May 19, 2024

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Which genes do cancer turn on/off in order to progress and metastasize?

Which genes do cancer turn on/off in order to progress and metastasize?



Which genes do cancer turn on/off in order to progress and metastasize? 

Scientists analyze nearly 2 million cells to reveal the mystery of epigenetic regulation of cancer evolution!

Genetic mutations play a pivotal role in the development of cancer. However, even when the genes themselves remain unchanged, there are still ways to alter gene function and influence cancer’s onset. This is where epigenetics comes into play.

The spatiotemporal dynamics of chromatin unwinding and subsequent transcription mechanisms play a crucial role in the pathogenic transformation of cancer, including its initiation, progression, and metastasis. This epigenetic regulation also plays a part in modulating tumor resistance to therapies. There are now numerous anti-cancer drugs that target epigenetic modifications, making it clear that understanding epigenetic changes in cancer can provide valuable insights.

On Nov 02, the journal Nature published new findings by a research team from Washington University in St. Louis and Princeton University. The researchers analyzed epigenetic changes in over 200 samples from 11 different cancer types, spanning more than a million cells, uncovering a wealth of valuable data, including cancer-specific epigenetic driving mechanisms.

Which genes do cancer turn on/off in order to progress and metastasize?

This study employed single-nucleus transposase-accessible chromatin sequencing (snATAC-seq) and single-nucleus RNA sequencing (snRNA-seq), allowing for the simultaneous analysis of the epigenomic and transcriptomic profiles of individual cells. This approach enables the direct comparison of chromatin accessibility and gene transcription associations.

The study used the NCI Human Tumor Atlas Network (HTAN) database, incorporating 158 primary tumor tissue samples, 52 metastatic tumor samples, and 15 normal adjacent tissue samples from 201 patients across 11 cancer types. These cancer types included colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), skin cutaneous melanoma (SKCM), endometrial cancer (UCEC), ovarian cancer (OV), breast cancer (BRCA), multiple myeloma (MM), glioblastoma (GBM), clear cell renal cell carcinoma (ccRCC), and more.

Which genes do cancer turn on/off in order to progress and metastasize?

The snATAC-seq analysis covered 1,019,175 cells, with an average of 4,530 cells analyzed per sample. They identified 126,196 accessible chromatin regions (ACRs), with the majority found in introns (49%), distal intergenic regions (39.8%), and promoters (8.6%).

Cross-cancer comparisons identified 56,001 differential accessible chromatin regions (DACRs) with tissue and cancer cell specificity. Many DACRs included tissue-specific gene promoters, such as keratin genes in squamous cell carcinoma, PAX8 in OV and UCEC, GATA3 in non-basal-like BRCA, PTRZ1 in GBM, and more.

Similarities were observed between cancer types from the same primary tissue, clustering head and neck squamous cell carcinoma (HNSCC) with cervical squamous cell carcinoma (CESC) and non-squamous cervical cancer with epithelial types.

When comparing cancer cells and normal cells, the researchers identified 22,187 regions with increased accessibility and 29,074 regions with decreased accessibility in cancer cells. Seventy-five percent of DACRs were aligned with changes in gene expression. Cancer type-specific DACRs included HOXA4 in GBM, known for its poor prognosis, FGF19 in BRCA, and EGLN3 in ccRCC, all serving as known pathological markers for their respective cancer types.

The study further analyzed epigenetic changes in primary tumors and metastatic cancers, identifying tissue-specific enhancers such as FOXA1 and GATA3 in non-basal-like BRCA, KLF4 and FOSL1 in CESC and HNSCC, and HNF1A and KLF9 in ccRCC. For CRC and PDAC, HNF4G and GATA6 were identified.

Comparative analysis of transcription factors and their accessibility scores in primary and metastatic cancer cells revealed several genes with higher accessibility in metastatic cells, including TWIST1 and PBX3, which promote CRC metastasis.

Finally, the researchers identified potential clinical relevance for epigenetic gene regulation. In the TCGA-PDAC cohort, increased KLF6 enhancer activity was associated with progression-free survival and overall survival differences. Similarly, increased PITX3 activity in GBM patients was linked to differences in progression-free survival.

The researchers also identified cancer-specific differentially expressed genes (DEGs) and DACRs that could serve as drug targets. These included well-known targets like ESR1 expression and accessibility in BRCA and UCEC, as well as VEGFA accessibility in ccRCC and CRC. Potential targets not yet applied in clinical practice were also discovered, such as EGFR accessibility in ccRCC, TOP1 expression in UCEC, MM, and ccRCC, and FGFR2 expression in GBM, ccRCC, and basal-like BRCA.

Understanding the chromatin structure of entire tumors, changes in chromatin accessibility during cancer progression, and the interplay between chromatin accessibility, genetic alterations, and transcription patterns is crucial for advancing cancer biology and clinical practice. While targeting transcription factors directly can be challenging with conventional therapies, the analysis of transcriptional programs can unveil indirect regulatory approaches.

Which genes do cancer turn on/off in order to progress and metastasize?


Reference:

[1] Terekhanova, N.V., Karpova, A., Liang, WW. et al. Epigenetic regulation during cancer transitions across 11 tumour types. Nature (2023). https://doi.org/10.1038/s41586-023-06682-5.

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