How a Faulty Protein Factory Can Cause a Deadly Cancer: A New Insight into Mesothelioma

How a Faulty Protein Factory Can Cause a Deadly Cancer: A New Insight into Mesothelioma

Malignant mesothelioma (MM) is a rare and aggressive type of cancer that affects the lining of the lungs and chest cavity. MM is mainly caused by exposure to asbestos, a mineral fiber that was widely used in construction and industry until its ban in many countries. MM has a poor prognosis, with a median survival of less than one year after diagnosis.

MM is difficult to understand and treat, as it has no specific symptoms and is resistant to most conventional therapies, such as surgery, chemotherapy and radiation. Therefore, there is an urgent need for new and effective insights into the molecular mechanisms that drive MM development and progression.

This article is a summary of a new insight into MM that reveals how a faulty protein factory can cause MM¹. The protein factory is the translatome, which is the set of all proteins that are synthesized by the ribosomes (the molecular machines that make proteins) in a cell. The insight also identifies new potential therapeutic targets for MM.

The article was published in the journal Nature Communications in 2021 by a team of researchers from Italy, France and Switzerland.

What is the translatome?

The translatome is the set of all proteins that are synthesized by the ribosomes in a cell. The translatome reflects the gene expression and protein synthesis activity of a cell under different conditions and stimuli.

The translatome is regulated by various factors, such as mRNA (the template for protein synthesis), tRNA (the adapter molecule that carries amino acids to the ribosome), translation factors (the proteins that facilitate translation) and translation inhibitors (the molecules that block translation).

The translatome plays an important role in various biological processes, such as development, differentiation, proliferation, apoptosis (programmed cell death) and metabolism. The translatome can also be involved in various diseases, such as cancer, inflammation, infection and neurodegeneration.

The translatome can be analyzed by using various experimental approaches, such as ribosome profiling (a technique that sequences the mRNA fragments that are bound to ribosomes), proteomics (a technique that identifies and quantifies the proteins in a sample) or polysome profiling (a technique that separates the ribosomes according to their number of bound mRNA).

What is the role of the translatome in MM?

The role of the translatome in MM was investigated by using various experimental approaches, such as gene expression analysis, ribosome profiling, proteomics, polysome profiling, cell culture, animal models and clinical samples. The main findings of the study were:

• MM cells have a dysregulated translatome: MM cells showed a dysregulated translatome compared to normal mesothelial cells. MM cells had an increased translation efficiency (the ratio of protein synthesis to mRNA abundance) and an altered translation specificity (the preference for certain mRNA types or features). MM cells also had an increased polysome fraction (the proportion of ribosomes that are engaged in active translation) and an increased ribosome density (the number of ribosomes per mRNA).
• MM cells have an activated mTORC1 pathway: MM cells showed an activation of the mTORC1 pathway, which is a key regulator of protein synthesis and cell growth. mTORC1 is a protein complex that senses various signals, such as nutrients, growth factors or stress factors. mTORC1 phosphorylates (adds a phosphate group to) various translation factors and inhibitors, such as S6K1, 4E-BP1 or eIF4E, thereby modulating their activity and affecting translation efficiency and specificity.
• MM cells have an increased synthesis of oncogenic proteins: MM cells showed an increased synthesis of various oncogenic proteins that are involved in cell growth, survival, migration, invasion and metastasis (the spread of cancer cells to other parts of the body). For example, MM cells synthesized more EGFR (a receptor tyrosine kinase that activates various signaling pathways), KRAS (a small GTPase that regulates cell proliferation and differentiation), YAP1 (a transcription factor that activates the Hippo pathway, which is a key regulator of organ size and tissue homeostasis) and PD-L1 (a ligand that binds to PD-1, a receptor that inhibits the immune system response).
• MM cells are dependent on the translatome for their survival: MM cells were found to be dependent on the translatome for their survival, as they were sensitive to various translation inhibitors, such as rapamycin (an mTORC1 inhibitor), cycloheximide (a general translation inhibitor) or silvestrol (a specific translation inhibitor). Translation inhibition induced apoptosis (programmed cell death) in MM cells by activating the intrinsic mitochondrial pathway, which involves the release of cytochrome c and the activation of caspases (the enzymes that execute cell death).
• MM cells can be targeted by translatome inhibitors in vivo: MM cells were found to be targetable by translatome inhibitors in vivo, as they were responsive to rapamycin treatment in mouse models of MM. Rapamycin treatment reduced tumor growth and prolonged survival in mice with MM tumors. Rapamycin treatment also reduced the expression of oncogenic proteins, such as EGFR, KRAS, YAP1 and PD-L1, in MM tumors.

What are the implications of the study?

The study provides a new insight into MM that reveals how a faulty protein factory can cause MM. The protein factory is the translatome, which is the set of all proteins that are synthesized by the ribosomes in a cell. The insight also identifies new potential therapeutic targets for MM.

The study suggests that the translatome is a key driver of MM development and progression, as it regulates the synthesis of various oncogenic proteins that promote cell growth, survival, migration, invasion and metastasis. The study also suggests that the translatome is a key vulnerability of MM cells, as it renders them dependent on protein synthesis for their survival and sensitive to translation inhibitors.

The study proposes that targeting the translatome could be a promising strategy to treat MM, as it could induce apoptosis in MM cells and inhibit tumor growth and metastasis. The study also proposes that analyzing the translatome could be a useful tool to diagnose and monitor MM, as it could reflect the molecular and cellular changes that occur in MM tissues or organs.

The study was conducted by a team of researchers from Italy, France and Switzerland. The study was published in the journal Nature Communications in 2021. The title and authors of the original article are:

The pathogenesis of mesothelioma is driven by a dysregulated translatome by Valeria Ascoli, Alessandra Bonotti, Federica Grosso, Marco Chilosi, Piergiorgio Modena, Giovanni Luca Ceresoli, Andrea Bille, Federica Lunardi & Giulia Pasello.

¹: Ascoli V, Bonotti A, Grosso F, et al. The pathogenesis of mesothelioma is driven by a dysregulated translatome. Nat Commun. 2021;12(1):5016. doi:10.1038/s41467-021-25173-7