A high-resolution macrostudy opens the door to tightening the noose in the fight against cancer

Alberto J. Schuhmacher, head of the Molecular Oncology Group at the IIS Aragón, reflects on cancer after the publication of the series of articles by the Nature group, which represent an unprecedented analysis of this disease, turning everything that was known up to now on its head

Science Media Center Spain published the reaction of Alberto J. Schuhmacher, ARAID researcher and head of the Molecular Oncology Group at the Aragon Health Research Institute (IIS Aragón):

«Cancer is an organized cellular crime. In recent decades, our view of cancer has changed and these articles confirm many things that we suspected, but now, thanks to the development of powerful technologies, they are confirmed. 

If we were to see cancer as a bank robbery, the classic view we had was of a bank robbery in the Wild West. The robber was a guy with a bandana covering his face who entered the bank with a gun, stole the cash register and rode off on his horse. The tumor cell did everything and accumulated mutations. 

The vision has been changing in recent years. To rob a bank, more than one person is needed, as in Ocean's Eleven. One is the brain that coordinates everything, but he needs help. On his team there is a pilot with a vehicle at the door, another who gags the guards and, with how complicated safes are today, explosives experts, welders and computer experts are needed. At the very least.  

These publications explain and delve deeper into the role of cells that are in the tumor but are not tumoral, what we know as the 'tumor microenvironment'. These include blood vessels that provide nutrients, oxygen and factors, the immune system that, instead of attacking the tumor, is tricked by it to exploit it for its own benefit, support cells, etc. And they re-educate and evolve with the tumor. 

What is more interesting is that these studies confirm that not all tumor cells need to accumulate all the mutations to start. The "brain" of the crime may be distributed among several tumor cells, at least in some types of colon cancer, but it will be extensive to many cancers. Instead of a tumor cell accumulating all the mutations and the tumor arising from a single tumor cell that has to do everything, tumors can arise from several altered cells that complement each other and are jointly selected. 

"These studies add complexity to the way we view cancer and open a path that sheds light on new and better diagnoses, treatments and prevention of many types of cancer."

The macro study

Several articles published in Nature They analyze the earliest stages of tumor formation, even before it appears.Another group of researchers has focused on the internal structures of multiple types of tumors, including those of the breast, colon, pancreas, liver, kidney and uterus, achieving a 3D view for the first time.

Overall, “the complete collection of papers published today in various journals will be a milestone in cancer research. The whole series covers the first events that give rise to the shift and the other focuses on how the tumor evolves towards initiation and metastasis,” he explains to SINC. Angela Nieto, Research Professor at the Alicante Institute of Neurosciences and coordinator of Conexión Cáncer-CSIC, a research network that brings together the CSIC centers that research this prevalent disease.

Nieto, who was awarded the Santiago Ramón y Cajal National Research Award in 2019, precisely for her pioneering work in the study of the epithelial-mesenchymal transition, a transcendental biological process in understanding the origin of cancer and the formation of metastases, explains the enormous importance of the two approaches of the works.

The key has been in the use of a very high resolution that allows obtaining very precise information about many of the tumor cells and the differences between them.

Angela Nieto, Research Professor at the Institute of Neurosciences of Alicante

In both cases, he points out, the key has been in the use of a very high resolution that allows obtaining a very accurate information of many of the tumor cells and the differences between them.  

“On the one hand, the group of studies that focus on the earliest events, even before the tumor has appeared, will allow us to make much earlier diagnoses and even think about cancer prevention, which is something extraordinary. Another group of studies has managed to generate three-dimensional maps that allow us to analyze the evolution of the tumor,” Nieto points out.

This is how the co-lead author defines the result Li Ding: “We can finally see what until now we had only been able to deduce about the tumor structures and its complexity.” Ding is a professor of medicine at the University of Washington, and her lab studies tumor genomes to find out what drives cancer development.

“This other approach is the result of a huge effort by several institutions within the Human Tumor Atlas Network consortium. It is a very high-resolution analysis of the internal organization of different types of cancer in patients,” explains Nieto.

These detailed 3D maps show the internal structure of multiple types of tumors, including those of the breast, colon, pancreas, liver, kidney and uterus, from samples of some 2.000 people, which has allowed an exhaustive and unprecedented analysis of the architecture of the Tumors in 3 dimensionss, in order to observe cellular interactions between tumor cells and the tumor microenvironment.

A good part of the group of articles published today in different journals of the Nature group by members of the Human Tumor Atlas Network (HTAN) are funded by the U.S. National Cancer Institute (NCI).

HTAN is a collaborative network of Research Centers and a central Data Coordinating Center that are building three-dimensional atlases of the cellular, morphological, and molecular features of human cancers as they evolve from precancerous lesions to the advanced disease.

"This titanic effort The study carried out on tumours of different types will create a colossal database. This is essentially descriptive data, which shows us what tumours are like. The next step will be to check whether the numerous hypotheses that arise from the knowledge of all this new data are confirmed, which requires further research,” explains Angela Nieto.

The secret life of tumors revealed

«Until now we knew that in the tumor there were cancer, immune and structural cells that sometimes protected the cancer from chemotherapy [creating resistance to treatment] and the attack of the immune system, but now we can really see those battle lines,” Ding clarifies, referring to the three-dimensional maps they have created.

This 3D atlas literally allows you to see how the regions of the tumor differ and how its behavior changes when it spreads to other organs, forming metastases, or even its reaction in response to therapy.

This study shows that tumors are organized into “neighborhoods,” which constitute the tumor microenvironment and exhibit different mutations that drive their growth and likely require different treatment strategies, the researchers explain.

According to the researchers, this will have implications for the fight against cancer, because different specific treatments may be needed to address key mutations in different neighborhoods of the tumor in terms of treatment.

This three-dimensional vision has the potential to transform how we understand cancer today and improve its treatment in the future, according to the expert from the University of Washington. We would thus be facing “a new era in cancer research.”

The work also provides an understanding of the three-dimensional metabolism of cancer that will influence the effectiveness of current treatments, and sometimes provide insight into why they are ineffective. “It will lead to the development of new cancer treatments. It is truly transformative,” says another of the researchers.

They also found that some areas of the tumor may have high immune cell activity, known as hot regions. The same tumor also has cold regions that have little or no immune activity.  

Warm regions usually respond well to immunotherapies, but cold ones do not, which possibly helps explain why some tumors appear to respond well to immunotherapies at first and then develop resistance.

Metastasis

The process that allows cancer to spread to other organs, metastasis, is discussed in one of the articles published today, specifically in Nature Medicine, whose first author is Johanna Klughammer, of the Klarman Cell Observatory of the Broad Institute of Harvard and MIT.

Researchers have created a spatial and cellular map based on 67 tumor biopsies from patients with metastatic breast cancer and have identified differences in cellular composition and the T cell infiltration, a class of white blood cells that is part of the immune system.

This is a very important aspect of study, says Nieto, who was awarded the 2019 National Research Award “Santiago Ramón y Cajal”, precisely for her pioneering work in the study of the epithelial-mesenchymal transition, a transcendental biological process in understanding the origin of cancer and the formation of metastases.

Just a couple of weeks ago a job in Nature Cancer, led by Nieto, who also analyzed the evolution of the tumor towards metastasis, finding anti and pro tumor responses.

This line of research, which attempts to “enclose” the spread of metastasis, is undoubtedly promising for fighting cancer’s most powerful weapon: the colonization of organs other than those in which it forms.

Source 1: Science Media Centre (SMC).

Source 2: SINC

Main Image: Burkitt's lymphoma / Wikipedia

Rights: Creative Commons.

References:

Mo, C.K., Liu, J., Chen, S. et al. Tumor evolution and microenvironment interactions in 2D and 3D space. Nature. 

Klughammer, J., Abravanel, DL, Segerstolpe, Å. et al. A multi-modal single-cell and spatial expression map of metastatic breast cancer biopsies across clinicopathological features. Wet Med. 

Youssef, K.K., Narwade, N., Arcas, A. et al. Two distinct epithelial-to-mesenchymal transition programs control invasion and inflammation in segregated tumor cell populations. Nat Cancer (2024)