A major breakthrough!

According to data from the World Health Organization, among the new cancers in the world in 2020, breast cancer will become the largest cancer in the world, and the incidence of breast cancer in China is also increasing year by year

Recently, Cai Shang's team from the School of Life Sciences of Westlake University made a major breakthrough

Screenshot of the paper

Original link: https://? ?

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The traditional concept holds that because of the existence of the immune system, most tissues and organs of the human body (except the intestines, mouth, and skin) are in a sterile state, and the same is true for tumor tissues

But around 2020, some scientists in Israel and the United States found that bacteria are also a component of cancer itself, and it exists in a wider range of cancer types other than colorectal cancer, such as pancreatic cancer, lung cancer, breast cancer,

Scientists speculate that it is precisely because the intracellular bacteria are located in tumor cells that they escape the attack of the human immune system and survive

So, what role do intracellular bacteria play in the occurrence and development of tumors? Dispensable bystanders, or players driving tumor progression?

Previous studies have suggested that the gut microbiota can regulate the progression of cancer indirectly by regulating the immune system or by producing metabolites, but so far there is no evidence that tumor bacteria can directly participate in the occurrence and development of cancer

In 2017, Cai Shang, who had just returned to China to join Westlake University, started a special study on this issue

Cai Shang graduated from Peking University with a bachelor's degree and a Ph.

Based on the classic mouse spontaneous breast cancer model, Cai Shang led the research team to build a strict tumor microbiome research system to explore the role of tumor microorganisms in tumor progression

At that time, "intracellular bacteria" was still an unproven conjecture, and their first task was to find "adversaries"

The content of "intracellular bacteria" in tumor cells is very low.

Intracellular bacteria present in a mouse model of spontaneous breast cancer

Then, exploring the functions of these bacteria became the focus of their work

A simple idea: get rid of these bacteria and see what happens to the tumor

The usual method of removal is with antibiotics
.
But how to ensure that antibiotics only target tumor bacteria?

There are few experimental protocols to follow
.
The research team started from scratch, continuously optimized the treatment methods of antibiotics, adjusted the combination of antibiotic combinations and injection methods, and finally achieved the goal of "targeted" removal of tumor flora
.

The results showed that after removing the tumor flora, tumor weight was not affected, but lung metastases decreased significantly
.
This suggests that the tumor microbiota most likely affects not tumor growth, but the metastatic process
.

Antibiotic clearance experiment proves that tumor microbiota is very important for tumor metastasis

Based on this finding, the research team hypothesized that intracellular bacteria in tumor tissue would migrate with tumor cells to distant organs and affect metastasis
.
In other words, the bacteria in the tumor will follow the tumor cells to other parts of the body
.

To test this hypothesis, they performed bacterial 16S sequencing of tumors in situ, macroscopic lung metastases, lung tissue containing micrometastases, and normal lung and breast tissue
.
The results of the analysis showed that the bacteria in the early stage of lung metastases may still have the flora characteristics of the in situ tumor, and as the tumor grows and spreads, it gradually begins to be affected by the lung microenvironment
.

By isolating and staining circulating tumor cells, the research team saw that circulating tumor cells can "run" to distant organs with intracellular bacteria; and when these intracellular bacteria were injected back into tumor cells, the tumor cells could be seen in the human body.
"The viability during running is stronger", and even those breast cancers that are not easy to metastasize begin to metastasize after the intracellular bacteria are injected
.

This strongly proves that intracellular bacteria can promote the metastasis of tumor cells
.

Bacterial infusion promotes breast cancer metastasis

Know it, know why
.
Why can intracellular bacteria promote tumor cell metastasis?

Cai Shang explained that, in fact, during the process of metastasis, cancer cells are not as "powerful" as we think, and the blood pressure (fluid pressure) in the blood vessels can cause damage to them
.
But they found that after intracellular bacteria invade tumor cells, they remodel the cytoskeleton through a specific signaling pathway (RhoA-ROCK), helping tumor cells resist the pressure in blood vessels and avoid damage during metastasis
.

This perfectly explains why tumor cells with intracellular bacteria have a greater ability to travel to distant organs
.

Intracellular bacterial invasion remodels the tumor cell's cytoskeleton to resist fluid pressure
.

Finally, the research team returned to the human body from mice, collected tumor tissue, paracancerous tissue and lymph node tissue of paired breast cancer patients, and used qPCR combined with 16S sequencing to quantitatively and qualitatively analyze the composition of the respective flora
.
The results showed that mouse breast cancer tissue and human breast cancer tissue shared the same microbial profile and dynamic changes, suggesting that human breast cancer microbiota may play similar roles in human cancer development and progression
.

After nearly 5 years, from conjectures and assumptions to step-by-step confirmation, the research of Cai Shang's team has identified new components in the tumor microenvironment that have been neglected for a long time, revealed new factors affecting tumor metastasis, and opened up new directions for tumor research.
Clinical control of tumor metastasis provides a new perspective
.

Researcher Cai Shang from the School of Life Sciences of West Lake University is the corresponding author of the paper; Fu Aikun, postdoctoral fellow of the School of Life Sciences of West Lake University, Yao Bingqing and Dong Tingting, doctoral students of West Lake University are the co-first authors of the paper
.
In addition, Mr.
Li Nan and Mr.
Li Hang from the High Performance Computing Center of West Lake University have made important contributions to this topic
.
This project is funded by the National Natural Science Foundation of China; the implementation of the project has received strong support from the West Lake Laboratory, the Experimental Animal Center of West Lake University, the Biomedical Experimental Technology Center, and the High Performance Computing Center
.

A 5 year expedition

The moment he saw the research results, Cai Shang was very excited
.

"This topic is very risky and full of unknowns.
When I decided to start the research, it was extremely controversial whether the tumor flora really existed
.
" Cai Shang said
.

The original idea came from a discussion when Cai Shang was a postdoctoral fellow at Stanford: what genes affect the development of breast cancer tumors
.
"When building a mouse model to induce knockout of the gene, I unexpectedly found that without knocking out the gene, just adding an inducer (an antibiotic), the metastasis of the tumor would be affected
.
I found it very incomprehensible
.
"

In 2016, during the experiment, antibiotics once again attracted the attention of Cai Shang
.
Previous articles have reported that antibiotics can affect tumor progression, but the reasons vary
.
Cai Shang is acutely aware that tumor metastasis may be related to the ability of antibiotics to kill bacteria
.

He boldly hypothesized: there may be bacteria in the tumor!

At the time, the common perception was that, with the exception of intestinal tumors, tumors in most organs were sterile
.
Because the human body has a very strong immune system, once there is bacteria, the immune system will quickly remove it
.

Looking back now, Cai Shang still feels that the idea at that time was a bit crazy
.
But the work of a scientist is itself an "exploration", "I am strongly attracted by this interesting phenomenon and feel that the mystery should be understood
.
"

With no previous experience and no experience to follow, he led the young team members of West Lake University, from the research system to the experimental method, from the breeding and passage of mouse models, updating and improving the use of antibiotics.
Everything started from scratch and built from scratch
.
Over the past five years, he has devoted almost 50% of his energy to this research
.

It was not until a Science paper in 2020 that scientists fully and clearly confirmed the existence of bacteria in the tumor, confirming that Cai Shang’s original hypothesis was correct.
At this time, Cai Shang’s team had already collected the physiological functions of the tumor flora.
A lot of data, with a deeper understanding
.
They wanted to go a step further and figure out exactly what role bacteria play in tumor metastasis
.

"Thanks to the school for giving me enough time and space, and creating a scientific research atmosphere that dares to explore the unknown and is not afraid of difficulties and failures
.
" Cai Shang said
.

As one of the first batch of PIs to join Westlake University, he has not been very productive in scientific research in recent years, and even a little "unknown"
.

"Fortunately, the school does not have assessment indicators in this regard, but only emphasizes cutting-edge research
.
" Sufficient scientific research funds and generous salaries also allow him to eliminate distractions, calm down, and insist on doing a "creation without following".
research”
.
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High risk, high reward, under the diligent watering of team members, the initial "flash of inspiration" seed finally took root in the academic soil that encourages free exploration
.

But Cai Shang emphasized: "This field is just emerging, and there are still many unsolved mysteries.
The clinical use of antibiotics is also full of complexity.
How to use this discovery to guide clinical treatment is still a complex and urgent scientific problem.
More scientific researchers will do a lot of basic and solid work
.
”

In his view, this achievement only opens a small window in the field of breast cancer research.
As for the scenery outside the window, I hope more latecomers will look at it together
.

Group photo of some members of Cai Shang's team

The research of Cai Shang's research group mainly uses the breast as a model organ to explore the maintenance of breast specific structure and function of breast stem cells during adolescence, pregnancy and lactation, as well as the role of breast cancer stem cells in the occurrence, development, drug resistance, recurrence and metastasis of cancer.
important role
.
The recent research has opened up a new direction of tumor research on the physiological function of tumor microbiota, which is an emerging field full of unknowns.
We look forward to the participation of excellent postdoctoral fellows who are interested in exploring tumor microbiota, and jointly solve the mystery of the interaction between microorganisms and cancer cells
.

Laboratory webpage: https://