Cancer study identifies molecular pathways used in tumor metastasis2023-02-16
- Metastasis, the process of the spread of cancer cells to a distant site from the tissue of origin, is the primary cause of cancer-related mortality.
- A recent study classified metastasized tumors with varying sites of origin into four subtypes based on differences in their gene expression profiles.
- Based on these molecular profiles, the researchers were also able to identify therapeutics that could potentially target each individual metastatic tumor subtype.
- These findings suggest that personalized treatments could be developed for metastatic cancer based on the gene expression profile of the tumor.
A recent study published in the journal Cell Reports Medicine reports that different types of cancers, such as breast cancer, prostate cancer, and lung cancer that had metastasized, could be categorized into four subtypes based on the differences in their gene expression profiles.
These findings suggest that a single treatment may not be suitable for all metastasized cancers and individualized treatments, developed in accordance with the gene expression profile of the tumor, could be more effective.
“Our study would have implications for targeted therapy, as different subtypes appear to rely on distinct oncogenes or pathways,” said Dr. Chad Creighton, the corresponding author of the study and a professor at Baylor College of Medicine in Texas. “Therefore, some therapies may work better for some patients versus others, as indicated by the tumor’s subtype.”
“Where we had molecular data for both the metastasis and the initial tumor from the same patient, we found that in most cases, the metastasis subtype differed from that of the paired initial tumor,” he added. “Our results might suggest avenues for future personalized medicine approaches, to treat the tumor based on pathway vulnerability as revealed by its molecular profile. At the same time, combination therapies may be needed to treat both the initial tumor and any potential metastatic cells, thereby reducing the development of therapeutic resistance.”
Gene expression profiling
Metastasis is the process by which cancer cells break off from the original or primary tumor and form a secondary tumor at a distant site.
Metastasis is the primary cause of death due to cancer, accounting for about 90% of cancer deaths. However, the molecular pathways and mechanisms underlying metastasis are not fully understood.
Cancer is characterized by alterations in the expression of genes, including those involved in cell growth, metabolism, immune function, and proliferation.
This can be due to mutations in the gene coding for proteins involved in these cellular functions or the transcription factors that regulate the expression of these genes. Besides small changes in the sequence of genes, cancer is also characterized by the gain or loss of the number of copies of genes.
Cancers can be classified into different types according to their location of origin and histology, i.e., the type of tissue in which the tumor originates.
More recently, scientists have also used differences in gene expression profiles to distinguish cancer subtypes that span various cancer types defined by origin site and histological characteristics.
A previous study demonstrated that 32 different types of primary cancers classified according to their origin site and histology could be divided into 10 different sub-types based on differences in their gene expression profiles.
Similarly, a few molecular mechanisms are considered to underlie metastasis, which is shared by different cancer types categorized by site or origin and histology. However, most studies have examined the molecular profile of only a single type of cancer.
Categorizing tumors according to their gene expression profiles can allow the use of treatments targeting the specific molecular pathways expressed by a particular tumor.
Challenges with gene expression profiling
One of the challenges associated with determining the gene expression profile of cancer cells in people is differentiating cancer from non-cancer cells.
More specifically, solid tumors contain not only malignant cells but also contain non-malignant tissue, known as the tumor stroma, that supports the maintenance of the tumor and its progression. The stroma consists of non-cancer cells such as immune cells, blood vessels, connective tissue cells, and extracellular matrix.
Thus, tissue samples from cancer patients used for analyzing gene expression profiles contain both non-cancer and cancer cells. The inability to discriminate between these cells can lead to inaccurate data.
To circumvent this issue, the researchers have used a model involving the transplantation of a portion of the biopsied tissue from cancer patients to rodents.
Upon transplantation of the biopsied tissue, the human stromal cells are replaced by the rodent stromal tissue, whereas the human cancer cells continue to proliferate and form a tumor in the rodent.
The transplanted human cancer cells can then be discriminated from rodent stromal tissue during gene expression profiling. This method is known as patient-derived xenotransplantation (PDX).
In the present study, the researchers used data from several individual studies assessing the gene expression profile of metastasized tumors of a single type to delineate molecular profiles of metastatic tumors that span different cancer types.
The present study consisted of data representing more than 3,000 cancer patients, obtained from 14 PDX studies and 24 studies involving patients with metastasized tumors. The cancer cells in the PDX studies were transplanted from the cancer patients to a different site in mice and, hence, represented a form of metastasis.
The researchers identified four distinct subtypes in the PDX datasets and subsequently found similar subtypes in the patient tumor metastases database.
In addition, using a database containing the gene expression profile of nearly 1,000 cell lines and their response to anticancer drugs, the researchers were able to classify each cell line according to their molecular subtype and identify the response of cancers of each subtype to anticancer drugs.
The first subtype, s1, showed higher expression of genes involved in DNA repair, such as BRCA2, and the transcription factor Myc. The Myc gene is a known proto-oncogene, which is a gene whose deregulation can cause cancer.
Notably, The s1 subtype tumors were responsive to the bromodomain inhibitor class of drugs that can inhibit MYC, several of which are currently under investigation. In addition, the s1 subtype tumors also showed a gain in the number of copies of certain regions of the DNA repair genes.
Metastatic cancers belonging to the s2 subtype showed higher expression of genes involved in prostaglandin synthesis and regulation. Studies have shown that prostaglandin E2 (PGE2) promotes tumor progression and is associated with tumor inflammation.
Moreover, studies have examined the potential of drugs that inhibit the enzyme involved in the synthesis of PGE2 for cancer treatment.
Subtype s3 was also associated with increased expression of DNA repair genes and those involved in DNA and chromosomal modifications that can influence gene expression patterns.
In addition, metastatic cancers belonging to subtype s3 showed higher expression of the transcription factor EZH2 and the genes regulated by EZH2. Notably, EZH2 is involved in DNA modification being overexpressed in many cancers. Currently, different types of EZH2 inhibitors are being studied in ongoing clinical trials involving different cancer types.
Subtype s3 tumors also showed elevated expression of the cancer-related gene BCL-2 that regulates cell death and showed an increase in the copy number of this gene. Consistent with this, the cell lines showing subtype s3 molecular profile were also responsive to BCL-2 and EZH-2 inhibitors.
Subtype s3 tumors also showed overexpression of the TERT gene, which can lead to the immortalization of cancer cells. Consistent with this, certain S3 subtype cell lines were sensitive to TERT inhibitors.
The subtype s4 cancers showed higher expression of proteins that are involved in the regulation of the immune system, including immune checkpoint proteins. This could potentially allow s4 tumors to be treated with drugs targeting the immune system, such as immune checkpoint inhibitors. Subtype s4 cancers also expressed higher levels of genes in the Notch pathway, which promotes tumor growth.
For some of the participants in the study, the researchers had the gene expression profiles for both the primary site tumor and the metastatic site.
They found that the molecular subtype of the tumor could differ between the primary and the metastasized tumor, indicating that the tumor changed gene expression patterns at the new site after metastasis. In such cases, different treatments specific to the primary and metastasized tumor would be necessary.
Reaction to the cancer study
Dr. Manmeet Ahluwalia, the chief of solid tumor medical oncology, deputy director, and chief scientific officer at Miami Cancer Institute, part of Baptist Health South Florida, who was not involved in the study, said, “What is a very interesting finding of this paper is that there is subtype switching thereby implying that the metastatic site may be different from the primary tumor.”
“This implies that one needs to perform tumor biopsies or take advantage of liquid biopsies on patients with cancers that are being treated with therapies, as there is a clonal evolution in cancer over time (especially under therapeutic pressure),” Ahluwalia told Medical News Today. “In the era of precision medicine, there is a need to perform tumor biopsies and or liquid biopsy when there is a new metastatic site to study mechanisms of resistance.”
Dr.Santosh Kesari, a board-certified neurologist and neuro-oncologist, currently chair and professor of the Department of Translational Neurosciences and Neurotherapeutics, Saint John’s Cancer Institute in California, and Regional Medical Director for the Research Clinical Institute of Providence Southern California, who was not involved in the study, said, “This study analyzed 4,000 tumors from 3,000 patients and identified four distinct subtypes based on RNA profiling and, remarkably, were not related to tumor origin.”
“This new understanding of metastases subtypes based on transcriptional profiling gives us insights on better treating metastatic diseases based on this classification versus based only on the original tissue of origin,” Kesair told Medical News Today.
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