From Lab to Clinic Proteomics is Poised to Reshape Cancer Diagnostics and Patient Care

Colorectal cancer (CRC) is the third most common cancer diagnosed and the third leading cause of cancer-related death in the United States. If caught early, the disease is highly treatable. However, once the cancer has spread or metastasized beyond the bowel, colorectal cancer is difficult to cure.

In a new study published in Cell Reports, scientists at Beth Israel Deaconess Medical Center (BIDMC) performed a first-of-its-kind analysis of primary colorectal tumors and colorectal cancers that spread to the liver. Using a “multi-omics” approach of accounting for all the DNA, RNA and protein molecules present in their samples, the team catalogued variations among the malignant cells, revealing six distinct subtypes of primary and metastatic CRC. This unprecedented, in-depth investigation provides new insights into the unique molecular features of the primary and metastatic tumors, opening the door to new diagnostics and potential treatment targets for colorectal cancer and paving the way to a new era of personalized medicine.

We asked lead author Michael H.A. Roehrl, MD, PhD, MBA, Chair of Pathology at BIDMC, to tell us more about the groundbreaking study.

What was the main goal of this study and what makes it first-of-its-kind?

Michael Roehrl: Our main goal was to understand what drives cancer from primary tumor to metastasis and to identify new drug targets for treatment of these hard-to-treat metastatic cancers.

The molecular journey of a disease and where we can intervene—that's the big picture.

Specifically, we wanted to identify new protein biomarkers to better predict patients’ prognoses and response to treatments. Biomarkers help stratify patients into different risk categories and also help us identify which patients will respond best to which treatment.

Our analysis was unique because it included the integration of multi-omics:

• Proteomics: the study of all the proteins in a given biological sample.
• Genomics: the study of all DNA present.
• Transcriptomics: the study of all the RNA molecules present.

Ours is also the first study that ever looked at the proteomics of primary cancers as well as cancer that has spread, or metastasized, to the liver, giving us new information about the progression of disease and how a primary tumor is different from metastases. Colon cancer is a disease that affects millions of people. Ultimately, it's the metastases that unfortunately kill people and that we really need to know how to treat.

Why is proteomics so important to the future of medicine?

MR: Proteomics is a cutting-edge field. It's the large-scale study of all the proteins and their structures, functions and interactions within a biological system. It involves the identification, quantification and characterization of all the proteins present in a given sample, such as a tumor.

We say DNA is the blueprint for life, but DNA can't do anything on its own. Proteins are literally the Machines of Life.

Proteins are essential to life, but they're also essential to disease. Every drug we develop— whether it's a small molecule, an antibody or CAR T-cell—interacts with proteins to treat disease.

How do these findings advance precision medicine?

MR: Precision medicine aims to optimize therapeutic benefit for particular groups of patients by using molecular profiling. Two patients might have a similar looking tumor, but one person responds to treatment and the other doesn't respond. We don't know why and that’s a huge problem.

I'm interested in studying proteins because I feel if you understand how drugs patients are prescribed interact directly with their proteins, we should understand the patients’ responses much better.

If a person is only evaluating genomics which looks at DNA, you are two steps removed from the process. DNA needs RNA to make things happen. But RNA needs to be translated into proteins; you’re still multiple biochemical steps away from where the action is.

That’s what this paper does. We found new molecular subtypes, new variations, of primary colon cancer and metastatic colon cancer. They looked very much alike under the light microscope. Even with genomic analysis, the mutations that the tumor carries with it are not fundamentally different.

But the tumors are in different environments in the body, so it's not surprising that at the proteome level those cells have different adaptations, different proteomic signatures.

It tells us that we probably need to study the biology of metastasis a lot more in depth, because using a primary tumor to extrapolate what happens in the metastatic tumor may be misleading.

Were there any findings in this study that surprised you?

MR: Looking at the primary tumor alone is not going to tell you what's going on in the metastasis, which is often of very high clinical relevance. We often wonder when a patient presents with tumors which lesion we should be analyzing. What our research shows is that one lesion is not going to tell you the whole story about the entire disease process.

It’s very likely that these subtypes have different responses to drugs. Clinically, we often observe that one lesion responds and others will grow, even when they’re within the same patient.