms to drive growth of major forms of human cancer. Science Advances, 20 August 2025, 11(34): eadt1798. DOI: 10.1126/sciadv.adt1798