Blockbuster highlight study that Nature magazine had to watch in November!

Time flies, November is coming to an end, and in the coming November, what are the highlights of Nature Magazine's research worth learning? The editor has sorted out the relevant articles and studied with you!

[1] Two Nature: Scientists reveal the critical role that epigenetic signatures play in cancer formation and behavior

doi：10.
1038/s41586-022-05202-1 doi：10.
1038/s41586-022-05311-x

Recently, published in the international journal Nature entitled "Phenotypic plasticity and genetic control in colorectal cancer evolution" and "The co-evolution of the genome and epigenome in colorectal cancer" two research reports, Scientists from the Institute of Cancer Research in London and other institutions have analyzed the key role
that epigenetics plays in the development of cancer behavior.

Scientists are revealing the critical role
that epigenetic signatures play in cancer formation and behavior.

Image source: Nature (2022).
DOI:10.
1038/s41586-022-05311-x

In the article, the researchers analyzed thousands of bowel cancer samples from different patients to follow examples of epigenetic changes, focusing on multiple samples taken from the same tumor tissue to look for changes
due to epigenetic characteristics 。 For years, medical scientists believed that most, if not all, cancers occur due to mutations in DNA that cause abnormal tissue growth in the form of tumors, and in recent years, researchers have found evidence that not all cancers have a simple genetic source, and indeed, there is research evidence that some epigenetic factors do exist in some cancers; Epigenetics, age, or environment have an impact
on how DNA code is expressed in cancer cells.

In both studies, all researchers hope to better understand the critical role
that epigenetics plays in the development and progression of cancerous tumors 。 In the first study, researchers collected and analyzed multiple types of bowel cancer tissue from 30 different patients, they studied a total of 1370 tissue samples, each of which was analyzed by whole transcript RNA sequencing and whole genome sequencing, and then tracked which tumors carried pure DNA and which did not, and found that only 166 tissue samples could be traced back to their basic genetic characteristics
.

[2] Nature: revealing the mechanism by which AP-1 regulates STING protein activity in cells

doi：10.
1038/s41586-022-05354-0

In a new study, researchers from the Ecole Polytechnique Fédérale de Lausanne (EPFL) in Switzerland have determined how a protein that plays a vital role in our first line of immune defense is regulated in cells to protect against autoinflammatory diseases
.
How does a cell "know" that it is infected? This is a key issue with innate immunity, and our first line of defense against any infection or injury consists of cells that rapidly recognize pathogens, such as viral DNA
.
To do this, these cells activate a signaling molecule
called STING using receptors that recognize nucleic acids.

IN A CASCADE OF REACTIONS --- WHAT SCIENTISTS CALL SIGNALING PATHWAY ---, STING COMES INTO PLAY AFTER CYCLIC GMP-AMP SYNTHASE (CGAS), SO THIS COMPLETE SIGNALING PATHWAY IS CALLED CGAS-STING
.
Its role is to detect foreign DNA that invades cells, such as DNA
from bacteria or viruses.
When foreign DNA invades cells, the cGAS-STING signaling pathway is turned on
.
STING leaves the endoplasmic reticulum in cells where proteins are synthesized and moves to the Golgi apparatus, where the proteins are modified and put on the finishing touches before being packaged and sent to the target destination
.
In the Golgi apparatus, an enzyme attaches some phosphate groups to STING--- a common mechanism called phosphorylation that provides energy to proteins within cells
.
STING then begins to activate genes, turning on the cell's defense mechanisms to fight infection
.

Research into STING has been active given how important it is for critical functions like innate immunity, especially in the Andrea Ablasser team
in EPFL's School of Life Sciences.
However, little is known about how STING is regulated and how it actually prevents genes from being turned on--- a key question
considering that STING can lead to some serious autoinflammatory diseases when it doesn't work.

[3] Nature: Revealing single-cell genomic variants induced by mutation processes in cancer

doi：10.
1038/s41586-022-05249-0

In a new study, researchers from Weill Cornell Medical College in the United States, Memorial Sloan Kettering Cancer Center, the University of British Columbia in Canada, and the IMAXT consortium used single-cell sequencing to reveal mutational processes
associated with breast and ovarian cancer.
The results were published online on October 25, 2022 in the journal Nature under the title "Single-cell genomic variation induced by mutational processes in cancer
.
" In this paper, they describe how they sequenced single-cell genomes on thousands of breast tissue cells and compared
their findings to the sequencing they performed on thousands of ovarian and breast tumor cell samples.

The authors began their research
after noting that cell-to-cell copy number changes that could trigger genomic instability in a variety of cancers have not been well addressed by the scientific community.
They also note that the ways in which this alteration can lead to phenotypic changes over the course of the evolution of different types of cancer have not been well studied
.
To correct this, they embarked on an ambitious sequencing effort that focused most directly on the mutational processes
associated with ovarian and breast cancer.

The authors' work was two-pronged
.
One of the experiments involved single-cell genome sequencing of 13,800 breast epithelial cells from women with or without the presence or absence of p53, BRCA1, or BRCA2 mutations that cause defects in homologous recombination
.
They then looked for mutation processes
by looking at haplopatterns and structural variants.
The second experiment involved single-cell genome sequencing
of 22,057 tumor cells from advanced ovarian or breast cancer.
They then compared
the pattern found in the first experiment, which they called the foreground event, with the pattern found in the second experiment.

[4] Nature: revealing novel molecular mechanisms and potential therapeutic targets for the occurrence of acute myeloid leukemia

doi：10.
1038/s41586-022-05365-x

Acute myeloid leukaemia (AML) represents a heterogeneous group of myeloid malignancies whose main features include mutations in epigenetic modifiers, transcription factors and kinases, and it is unclear to what extent mutations in AML drive changes in the 3D structure of chromatin and promote bone marrow transformation
。 Recently, a research report entitled "Subtype-specific 3D genome alteration in acute myeloid leukaemia" published in the international journal Nature, scientists from Northwestern University and other institutions have found that patients with acute myeloid leukemia may show large-scale genomic mutations and changes in DNA folding patterns, which may be expected to help identify potential therapeutic targets
。

Uncover novel molecular mechanisms and potential therapeutic targets for the occurrence of acute myeloid leukemia
.

Image source: Nature (2022).
DOI:10.
1038/s41586-022-05365-x

According to the American Cancer Society, more than 20,000 people are diagnosed with acute myeloid leukemia in the United States every year, and the prognosis of patients is poor, with a 5-year survival rate of only 30%.

Acute myeloid leukemia occurs when bone marrow cells intervene in the production of other hematopoietic cells, which exhibit different combinations of genomic mutations in different patients that interfere with normal cell function, including the organization
of chromatin 3D structures that regulate cell replication, differentiation and transcription.
Different subtypes of acute myeloid leukemia are often driven by these different genomic mutations, which often creates barriers to therapy, i.
e.
, patients with different subtypes often respond differently
to the same therapy.

Therefore, it may be crucial
to understand how mutations in these defined subtypes create the leukemia cell phenotype by altering the 3D structure of chromatin, said Yue, the researcher 。 In the current study, the researchers used deep sequencing and whole genome sequencing technology to analyze blood samples from patients with and without acute myeloid leukemia, and found that patients with acute myeloid leukemia carried large-scale genomic changes, which may be related to special DNA folding patterns or chromatin loops in leukemia cells.
Thousands of novel ring-shaped structures may directly control key acute myeloid leukemia oncogenes
.

[5] Nature: New study reveals cells that cause metastatic colon cancer to recur

doi：10.
1038/s41586-022-05402-9

Colon cancer is the third most common cancer in the world, with about 2 million new cases
each year.
Most patients are diagnosed while the tumor is still in the colon or rectum
.
These tumors are removed surgically and, in many cases, chemotherapy to prevent the tumor from returning
.
However, for 20% to 35% of patients, colon cancer reappears in other vital organs as metastases
.
These are caused
by residual tumor cells that remain hidden at the time of surgery.
Cancer metastasis is the leading cause of death for almost all types of cancer, including colon cancer
.
Most colon cancer research has focused on primary colon cancer
.
In recent years, important advances
have also been made in characterizing metastatic colon cancer after its emergence.
Until now, however, it has not been possible to study this small group of tumor cells that have spread to other parts of the body and are not seen in diagnostic techniques used in clinical use
.
This lack of knowledge has led to a lack of effective therapies to eliminate residual tumor cells and prevent recurrence of metastatic colon cancer with poor prognosis
.

Now, in a new study, researchers from the Institute of Science and Technology in Barcelona, Spain, have for the first time identified residual tumor cells hidden in the liver and lungs and described how they evolved into metastases
that appear in these organs.
The results of the study were published online in Nature on November 9, 2022, under the title "Metastatic recurrence in colorectal cancer arises from residual EMP1+ cells.
"
Researcher Dr Eduard Batlle said, "Understanding and avoiding colon cancer recurrence after surgery is an unanswered medical need
.
After years of research on colon cancer, we have taken the first step
in preventing cancer metastasis in patients with localized colon cancer.
”

The authors developed a new experimental mouse model that reproduces the process
experienced by patients with recurrent colon cancer.
This usually goes through a phase of diagnosis, surgical removal, and subsequent recurrence
.
At the same time, they devised a technique that isolates a very small fraction of tumor cells
hidden in the liver that have spread.
The researchers say this model is very similar to the progression of metastatic colon cancer in patients with recurrent colon cancer, which allows us to describe in detail the dynamics of
residual disease.
We studied metastases from 3 or 4 cells at the microscopic scale to medium size or even larger and detailed the evolution
of each of these cells during this disease progression.

[6] Nature: The first neoTCR-T cells developed using non-viral precision genome editing have made positive progress in clinical trials for the treatment of solid cancer

doi：10.
1038/s41586-022-05531-1

The human immune system has specific receptors on the surface of T cells, known as T cell receptors (TCRs), that can specifically recognize cancer cells and distinguish them from normal cells
.
These receptors are different for each patient, so finding an effective way to isolate them and introduce them into T cells to generate a personalized T cell therapy to treat cancer is key
to making this approach viable at scale.
In a new study, researchers from UCLA and PACT Pharmaceuticals are the first to use CRISPR technology to introduce foreign genes into immune cells called T cells, allowing these genetically engineered T cells to focus on attacking cancer cells, potentially leaving normal cells unharmed, thereby improving the effectiveness of
immunotherapy.
The findings were published online in the journal Nature on November 10
, 2022.

CRISPR technology has previously been used in the body to remove specific genes that allow the immune system to fight cancer
more effectively.
In the new study, the authors developed a clinical-grade method based on CRISPR/Cas9 non-viral precision genome editing while knocking out two endogenous TCR genes in T cells: TCRα (TRAC) and TCRβ (TRBC), and inserting two strands of neoantigen-specific TCR (neoTCR) on the TRAC locus.
The neoTCR used is isolated from the patient's own circulating T cells, and the resulting T cells are called neoTCR-T cells
.

For the first time, 16 patients with refractory solid cancer, including colon, breast, and lung cancer, received up to three different neoTCR-T cell infusions in a dose-increasing Phase 1 clinical trial of neoTCR-T cells (NCT03970382), each expressing patient-specific neoTCR
.
One patient developed grade 1 cytokine release syndrome and one patient developed grade 3 encephalitis
.
Before receiving neoTCR-T cell infusion, all patients received chemotherapy for lymphocyte clearance and experienced expected side effects
after chemotherapy.
After receiving neoTCR-T cell infusion, 5 patients were in stable condition and the other 11 patients experienced disease progression
.
neoTCR-T cells were detected in tumor biopsies after treatment with neoTCR-T cells at a higher frequency than T cells
expressing endogenous TCR before treatment.

[7] Nature: Revealing that ILC2 plays an important role in protecting the body's barrier tissue from intestinal damage caused by parasitic infection and inflammation

doi：10.
1038/s41586-022-05297-6

Congenital lymphocytes (ILCs) are a recently discovered family of white blood cells found in the skin, gastrointestinal tract, respiratory tract, and other barrier tissues
of the body.
In a new study, researchers from institutions such as Weill Cornell Medical College in the United States, Mount Sinai Icahn School of Medicine and Charité Hospital in Germany found that group 2 innate lymphoid cells (ILC2) play an important role
in protecting these barrier tissues from parasitic infections and from damage associated with allergic inflammation and asthma.
The findings were published online in Nature on November 2, 2022
.

NMUR1-eGFP is highly expressed in lymphoid and non-lymphoid tissues and is enriched in ILC2

Image source: Nature, 2022, doi:10.
1038/s41586-022-05297-6
.

This finding resolves the debate
about possible redundancy between ILC2 and other cells in the body.
The new study also suggests that a unique set of regulatory networks controlled by intestinal neurons could be viable targets for future drug therapies against chronic inflammatory diseases, including asthma, allergies and inflammatory bowel disease
.
The new study shows that although ILC2 shares many functional similarities with immune cells called helper T cells type 2 (Th2), the latter's cell type does not adequately compensate for the loss
of ILC2's protective response to intestinal parasitic infections as well as intestinal inflammation.
By highlighting the clinical significance of the new study, the authors found evidence that
ILC2 in humans responds in a similar way to ILC2 in mice.

Researcher David Artis said, "This advances our understanding of the complexity of the immune system and provides a range of potential new targets for us to develop therapies in the future
.
" "ILC2 is part of
the ILC.
Due to their strong presence in barrier tissues, ILCs are often considered sentinels and first responders
against many types of infections.
But scientists also recognize that ILC may be key
to understanding common inflammatory and autoimmune diseases such as asthma and inflammatory bowel disease.
ILC2 and Th2 cells are thought to appear, at least in part, to protect the body from parasitic infections, insect bites, and other environmental triggers
.
When subjected to such challenges, both help trigger the so-called type 2 immune response
.
These similarities have led scientists to think they are functionally almost identical, but ILC2 specifically triggers older, more localized responses, while Th2 cells flow more in the bloodstream, clustering in multiple tissues
when needed.

[8] Nature: Major progress! In Alzheimer's disease, the protein medin interacts with β amyloid and is co-deposited in blood vessels in the brain

doi：10.
1038/s41586-022-05440-3

The protein medin is deposited with β amyloid (Aβ) in the blood vessels of the brain of Alzheimer's patients
.
In a new study, researchers from research institutions such as the German Research Center for Neurodegenerative Diseases and the University of Tübingen discovered this so-called co-aggregation
.
The results of the study were published online in the journal Nature on November 16
, 2022.

The researchers say medin has been known for more than 20 years, but its impact on the disease has previously been underestimated
.
We were able to find that pathological changes in the blood vessels of Alzheimer's patients were significantly enhanced
by medin.
"The protein medin belongs to amyloid
.
Of these proteins, Aβ is the most famous because it clumps
in the brains of people with Alzheimer's disease.
These aggregates are then deposited both directly in the brain tissue as so-called plaques and in its blood vessels, damaging nerve cells and blood vessels
, respectively.
But while much of the research has focused on Aβ, medin has not been in the spotlight
.

Neher explains, "There is little pathological evidence --- clinically compelling findings associated with medin, which is often a prerequisite
for more in-depth research on one amyloid protein.
" "However, medin is actually present in the blood vessels of almost all people over the age of 50, making it the most common known amyloid protein
.
" Neher and his team initially found that medin produces even in aging mice, and reported the findings two years ago in the journal PNAS (PNAS, 2020, doi:10.
1073/PNAS.
2011133117).

The older the mice, the more medin accumulated in the blood vessels of the brain, which was discovered
at the time.
What's more, when the brain becomes active and triggers an increase in blood supply, blood vessels with medin deposits expand more slowly
than those without medin.
However, the ability of blood vessels to dilate is important
for optimally supplying oxygen and nutrients to the brain.

[9] Nature: Chinese scientists have found that THP9 can improve corn seed protein content and nitrogen use efficiency

doi：10.
1038/s41586-022-05441-2

Teosinte, the wild ancestor of maize, has three times
the seed protein content of most modern corn strains.
In a new study, researchers from the Chinese Academy of Sciences and Shanghai Normal University tracked the mechanisms
that caused seed protein levels to decline in maize hybrids and inbred lines.
Their findings open up new avenues for maximizing seed protein content and quality in future maize breeding, with implications
for nitrogen use efficiency and food security.
The results of the study were published online in the journal Nature on November 16
, 2022.

"There are economic and environmental pressures to reduce nitrogen levels applied to soil while maintaining high yields
of maize.
Therefore, it is crucial
to identify genetic factors that improve nitrogen use efficiency.
"For thousands of years, plant breeders have genetically modified plant species to create seeds with a greater proportion of metabolites to improve nutritional value and utility
.
As corn becomes the main source of feed for livestock, plant breeders prioritize starch content and yield, while protein content and taste become secondary considerations
.
The use of nitrogen fertilizers further reduces the importance of
seed nitrogen content.
Therefore, modern corn hybrids only contain 5~10% protein; In contrast, according to this new study, the protein content of Bulbophyllum is 20~30%.

Image source: Nature, 2022, doi:10.
1038/s41586-022-05441-2
.

Scientists can track the decline in protein content in modern corn seeds, but the genetic mechanisms remain elusive
.
The authors set out to identify the genes
responsible for the difference in protein content between Bulbophyllum and corn by constructing a complete genome sequence.
By hybridizing Cymbidium with maize and analyzing the resulting offspring, they were able to identify quantitative trait locus (QTL), the specific chromosomal region
associated with the trait in question.
"Since modern maize was domesticated from Bulbophyllum chinensis, we infer that characterizing the genes responsible for high-protein traits in Rhizophyllum may reveal a more diverse set of QTLs
than recent inbred maize populations," said Wu Yongrui.
These results may also help us understand why
seed protein levels declined during corn domestication.
”

[10] Nature: Revealing the core function of innate immune cells ILC2

doi：10.
1038/s41586-022-05395-5

Inflammation and increased mucus secretion are typical symptoms of
helminth infections and allergies.
This immune response involves our innate immune cells, but their exact function is not fully understood
.
In a new study, researchers from the Charité Academy in Berlin, Germany, have now shed light on the key tasks
performed by innate immune cells.
Based on this, they also identified potential treatments
for allergies.
The findings were published online in Nature on November 2, 2022
.

The human immune system consists of two interrelated branches: the adaptive immune system, which learns something new with each infection and develops throughout life; The latter is not as specialized, but particularly responsive and effective
.
Cells in the innate immune system are located on the mucous membrane of the respiratory tract and intestines, they form the first line
of defense at the point of entry of pathogens.
These cells include group 2 innate lymphoid cells (ILC2), which are active in the intestines when developing parasitic diseases and in the respiratory tract when suffering from allergies
.

Researcher Dr.
Christoph Klose explains, "Congenital lymphocytes (ILCs) were discovered more than a decade ago, and we already know a lot about them, but their exact function in immune system mechanisms is not fully understood
.
A group of adaptive immune cells--- type 2 helper T cells (Th2) --- perform some similar functions as part of a type 2 immune response, so it was previously thought that the role of ILC2 might be redundant and could be easily replaced
by Th2 cells.
”

However, the new study now disproves that notion
.
Using an animal model and state-of-the-art molecular methods, such as single-cell sequencing, the authors elucidated the core function
of ILC2.
Dr.
Klose explains, "When ILC2 is missing, certain types of immune cells--- eosinophils, --- unable to develop
properly.
The relationship was previously unknown and a big surprise
.
(Biovalley Bioon.
com)

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