Category Archives: Research Highlight

Oncogenes Hijack Enhancers to Promote the Onset of Cancer

Medulloblastoma, a common childhood brain tumor, is classified into 4 subgroups that vary dramatically in terms of the aggressiveness of the disease. For Group 3 and Group 4 tumors,  hardly any characteristic genomic changes that drive tumor growth and would make potential targets for drug development have been identified. To propose a solution for this challenge, some investigators were systematically analyzing all genomic alterations in pediatric brain cancer to discover new targets for treatment.


They discovered, from 137 cases of aggressive patients, that in some of tumor genomes large regions of DNA had been deleted or duplicated or had changed their orientation. These varying structural changes had common consequences in all tumors under investigation: One of two oncogenes called GFI1 and GFI1B, which are not active in healthy brain tissue, is transcribed in these tumors and thus contributes to the development of cancer.

They also noticed that different structural changes had moved the oncogene from a usually inactive environment to a position close to DNA sequences called “enhancers”, which are involved in the activation of genes. In mice, the researchers subsequently proved that activated GFI1B leads to the development of brain cancer, providing evidence that the “hijacked” gene enhancers promote the onset of cancer.

This research directly contribute to the development of better treatments for children with brain cancer. Substances that block the effects of the GFI1 and GFI1B oncogenes are already being tested in clinical trials and might now also be used to slow down the growth of aggressive Group 3 and Group 4 medulloblastomas.

Another team, dedicated to investigating the epigenetic regulation of gene activity, compared patterns of DNA methylation across the whole genome from 42 medulloblastomas with the patterns found in healthy control tissue. As discovered in this study, numerous genes in tumor cells exhibited low levels of methylation compared to healthy counterparts. At the same time, they were transcribed significantly more frequently than in healthy cells.


Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 2014; doi:10.1038/nature13379

Using various ARKO mouse models to study AR roles in various tumors

The androgen receptor (AR) is expressed in many cell types and the androgen/AR signaling has been found to have important roles in modulating tumorigenesis and metastasis in several cancers including prostate, bladder, kidney, lung, breast and liver. However, whether AR has differential roles in the individual cells within these tumors that contain a variety of cell types remains unclear. Generation of AR knockout (ARKO) mouse models with deletion of AR in selective cells within tumors indeed have uncovered many unique AR roles in the individual cell types during cancer development and progression.


A recent review published in “Oncogene” discussed the results obtained from various ARKO mice and different human cell lines with special attention to the cell type- and tissue-specific ARKO models. The understanding of various results showing the AR indeed has distinct and contrasting roles in each cell type within many hormone-related tumors (as stimulator in bladder, kidney and lung metastases vs as suppressor in prostate and liver metastases) may eventually help us to develop better therapeutic approaches by targeting the AR or its downstream signaling in individual cell types to better battle these hormone-related tumors in different stages.


Androgen receptor (AR) differential roles in hormone-related tumors including prostate, bladder, kidney, lung, breast and liver. Oncogen. 2014;33:3225-3234

Insight into Immunotherapy: Research Review and Drug Discovery

Immunotherapy is just a concept for a long while, and real advances in our understanding about how to do this have been made in recent years. Scientists now learn the cancer microenvironment plays essential roles in cancer growth, cancer spread and responses to therapy, and involves cells and molecules of the immune system implementing fundamental functions.  Also, they learn how Tumors make use of these control mechanisms to evade an attack from the immune system.

The immune system is recruited to specifically target cancer cells for therapeutic purposes. It shows promise for causing long-lasting regression and preventing relapse in cancer patients, by means of Tumor-specific immunological memory. Scientists investigate immunomodulatory mechanism of Tumors, including the blockage of immune checkpoints, in order to enhance anti-cancer immune responses.

The composition and characteristics of the cancer microenvironment are important in determining the anti-Tumor immune response. For example, certain cells of the immune system, such as effector T cells, dendritic cells (DCs), and natural killer cells, are capable of driving potent anti-Tumor responses. However, Tumor cells often make their microenvironment immunosuppressive, and thereby favour the development of immunosuppressive populations of immune cells, such as regulatory T cells.

Recent research reviews

12 representative citations, focusing on Tumor immunology & immunotherapy, are specifically retrieved from Nature Reviews Cancer (IF=35,2013 year)and Nature Reviews Immunology(IF=33,2013 year) , and are listed as follows. They are available for describing research progress in understanding the complexity of the immune system in cancer biology and the promise of immunotherapy.

Research Reviews by Year(2012-2014)


Novel Drug Discovery

There are more than a hundred other trials going on for cancer, a large number of them for immunotherapy drugs. As we know, significant immunotherapy compounds include Merck’s MK3475 for melanoma and other cancers, Roche’s MPDL3280A for lung cancer, and Bristol-Myers Squibb’s Elotuzumab. Many of these drugs are based on a discovery made two decades ago, called immune checkpoints, used by the body to prevent the attack of normal cells by the immune system.

Immune checkpoints are used to prevent the body from rejecting cells that are beneficial. While cancer cells use this mechanism to trick the immune system, and companies are developing drugs to stop the cancer cells from exploiting immune checkpoints.



1. Tumor immunotherapy — leukocytes take up the fight. Nat Rev Immunol. 2012 Apr;12(4):237.

2. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013 Dec;13(12):862-74.

3. Immunotherapy: Cancer mutation-specific immune responses. Nat Rev Cancer. 2014 May 23;14(6):387.

Capture of Culprit mutations for Targeted Therapies

As the rocketing development of sequencing techniques, oncogene discovery enters an era of exponential growth, which supports many therapeutic targets for certain types of cancer. The statistical data reported is that 78% of cancer patients have one or more “culprit” mutations. Thus, establishing The pathogentic relevance of individual mutations is a major challenge to be solved.

Scientists can figure out the genetic rules of cancer in the support of diagnosis, risk stratification and individualized treatment, after large-scale cancer genomes have been sequenced. “We’re finding clinically relevant information in the tumor samples we’re sequencing for discovery-oriented research,” says Elaine Mardis, PhD, co-director of the Genome Institute at the School of Medicine. “Genome analysis can play a role at multiple time points during a patient’s treatment, to identify culprit mutations in the tumor genome and to determine whether cells carrying those mutations have been eliminated by treatment.”

Identify “Culprit” Genes for Cancer Treatment

Information of cancer genomes has been screened to identify specific culprit genes, which determine patients’ response to drug. In patients with advanced lung cancer, TORCH (Tarceva or Chemotherapy) investigators have found culprit mutations in EGFR that can be targeted by Erlotinib.


Additionally, Mardis has also found numerous culprit mutations in genes that have not previously been associated with breast tumors. A number of these genes have been identified in prostate, colorectal, lung or skin cancer, and leukemia. Drugs that target mutations in these genes, including imatinib, ruxolitinib and sunitinib, are already on the market.

Optimize Treatment

A series of mutations in the breast tumors, screened by GWAS strategies, have small-molecule inhibitor drugs that target defective proteins. For patients who are not responding to aromatase inhibitors, treatment options may encompass adding the indicated small-molecule inhibitor into conventional chemotherapy.

“We felt it was important to show that there could be therapeutic options available to patients who are resistant to aromatase inhibitors,” says PhD Mardis,. “As we move forward, we think sequencing will contribute crucial information to determining the best treatment options for patients.”


The Next-Generation Sequencing Revolution and Its Impact on Genomics. Cell 2013;

155(1): 27–38

Track Landmarks in Cancer

For over a century, scientists have been exploring the mechanisms of cancer growth and spread, which deepen our understanding of cancer from molecular and cellular perspectives. Some landmark discoveries are picked out in the support of advisors, based on the context of the prevailing concepts and current knowledge. Special supplements released on the Nature website cover these landmarks, including a Timeline of the earliest papers.


Review-type articles in cancer

Nature Publishing Group (NPG) library contains research and review-type articles on the topic of cancer from 9 journals, such as Nature, Nature Medicine, and Nature Reviews Cancer. To introduce cancer research of landmark significance, Special supplements highlight 3 articles of review listed as follows.

Dr. Scott W at Cold Spring harbor laboratory, New York, published an article entitled ” Intrinsic tumour suppression” in the Nature journal. “Evolution installs in the proliferative programmes of mammalian cells a variety of innate tumour-suppressive mechanisms that trigger apoptosis or senescence. These contingent processes rely on a series of sensors and transducers that act in a coordinated network to target the machinery responsible for apoptosis and cell-cycle arrest at different points ” mentioned Scott. “Although oncogenic mutations that disable such networks can have profound and varied effects on tumour evolution, they may leave intact latent tumour-suppressive potential that can be harnessed therapeutically. “

DR. Vogelstein B in Howard Hughes medical institute, issued a review of “cancer genes and the pathways they control ” in the Nature Medicine journal. “The revolution in cancer research can be summed up in a single sentence: cancer is, in essence, a genetic disease.” described Vogelstein, ” In the last decade, many important genes responsible for the genesis of various cancers have been discovered, their mutations precisely identified, and the pathways through which they act characterized. The purposes of this review are to highlight examples of progress in these areas, indicate where knowledge is scarce and point out fertile grounds for future investigation.”

Dr. Bruce A. Chabner in the division of hematology/oncology, Massachusetts General Hospital, published an article with title of “Chemotherapy and the war on cancer” in the Nature Reviews Cancer journal. ” The era of chemotherapy began in the 1940s with the first uses of nitrogen mustards and antifolate drugs” wrote Bruce, ” Cancer drug development since then has transformed from a low-budget, government-supported research effort to a high-stakes, multi-billion dollar industry. The targeted-therapy revolution has arrived, but the principles and limitations of chemotherapy discovered by the early researchers still apply. This article chronicles the history of modern chemotherapy and identifies remaining challenges for the next generation of researchers. “


1. Intrinsic tumour suppression. Nature 2004. 432, 307−315

2. Cancer genes and the pathways they control. Nature Medicine 2004. 10, 789−799

3 Chemotherapy and the war on cancer. Nature Reviews Cancer 2005. 5, 65−72

Disclose the Action Film of Invasive Tumour Cells

Mikala Egeblad observed the action film of tumour cells by recording their landscapes inside live mice. In the previous study, cells stayed still, frozen on microscope slides, but now viewing them in a living animal brings cells to life. “You turn on the microscope and look in the live mouse and suddenly these same cells are running around like crazy,” says Egeblad, a cancer researcher at Cold Spring Harbor Laboratory in New York. “It really changed my thinking.”


Novel technique offer the chance to spy on the action of individual tumour cells, and investigators thereby utilize relative clues to hypothesis about how cancers grow ,spread and resist treatment. As an promising approach, Tracking Cancer in Live Animals over Time(TCLAT, also called intravital imaging) allows biologists to piece together timelines for key cellular and molecular events, and zoom in some lesion cells that drive the disease or resist treatment.

Intravital imaging involves focusing powerful microscopes directly onto exposed tissue in a live mouse. Microscopy technology, In combination with markers, make this approach powerful. A growing library of molecular makers are available to enhance the color identification and enable researchers to visualize different types of cells and structure, such as immune-system cells.

Recording cancer response to drug

Some scientists are using intravital imaging to track cancer drugs in the body, and to explore why some drug treatments fail. Cancer biologists typically test the effect of chemotherapies in vivo by measuring changes in cancer growth and size in mice. Intravital imaging gives a more direct view, revealing which cells in a lesion take up the drugs, and whether those cells live or die.

Egeblad and her team have made films of doxorubicin, a naturally fluorescent cancer drug, as it infiltrated mammary tumours in mice. They were surprised by the degree of variability — even within small regions of the tumour — in the amount of the drug that got into the cells, and in the number of cells that died.

Viewing action film of tumour cells help aware that the microenvironment, not just genetics, can influence cancer. The further study is an opportunity to reply the questions with deep and  broad insights: how do different components of the tumour and its environment co-evolve?


1. Intravital microscopy through an abdominal imaging window reveals a pre-micrometastasis stage during liver metastasis. Sci Transl Med. 2012 Oct 31;4(158):158ra145.

2. Tumor microenvironment of metastasis in human breast carcinoma: a potential prognostic marker linked to hematogenous dissemination. Clin Cancer Res. 2009 Apr 1;15(7):2433-41.