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Unraveling Epigenetic Drivers in Cancer Progression

Discover how the mysterious world of epigenetics is revealing new insights into cancer. This groundbreaking study maps the role of gene accessibility in driving cancer's initiation, growth, and spread, paving the way for future research and potential treatments.

At a Glance

  1. This study dives into the world of epigenetics, exploring how changes in gene activity, known as chromatin accessibility, can drive the onset, growth, and spread of cancer.

  2. The researchers collected data from 225 samples across 11 types of cancer, studying over a million cells to identify patterns, known as "epigenetic drivers," that could be key to understanding cancer transitions.

  3. They found some epigenetic drivers common to many cancers, while others were specific to certain types. Certain pathways in the body were also identified as being altered in ways that could lead to cancer onset or help cancer spread.

  4. The study uncovered a link between how accessible certain parts of our genes are and how they behave, revealing that changes in our genes and these epigenetic drivers can work together.

  5. The findings provide a starting point for more research into how these epigenetic changes can lead to cancer, potentially paving the way for future cancer detection and treatment strategies.

Unlocking the Mysteries of Cancer with Epigenetics

Cancer remains one of the most pressing health challenges of our time. While significant strides have been made in unravelling the genetic underpinnings of cancer, there is still a vast frontier to explore: the world of epigenetics. Epigenetics, which involves changes in gene activity without altering the DNA sequence, plays a critical role in cell function and identity. Among these changes, chromatin accessibility, or how tightly DNA is packed and thus how accessible it is for gene expression, is a key player. Alterations in chromatin accessibility have been implicated in the onset, growth, and spread of cancer. However, our understanding of these so-called 'epigenetic drivers' in cancer remains limited.

Now, a new study pushes the boundaries of our knowledge further. This research offers a comprehensive look at epigenetic and transcriptomic data across 11 different types of cancer, using hundreds of patient samples. The insights derived from this study help identify patterns and correlations that could drive cancer transitions, linking specific epigenetic changes to cancer initiation and metastasis.

This article presents an exciting study that opens up new possibilities for understanding and potentially treating cancer. By mapping the landscape of epigenetic changes in cancer, the research offers a fresh perspective on how cancer evolves, and paves the way for future studies. So, let's delve into the details of this groundbreaking work.

Understanding Epigenetic Drivers in Cancer Development

We created and investigated a large-scale single-cell multi-omic atlas of tumours and NATs from 225 samples across 11 cancer types, unveiling diverse cancer and normal tissue cell types. Advancing beyond previous bulk ATAC/RNA-seq studies, our analysis provides nuanced insights into cancer biology, including cancer-specific epigenetic architecture, relationships between normal and malignant cells, and primary-to-metastatic transitions in the same lineage.

The way our genes work and identify themselves can change how cancer starts, grows, and spreads. We know a lot about how changes in our genes can lead to cancer, but we're still learning about other factors, called epigenetic drivers. In a new study, researchers collected and examined a lot of data related to these epigenetic drivers from 225 different samples.

  • They looked at over a million cells and found some patterns. Some of these patterns seemed to be involved in many types of cancer, while others were only found in specific types.

  • They also observed that certain pathways in the body were changed in ways that could lead to the start of cancer, while others might help cancer spread.

  • And they also found a link between how accessible certain parts of our genes are and how they behave, and saw that changes in our genes and these epigenetic drivers can work together.

This collection of data helps us understand more about how these epigenetic changes can lead to cancer, and gives us a starting point for more research.

Shedding Light on the Role of Epigenetic Drivers in Cancer

Think of the human body as a city and genes as structures within it. Changes in this 'city', such as the construction of new buildings or the closure of old ones, can affect how cancer begins, develops and spreads. We already understand that these changes in our 'structures' or genes can contribute to cancer. However, we are still learning about other factors at play, such as the 'city planning guidelines', referred to as epigenetic drivers.

In this study, a detailed 'city map' of the genetic landscape across 11 major types of cancer was created using data from over 200 patients. Instead of just viewing the 'city' from above, researchers zoomed in to examine each 'building' or cell in great detail. This allowed them to identify patterns linked to the initiation and progression of cancer.

Some of these patterns appeared in many types of cancer, similar to how certain buildings are seen in many cities. Conversely, some patterns were unique to specific types of cancer, akin to unique landmarks in different cities. The study also revealed that some changes in the 'city planning guidelines' seemed to collaborate with changes in the 'buildings' themselves.

This research provides a detailed 'city guide' to the genetic landscape of cancer. It improves our understanding of how changes in our genes and their 'planning guidelines' can lead to cancer. This information could potentially enhance future cancer detection and treatment strategies.

Investigating Chromatin Accessibility in Cancer Cells

The study, which is a part of the NCI Human Tumour Atlas Network (HTAN), collected 225 samples from 158 primary and 52 metastatic tumour samples, as well as 15 normal adjacent tissues from 201 patients across 11 different types of cancer. This set included metastatic samples from colorectal, pancreatic, skin cutaneous melanoma, uterine corpus endometrial, ovarian, and breast cancer, some of which were paired with primary tumour samples. The researchers performed an analysis of single-nucleus chromatin accessibility (snATAC-seq) and RNA sequencing on 206 of these samples.

  • They examined over a million nuclei from the samples, identifying accessible chromatin regions (ACRs), which are important for gene regulation.

  • They found that most of these regions were located in intronic (within genes), distal intergenic (between genes), and promoter regions of the genome.

  • Using this data, the researchers were able to identify different cancer cell populations and map the progression of cancer from normal cells to primary and metastatic tumours.

  • They also found specific differentially accessible chromatin regions (DACRs) associated with each type of cancer.

This work helps to shed light on the role of chromatin accessibility - a key epigenetic factor - in cancer development and progression. It could lead to a better understanding of how different types of cancer develop and potentially provide new targets for cancer treatment.

Key Discoveries in Chromatin Accessibility and Cancer Gene Expression

The researchers aimed to identify the genetic and epigenetic changes that transition normal cells into cancer cells. They compared cancer cells and normal cells based on chromatin accessibility and gene expression, identifying the closest normal cells (CNCs) for different types of cancer.

They used these CNCs to identify changes in chromatin accessibility specific to cancer cells. These changes were found in 22,187 areas where accessibility increased and 29,074 areas where it decreased in cancer cells. They mapped these changes to the closest genes based on proximity.

Around 53% of these changes were found in enhancer regions and 37% in promoter regions, indicating their potential relevance to changes in gene expression. In fact, about 75% of these changes matched the direction of the expression change of the nearest gene.

They also identified several genes that showed increased accessibility of nearby genomic regions across different types of cancer. Some changes were specific to certain types of cancer.

The researchers also identified hallmark pathways enriched in specific changes in cancer cells. A large number of these changes were found in genes downregulated in response to ultraviolet radiation in five out of seven cancer types.

The study also found two particularly notable changes. One was an increase in the accessibility of the enhancer of ABCC1, a gene associated with drug resistance and tumor growth, in three types of cancer. Another was increased accessibility of the enhancer of VEGFA, a known factor promoting the formation of blood vessels, in three types of cancer.

Exploring the Impact of Enhancer Accessibility on Gene Regulation in Cancer

Using snMultiome-seq, the researchers looked at more than 500,000 enhancer ACRs in 122 tumor samples from 8 different types of cancer. They found that enhancer accessibility is more specific to cancer types and tissues than promoter accessibility, and better reflects transcript expression, indicating its crucial role in regulating gene expression. The study also revealed that most enhancer ACR-to-gene links are specific to the type of cancer, reinforcing the specificity of enhancers. The majority of these links had not been previously reported.

The team proceeded to identify which linked ACRs and genes might be connected to the transition from normal to primary cancer cells. They discovered 397 linked ACRs, mostly enhancers, gaining accessibility in most primary PDAC tumors. Particularly, one proximal and two distal enhancers were linked to the expression of the oncogenic ASAP2 in PDAC, while the accessibility of its promoter did not change. ASAP2 was shown to promote the proliferation of PDAC and HCC cancer cells and was an unfavorable prognostic factor in the TCGA PDAC cohort.

TF genes KLF6 and PPARG are two other well-known examples of ACR-to-gene links. They are both connected to enhancers that make them easier for PDAC cancer cells to access. PPARG expression in pancreatic cancer is linked to worse survival. Another unfavorable prognostic marker of PDAC, FLNB, was linked to five enhancer regions, indicating extensive epigenetic regulation. In the basal BRCA cohort, several enhancers were linked to the genes EN1, VIM, and VEGFA. These findings highlight the strength of ACR-to-gene analysis in identifying potential regulatory relationships between distal elements and clinically relevant genes.

Uncovering Transcriptional Regulations Involved in Cancer Development

The researchers tried to figure out how transcriptional regulation affects the growth of cancer. They focused on finding the target genes of transcription factors (TFs), which can show the state of a cell. They found 258 regulons, or regulatory units, each containing between 20 and 4,310 target genes. Among these, 87 regulons were highly specific to certain types of cancer. Some regulons were tissue-specific, while others were specific to cancer cells. For instance, FOXA1 and GATA3 were found in non-basal breast cancer, KLF4 and FOSL1 in cervical and head and neck cancer, HNF1A and KLF9 in clear cell renal cell carcinoma, and HNF4G and GATA6 in colorectal and pancreatic cancer.

Cancer cells had higher levels of activity for some regulons compared to healthy cells. These included MYBL1 in basal breast cancer, TP73 in cervical and head and neck cancer, KLF6 in pancreatic and clear cell renal cell carcinoma, and NRF1 in pancreatic cancer. This increased activity was also supported by increased accessibility of these TFs.

Researchers used a number of different methods to confirm their results, which showed that the target genes of cancer-cell-specific regulons were linked to pathways that are specific to cancer. They further validated the target genes for each TF using chromatin immunoprecipitation followed by sequencing (ChIP-seq) data. This research not only confirms existing knowledge but also uncovers new information with the help of a larger pan-cancer cohort.

Diving Deeper into the Epigenetics of Metastatic Cancer

The study included 52 metastatic samples from six types of tumors. Certain transcriptional programs were found to be involved in metastasis. The study identified several important markers for prognosis. For example, the LAMA5 regulatory regions were upregulated in colon cancer liver metastasis samples, consistent with the known role of LAMA5 in promoting the growth of these metastases.

The researchers also compared the accessibility of transcription factor motifs between primary and metastatic cells across four types of cancer. They found that certain transcription factors had higher accessibility in metastatic cells compared to primary cancer cells.

The study also looked at the pathways that were more active in differentially accessible chromatin regions (DACRs) that were higher in samples of metastasized tumors compared to samples of primary tumors. The researchers found that development-related pathways were significant in three of the four cohorts studied.

The researchers also analyzed data for nine cases of colon and uterine cancer that had both primary and metastasis samples available. They found that all of the paired primary–metastatic samples followed a linear trajectory, gradually progressing from normal to primary to metastatic cells.

Finally, the researchers used available whole-exome sequencing data to look at the genetic makeup of the 176 tumor samples and found somatic mutations and copy-number variations. They found that the mutation burdens across cancer types were similar to those previously reported. The researchers also investigated the impact of TP53 missense and truncation mutations on chromatin accessibility within breast cancer samples.

Overall, the study provides a detailed understanding of the epigenetic programs involved in cancer metastasis.

Building a Comprehensive Map of Epigenetic Drivers in Cancer

The researchers conducted a study to identify clinically important changes in gene activity related to cancer. They found that certain genes, known as regulons, were more active in certain types of cancer cells and that this increased activity was linked to worse outcomes for patients. For example, they found that high activity of the PITX3 regulon was connected to poor survival in patients with glioblastoma (a type of brain cancer), and high activity of the KLF6 regulon was linked to poor survival in patients with pancreatic cancer.

The researchers also investigated the impact of the human papillomavirus (HPV) on gene activity in cancer. They found that one particular regulon, KLF4, was less active in HPV-positive tumours compared to HPV-negative ones. They also identified other regulons that were differently active in HPV-positive versus HPV-negative samples, as well as three additional factors that affected patient survival in head and neck cancer.

Finally, the researchers looked for alterations in genes that could potentially be targeted with drugs. They found several examples of such changes, including some in cancer types where those targets are not currently used in treatment.

To sum up, the researchers created a detailed map of genetic activity in different types of cancer cells and linked these patterns to patient outcomes. They also identified potential new targets for drugs. This work could help to advance our understanding of cancer and improve treatment strategies.

Here we constructed a pan-cancer epigenetic and transcriptomic atlas using single-nucleus chromatin accessibility data (using single-nucleus assay for transposase-accessible chromatin) from 225 samples and matched single-cell or single-nucleus RNA-sequencing expression data from 206 samples. With over 1 million cells from each platform analysed through the enrichment of accessible chromatin regions, transcription factor motifs and regulons, we identified epigenetic drivers associated with cancer transitions. [...] This atlas provides a foundation for further investigation of epigenetic dynamics in cancer transitions.

What's next?

In conclusion, our understanding of cancer has taken a significant leap forward with this study. By revealing the hitherto unseen role of epigenetic drivers in various stages of cancer, we now have a map to navigate the complex landscape of this disease. However, this is just the tip of the iceberg. With further research and exploration of this area, we could potentially develop more targeted treatments and possibly even preventions. Our fight against cancer is far from over, but armed with this new knowledge, we are better equipped than ever before. As we continue to unravel the mysteries of cancer, we move closer to the day when this devastating disease is no longer a death sentence but rather a manageable condition.

If you want to find out more about epigenetics, we also recommend the information provided by the Centre for Disease Control and Prevention.

If you want to learn more about Scalable Prediction of Acute Myeloid Leukaemia using high-dimensional machine learning and blood Transcriptomics, you can also take a look at a study by our experts Dr Patrick Günther and Dr Kevin Baßler and their colleagues.