Scientists from Montreal Neurological Institute and McGill University have accomplished a new finding: one universal protein in human cells may be a key switch that could activate cancer cell metastasis. This finding is largely ignored so far. The finding of this protein expands our knowledge on epithelioma such as breast cancer and lung cancer. This study was published in JCB.

Rab  GTPases are master regulators of membrane trafficking controlling the formation of vesicles, vesicle transport via the actin and microtubule cytoskeletons, and vesicle tethering and fusion. Rabs are activated by guanine-nucleotide exchange factors(GEFs) that catalyze the exchange of GDP for GTP. The DENN(differentially expressed in normal and neoplastic cells) domain is an evolutionarily ancient and structurally conserved protein module.

Currently, there are 26 identified DENN domain proteins, the majority of which are poorly characterized. One such protein, DENND2B, is a member of the DENND2A-D subfamily that contains a C-terminal DENN domain but few other distinguishing features. DENND2B was originally identified by screening a cDNA expression library for gene products that suppress the tumorigenicity of HeLa cells in nude mice and was named ST5.

In this study, researchers demonstrate that DENND2B localizes to the cell surface in association with the actin regulatory protein MICAL-L2, a Rab13 effector that induces membrane ruffles when bound to active Rab13. They develop and optimize a novel Forster resonance energy transfer(FRET)-based Rab13 biosensor that reveals selective activation of Rab13 on membrane ruffles at the dynamic leading edge of migrating cells, and they demonstrate that Rab13 activation by DENND2B at the cell surface is required for cell migration and invasion.

Finally, they find that disruption of the Rab13-DENND2B trafficking pathway dramatically reduces the migration of highly aggressive breast cancer cells in vivo. These findings provide evidence for a DENND2B-centered module that appears critical for the metastasis of cancer cells.

Reference:

Ioannou M S, Bell E S, Girard M, et al. DENND2B activates Rab13 at the leading edge of migrating cells and promotes metastatic behavior[J]. The Journal of cell biology, 2015, 208(5): 629-648.

Recurrence is the main cause of death after tumor treatment. Tumor cells remain inactive and are activated again with more aggressively. This phenomenon has been one of the biggest mystery of tumor. Researchers from University of California San Francisco have identified the key protein HIGD1A in this process. The study was published in Cell Reports.

Hypoxia inducible factor(HIF-1) is a widely expressed transcription factor that regulates the survival of cells during oxygen and glucose deprivation. HIF can also regulate tumor metabolism by repressing respiration while promoting glycolysis, which enables rapid tumor cell proliferation.

It has been confirmed that some of the most metabolically compromised tumor regions found around their necrotic cores fail to induce HIF activity, potentially due to glucose starvation. Interestingly, these regions still express the HIF-1 target HIGD1A.

In this study, scientists found that HIGD1A interacts with the mitochondrial electron transport chain, modulates oxygen consumption, ROS production, and AMPK activity to promote cell survival during glucose starvation, while simultaneously suppressing tumor growth invivo. Their studies confirm these observations and identify HIGD1A as an important upstream component of this signaling cascade. Furthermore , HIGD1A repression is associated with tumor recurrence in breast cancers following therapy, consistent with their observations that HIGD1A expression helps repress tumor growth.

These findings therefore provide novel insights into tumor cell adaptation mechanisms to extreme environments and suggest that HIGD1A may play an important role in tumor dormancy or recurrence mechanisms.

Reference:

 Ameri K, Jahangiri A, Rajah A M, et al. HIGD1A Regulates Oxygen Consumption, ROS Production, and AMPK Activity during Glucose Deprivation to Modulate Cell Survival and Tumor Growth[J]. Cell reports, 2015, 10(6): 891-899

By silencing a mechanism that allows cancer cells to reject anti-cancer drugs, a new breakthrough out of MIT and Harvard could dramatically increase the efficacy of treatment.

In addition to disabling a tumor’s defenses and delivering anti-cancer drugs, the new nanodevice fluoresces can help scientists monitor treatment.

In the war against cancer, scientists often have to act like battlefield commanders, devising creative attack strategies to bring the disease to its knees. A new tactic developed by researchers from MIT, Harvard Medical school and Queen Mary University of London involves a super-small device that disarms cancer cells so tumor-shrinking drugs can be delivered.

The device, known as a “nanobeacon,” consists of a gold nanoparticle covered with strands of DNA. Before the nanobeacon is activated inside a cell, the DNA strands are folded back on themselves like hairpins. When they arrive at the right spot inside a cancer cell, however, the strands open up, releasing anti-cancer drugs and binding to messenger RNA (mRNA), “the snippet of genetic material that carries DNA’s instructions to the rest of the cell,” according to an MIT news report about the research published Monday in Proceedings of the National Academy of Sciences.

Specifically, the nanobeacons latch onto the strand of mRNA responsible for making a protein known as MRP-1. When overexpressed, this protein, found in all cancer cells to varying degrees, can act like a pump that eliminates treatment drugs, rendering them ineffective. When the nanobeacons connect with the RNA, however, this mechanism is disabled. In effect, the drug-resistant gene inside the cancer cell is shut down cold.

Additionally, Artzi adds that the nanobeacons can be engineered to interact with other genes inside cancer cells — not just those responsible for producing drug-resistance proteins. In fact, the researchers are now experimenting with using the method to shut down a gene that causes gastric tumors to spread to the lungs.

A new study show that scientists develop a new test which can predict the survival chances of women with breast cancer by analysing images of ‘hotspots’ where there has been a fierce immune reaction to a tumour. The finding is published in the journal Modern Pathology.

Investigators analysed tumor samples from 245 woman with a type of breast cancer called oestrogen receptor negative, via using statistical software to track the extent to which the immune system was homing in and attacking breast cancer cells.

They found that images of hotspots where immune cells were spatially clustered together around breast cancer cells provided a better measure of immune response than simply the numbers of immune cells within a tumour.

The patients were split into two groups based on the numbers of immune hotspots spots within their tumours. And researchers found that women whose cancers had a high number of spots lived an average of 91 months before their cancer spread, compared with just 64 months for those with a low number of spots.

Promise of Diagnostic Test

The test, described in the paper, become the first objective method of measuring the strength of a patient’s immune response to their tumour. Its automated analysis could complement existing methods where pathologists examine tumour samples under the microscope to gain a sense of whether there is a strong immune response.

The research aims to develop completely new ways of distinguishing more and less aggressive cancers, based on how successful the immune system is in keeping tumours in check. It is required to assess how many immune cells there are, but whether these are clustered together into cancer-busting hotspots, therefore mesuring the strength of an immune response to a cancer.

By analysing the complex ways in which the immune system interacts with cancer cells, investigators can split women with breast cancer into two groups, who might need different types of treatment, such as immunotherapy. The study has found an ingenious approach to generate and understand data from images of biopsy samples, which are already taken from patients but not analysed in a mathematical way.

Reference:

Beyond immune density: critical role of spatial heterogeneity in estrogen receptor-negative breast cancer. Modern Pathology, 2015; DOI: 10.1038/modpathol.2015.37

Breast cancer is immunogenic, and infiltrating immune cells in primary breast tumors convey important clinical prognostic and predictive information. Furthermore, the immune system is critically involved in clinical responses to some standard cancer therapies.

Early breast cancer vaccine trials have established the safety and bioactivity of breast cancer immunotherapy, with hints of clinical activity. Novel strategies for modulating regulators of immunity, including regulatory T cells, myeloid-derived suppressor cells and immune checkpoint pathways (monoclonal antibodies specific for the cytotoxic T-lymphocyte antigen-4 or programmed death), are now available. In particular, immune checkpoint blockade has enormous therapeutic potential. Integrative breast cancer immunotherapies that strategically combine established breast cancer therapies with breast cancer vaccines, immune checkpoint blockade or both should result in durable clinical responses and increased cures.

Reference:

Leisha A Emens. Breast cancer immunobiology driving immunotherapy: vaccines and immune checkpoint blockade [J].NIH Public Access.

A new research recently has discovered some key gene mutations that drive testicular germ cell tumors(TGCTs), and identified the key resistance genes which cause this cancer. It is the first time to apply the latest gene sequencing technology to look for the related details of TGCTs which is the most common cancer in young male. This study was published in Nature Communications.

Testicular germ cell tumors are the most common cancer affecting young men, with a mean age at diagnosis of 36 years. The main TGCT histologies are seminomas, which resemble undifferentiated primary germ cells, and non-seminomas, which show differing degrees of differentiation.

Overall, TGCTs are markedly aneuploid with recurring gain of chromosomes 7, 8, 21, 22 and X. In addition, gain of chromosomal material from 12p is noted in virtually all cases, with genomic amplification and overexpression of genes in the 12p11.2-p12.1 region reported in ~10% of TGCTs.

In this study , scientists perform whole-exome sequencing(WES) of 42 TGCTs to comprehensively study the cancer’s mutational profile. The mutation rate is uniformly low in all of the rumors as compared with common cancers, consistent with the embryological origin of TGCT. In addition to expected copy number gain of chromosome 12p and mutation of KIT, they identify recurrent mutations in the tumour suppressor gene CDC27. Copy number analysis reveals recurring amplification of the spermatocyte development gene FSIP2 and a 0.4 Mb region at Xq28.

Their findings provide further insights into genes involved in the development and progression of TGCT.

Researchers from Harvard Medical School have developed a new dynamic analysis method called DBP, which is used to predict cancer response to chemotherapy. This development may improve the effectiveness of specialized chemotherapy medicine against cancer and be very important in the development of personalized therapeutic treatment . The study was published in Cell.

A fundamental challenge across is medicine to assign to a patient the drug or combination of drugs that will be of greatest benefit. In oncology, this choice has historically been driven by the anatomic location and histology of the tumor. There is a lack of effective predictive biomarkers to precisely assign optimal therapy to cancer patients. While most efforts are directed at inferring drug response phenotype based on genotype, there is very focused and useful phenotypic information to be gained from directly perturbing the patient’s living cancer cell with the drug in question

In this study, to satisfy this unmet need, scientists developed the Dynamic BH3 profiling(DBP) technique to measure early changes in net proapoptotic signaling at the mitochondrion induced by chemotherapeutic agents in cancer cells, not requiring prolonger ex vivo culture.

They find in cell line and clinical experiments that early drug-induced death signaling measured by Dynamic BH3 Profiling predicts chemotherapy response across many cancer types and many agents, including combinations of chemotherapies.

The Dynamic BH3 Profiling can be used as a broadly applicable predictive biomarker to predict cytotoxic response of cancers to chemotherapeutics in vivo.