Journal News

MCP: Proteome profiling dissects variations in tumors

Saddiq Zahari
April 1, 2018

It is well established that tumors, even those of the same type, exhibit differences in genetics and morphology. This heterogeneity not only exists for tumors from different patients but also across regions within the same tumor. The latter, termed intratumoral heterogeneity, is of particular interest because it directly affects diagnosis and prognosis.

This microscopic photo shows tumor cells from a fine needle aspiration cytology smear of a liver mass. Tumor cells exhibit nuclear enlargement, opened chromatin and multiple nucleoli.Courtesy of Jian-Hua Qiao/NIH flickr

Martin Beck and others at the European Molecular Biology Laboratory study intratumoral heterogeneity. “This has important implications for tumor development because certain cells might be more aggressive than others,” Beck said.

Most studies have looked at intratumoral heterogeneity at the genomic level. It remains largely unknown to what extent the local proteome of tumors intrinsically varies. In a new study in Molecular & Cellular Proteomics, Beck and a group of researchers at the EMBL attempt to answer this question. “We were interested to find out if the proteins contained within individual cells of the tumor are the same or different,” Beck said. Since heterogeneity in the tumor microenvironment, such as the presence of a neighboring blood vessel, may drive genetic changes, he reasoned that it might also be reflected on the level of proteins.

The researchers looked at hepatocellular carcinoma, or HCC, the most common type of liver cancer. They used HCC samples biopsied from patients and then formalin-fixed and paraffin-embedded on microscope slides. Such samples, commonly referred to as FFPE, preserve the integrity of the tissue architecture of the original tumor, allowing the researchers to study the spatial differences in protein expression.

FFPE samples, however, present technical challenges for proteomic analysis, particularly because only a limited amount of proteins can be extracted. To overcome this problem, the researchers developed a novel method that efficiently extracts proteins from FFPE samples. To profile the spatial expression of proteins, they combined this method with a technique called laser-capture microdissection to carve out microscopic regions within the tumor. The extracted proteins then were run on a mass spectrometer for identification.

The researchers first looked at the differences of protein expression between the tumor tissue and the normal tissue immediately adjacent to it. They detected consistent changes of multiple proteins known to be associated with HCC. More importantly, they also identified a few proteins that previously were not known to be HCC-related, opening possibilities for candidate biomarker development. Among these were members of the NADH dehydrogenase complex I. This finding was striking because the researchers showed that the changes were not reflected at the gene expression level, underscoring the importance of proteome profiling.

The researchers went deeper and dissected different regions within the tumor bulk. Here they found significant variations in expression of multiple proteins between areas from the center and the periphery of the tumor. “We could show that even between seemingly identical cells, with the same morphology and the same genome, there are surprisingly pronounced differences on the level of the proteins,” Beck said.

These spatial differences of protein expression include proteins that have previously been identified as HCC biomarkers. “In our analysis, we saw that even proteins that have been proposed as such biomarkers are not evenly distributed across the tumor,” Beck said.

This finding is of immediate clinical importance. Only a small fraction of a tumor can be obtained in a diagnostic or pretreatment biopsy, and thus the region of withdrawal could have a direct impact on the acquired expression profile. “It is possible that the tissue sample taken during biopsy does not reflect the actual state of the entire tumor,” Beck said.

Beck believes the method developed in this study not only allows for studying intratumoral heterogeneity but also can improve cancer proteomics research in general. “Proteomic intratumoral heterogeneity should be taken into account for future cancer research,” he said, “for example in the design of biomarker discovery experiments.”

Enjoy reading ASBMB Today?

Become a member to receive the print edition monthly and the digital edition weekly.

Learn more
Saddiq Zahari

Saddiq Zahari is the editor for manuscript integrity at MCP.

Related articles

From the journals: MCP
Nivedita Uday Hegdekar
From the journals: MCP
Courtney Chandler
From the journals: MCP
Nuala Del Piccolo & Laurel Oldach
From the journals: MCP
Kian Kamgar-Parsi
From the journals: MCP
Nivedita Uday Hegdekar

Get the latest from ASBMB Today

Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.

Latest in Science

Science highlights or most popular articles

Predicting PROTAC properties
Feature

Predicting PROTAC properties

Dec. 8, 2022

Best of BMB 2022: Proteolysis-targeting chimeras bring together a drug target protein and a ubiquitin ligase to remove the target from the cell. But sometimes the process stalls out.

Cataloging itty-bitty proteins in large numbers
Feature

Cataloging itty-bitty proteins in large numbers

Dec. 7, 2022

Best of BMB 2022: Ribosome profiling has identified thousands of short protein-coding genes, many in unexpected parts of the genome. Research suggests some play important regulatory roles.

Giant, intricate structures
Feature

Giant, intricate structures

Dec. 6, 2022

Best of BMB 2022: In a “triumph of experimental structural biology,” multiple teams tackle the nuclear pore complex.

Evolutionary constraints on disordered proteins
Feature

Evolutionary constraints on disordered proteins

Dec. 5, 2022

Best of BMB 2022: “There’s evidence that there must be conservation of function — so how does this happen, if the sequence changes so much?”

COVID-19, preprints and journalists
Science Communication

COVID-19, preprints and journalists

Dec. 3, 2022

Researchers find that news stories often fail to mention when studies haven’t been peer reviewed.

From the journals: MCP
Journal News

From the journals: MCP

Dec. 2, 2022

Muscling in on a signaling pathway. Probing weaknesses in the T cell surface. Improving single-cell proteomics two ways. Read about papers on these topics recently published in the journal Molecular & Cellular Proteomics.