A sugar rush can fuel many things. It can power the late-night experiments demanded by reviewer number 3 or it can drive tumor evolution. Fueled by both these factors, new insight into the linked metabolic-epigenetic mechanisms of metastasis comes at you from a collaborative effort led by the lab of Andrew Feinberg in the Center for Epigenetics at Johns Hopkins University School of Medicine.
ASSEMBLY, MODULAR ORGANIZATION, AND CHROMATIN INTERACTIONS. A major barrier to our understanding of the normal functions, the tissue-specific roles, and, importantly, the diverse impacts of mutations on mSWI/SNF complex mechanisms lies in the lack of information regarding subunit organization, assembly, and 3D structure. Cancer is driven by somatic mutations in critical genes, but few non-coding drivers are known. In a pan-cancer analysis, Zhu et al. Identified frequently mutated, multi-tissue regulatory elements with chromatin loops to distal genes. Genomic deletion of one region caused deregulation of cancer genes, pathways, and proliferation in human cells.
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer that is all too common. The mechanisms of its metastasis remain a mystery since both primary tumors and far-flung secondary (metastatic) tumors share the same driver mutations. By examining matched primary and metastatic PDAC lesions, the team was able study tumor evolution in extensively sequenced samples that had no metastasis-specific driver mutations. Thus, they had the perfect samples to study the epigenomic mechanisms of cancer’s spread, which they confirmed in cell lines.
The dramatic changes in gene expression required for development necessitate the establishment of cis- regulatory modules defined by regions of accessible chromatin. Pioneer transcription factors have the unique property of binding closed chromatin and facilitating the establishment of these accessible regions. Nonetheless, much of how pioneer transcription factors coordinate changes in. DNA methylation-based chromatin compartments and ChIP-seq profiles reveal transcriptional drivers of prostate carcinogenesis. Simmonds P (1) (2), Loomis E (3), Curry E (4).
Immunohistochemistry of histone post-translational modifications (PTMs) revealed global epigenomic reprogramming during the evolution of distant metastases. The team then characterized the specific locations of the modifications by launching an integrated assault on the epigenomic landscape. They used ChIP-seq to analyze histone PTMs (H3K9me2, H3K9me3, and H3K27me3 as marks of heterochromatin and H3K27ac and H3K36me3 as marks of euchromatin), whole-genome bisulfite sequencing (WGBS) for DNA methylation, and RNA-seq for gene expression.
Here’s what they found:
- The epigenomic reprogramming is targeted to thousands of large-scale euchromatin and heterochromatin domains.
- The large heterochromatin domains are large organized chromatin (H3)K9-modications (LOCKs) domains and their partially overlapping large DNA-hypomethylated blocks.
- They also came across a familiar and interesting hybrid feature, resembling LOCK euchromatin islands (LOCK-EIs). There are highly localized reciprocal changes to H3K27ac and H3K9me2, within promoters, coupled to similar reciprocal changes of H3K36me3 and H3K27me3, in gene bodies, within LOCK genes.
- The team also found reprogramming in a unique subset of very large LOCK domains.
- A connection between metabolism and histone modifications, where distant metastases co-evolve a dependence on the oxidative branch of the pentose phosphate pathway (oxPPP).
- This lets tumors binge on glucose to feed the metabolic sweet tooth that is critical to their growth in their new environment.
- This mechanism was confirmed by inhibiting phosphogluconate dehydrogenase (PGD), a key enzyme in the oxPPP, either with RNAi or pharmacologically, which reversed the reprogrammed chromatin and gene expression, as well as the tumorigenesis.
Overall, these findings detail a non-genetic form of natural selection critical to tumor evolution, where linked metabolic-epigenetic programs are selected for and allow distant metastases to take advantage of their new glucose rich environments.
Offering a humble peek behind the scientific curtain, Feinberg concludes, “I would actually like to say something about peer review. We all complain about it but we are also the reviewers. In this case, the amount of work and resources doubled in response to reviewers’ criticisms, but in the end I thank them for that. The additional work made a much more convincing case that the epigenetic changes drive distant cancer metastasis and that they are linked to a metabolic pathway that we might be able to manipulate therapeutically, increasing the chances that this work will benefit patients’ lives.”
Catch all the evolutionary links over at Nature Genetics, January 2017
As part of the new class of Pew-Stewart Scholars, geneticist Chao Lu, PhD, is taking a close look at chromatin’s role in cancer and other human diseases. Work in the Lu lab has revealed that cancer-associated mutations in chromatin modulators are drivers of tumor development. A key goal is to determine which of these chromatin mutations are druggable, and down the road, to add innovative chromatin-based therapies to current oncology practice.
Dr. Lu, assistant professor of genetics and development at Columbia University Irving Medical Center and a member of the Herbert Irving Comprehensive Cancer Center (HICCC) at NewYork-Presbyterian/Columbia, is one of just seven new Pew-Stewart Scholars for Cancer Research announced June 14 by the Pew Charitable Trust. The prestigious four-year grant, funded by the Alexander and Margaret Stewart Trust and administered by Pew, supports promising early career scientists whose research will accelerate discovery and advance progress to a cure for cancer. In 2019, the seven scientists were selected out of a pool of 62 nationwide, and to date, there are 32 Pew-Stewart Scholars working to solve cancer.
Dr. Lu is bringing his interdisciplinary expertise in cancer biology and chromatin regulation to examine the fundamentals of tumor development and identify new potentially druggable targets, looking beyond single genetic mutations that contribute to cancer.
In its textbook role, chromatin’s primary function is to package long, complex DNA molecules in a precise way that protects DNA’s structure and plays a crucial role in many important biological processes, including cell division and gene expression regulation. As Dr. Lu puts it, “It has been known to be a ‘boring’ mechanism to study.” But in the past 20 years with the advent of next-generation sequencing technology, scientists have been able to systematically sequence the tumor genome, and in doing so, have revealed much more that how aberrant chromatin organization can potentially drive tumorigenesis.
“When scientists first started to sequence different cancer types, obviously they got some of the usual suspects, which are the genes we know that cause cancer but they also got a lot of surprises,” says Dr. Lu. “Among the genes we didn’t know that were involved in the tumorigenic process are chromatin-associated proteins which are involved in genome regulation. Chromatin’s function in packaging DNA itself contains a lot of regulation, and we now appreciate that if that process is abnormal, all kinds of disease can happen, not just cancer.”
Drivers Chromatin Test
Dr. Lu and his lab are trying to understand how chromatin regulators promote tumorigenesis and to consider new strategies for therapeutically targeting tumors with chromatin mutation. “This is not your conventional, textbook oncogenes and tumor suppressors. We’ll need a new way to target them,” notes Dr. Lu.
Through a combination of high-throughput genetic approaches and biochemistry, Lu and his group are aiming to discover how the mutation in chromatin regulators change the genome regulation landscape, which in turn are effecting different cancer hallmarks.
Dr. Lu joined Columbia University in the spring of 2018 from Rockefeller University, where he was a post-doctoral fellow in Dr. C. David Allis’ Laboratory of Chromatin Biology and Epigenetics. Dr. Lu wanted to pair his previous training in cancer biology to a broad area of basic research, which is what attracted him to chromatin, specifically chromatin malfunction as a new mechanism responsible for cancer progression.
Drivers Chromatin Model
“In addition to its link to cancer, I was and am intrigued by the chromatin itself and by its very complex interaction to ensure our genes are properly regulated,” says Dr. Lu. “I continue to be amazed by the sophisticated process in which our cells package our genome and access them in a highly regulated manner.”
Dr. Lu joins an innovative class of Pew-Stewart scholars whose research aims to better understand the origins, diagnosis, and treatment of cancer. Pew scholars gather annually in March for Pew's annual meeting in the biomedical sciences, where they are recognized and network with peers in the field. In 2018, Dr. Lu received the AACR Gertrude B. Elion Cancer Research Award and in 2017, the Damon Runyon-Dale F. Frey Award for Breakthrough Scientists and Blavatnik Regional Award for Young Scientists.
Drivers Chromatin Definition
-Melanie A. Farmer