The anti-cancer mechanism of low-protein diet has been found
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The anti-cancer mechanism of low-protein diet has been found
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“Nature”: The anti-cancer mechanism of low-protein diet has been found!
The results of a study published by the Dr. Li Ming team of Memorial Sloan Kettering Cancer Center recently in the journal Nature [1] are a bit unexpected.
They found that changes in protein uptake levels reprogram tumor-associated macrophages (TAMs) and alter the pattern of competition between TAMs and cancer cells .
Specifically, under normal dietary conditions, breast cancer cells with overexpression of the oncogene MYC will be in the state of competition winners. They will cause breast cancer cells with low expression of MYC to die through competition, absorb nutrients released by dead cancer cells, and promote own growth .
Surprisingly, once switched to a low-protein diet, MYC- overexpressing cancer cells became losers in a competition that turned out to be TAMs . What’s even more amazing is that, as the winners of the competition, TAMs will not help the development of the tumor, but become “good guys”, directly swallowing the apoptotic cancer cells due to the failure of the competition, and finally achieve the effect of controlling tumor growth.
Dr. Li’s team revealed the molecular mechanism behind this phenomenon in detail, and discovered a new innate immune anti-cancer pathway, which is expected to lead to new anti-cancer immunotherapy .
Screenshot of paper home page
As an immunologist, Dr. Li noticed that some studies have found that in malignant tumors, cancer cells with high MYC expression (MYC hi ) are often adjacent to dying cancer cells with low MYC expression (MYC lo ) [2].
This phenomenon, he argues, suggests that MYC- mediated cell competition may define patterns of social cell behavior in tumors . He therefore wondered how other oncogenic pathways contribute to the supercompetitor status of MYC- overexpressing cancer cells, and whether host factors regulate MYC- mediated cancer cell competition.
In order to solve the above problems, Dr. Li’s team first constructed two mouse models of breast cancer: a mouse model driven by PyMT (which can activate PI3K) (PyMT mouse), and a PyMT mouse model capable of expressing MYC (MYC – PyMT mice).
The PyMT-driven breast cancer mouse model was chosen because breast cancer patients with MYC amplification and PIK3CA gene gain-of-function mutations had the shortest recurrence-free survival compared with other genotypes of breast cancer . Therefore, using the PyMT mouse model as a research object is expected to find a better treatment for this refractory breast cancer.
Poor prognosis in breast cancer driven by MYC amplification and PIK3CA mutation
Based on the above two mouse models, their preliminary research found that compared with PyMT mice, tumors in MYC-PyMT mice occurred earlier and grew faster.
Similar to previous studies, they also found apoptotic MYC- low cancer cells adjacent to MYC- high cancer cells, implying that MYC – mediated cancer cell competition occurred in MYC-PyMT tumors.
Furthermore, MYC-high MYC-expressing cancer cells, the competition winners of MYC-PyMT mice, are metabolically active and large in cell size, and these phenomena are associated with overactivation of mTORC1 .
Based on the above findings, Dr. Li’s team speculated that mTORC1 signaling plays a crucial role in promoting the competitive ability of MYC -high-expressing cancer cells in MYC-PyMT mice.
MYC- mediated cancer cell competition occurs in MYC -PyMT tumors
In order to confirm the above speculation, Dr. Li’s team performed RNA sequencing on PyMT and MYC-PyMT tumors.
Sequencing results revealed that MYC-PyMT tumors have a unique gene expression program, with higher expression of genes supporting amino acid metabolism and amino acid tRNA biosynthesis, but lower expression of genes that promote cellular cooperative behavior.
Notably, these features were identical to human breast tumors with MYC amplification and PIK3CA gain-of-function mutations, suggesting that the mouse model well reflects the molecular features of these tumors.
Of note, RNAs related to cellular responses to starvation were also substantially enriched in MYC-PyMT tumors . They take this to mean that MYC-PyMT cancer cells need access to large amounts of nutrients such as amino acids in order to survive.
This phenomenon led Dr. Li’s team to think that the competition between cancer cells may be regulated by amino acids in the diet. So they prepared mice with two diets: a normal diet (NP) with 15 percent protein and an isocaloric low-protein diet (LP) with 2 percent protein .
They then fed the two diets to tumor burden-matched MYC-PyMT mice and PyMT mice, respectively. The feeding results showed that the LP diet selectively inhibited tumor growth in MYC-PyMT mice compared to the NP diet, but did not affect tumor growth in PyMT mice .
Surprisingly, when they carefully studied the tumor microenvironment, they found that macrophages were actually depleted in MYC-PyMT tumors under NP diet conditions, but appeared in MYC-PyMT tumors treated with LP diet. A group of TAMs with high mTORC1 activity . And, like mTORC1-overactive cancer cells, TAMs with high mTORC1 activity had larger cell volumes.
These findings suggest that NP and LP diets have opposite regulatory effects on mTORC1 activity in cancer cells and TAMs in MYC-PyMT mice, and that overactivation of mTORC1 is also associated with the growth and expansion of TAMs.
Effects of NP and LP diets on TAMs
The emergence of macrophages, and the effect of different nutritional states on macrophage activity, make this research interesting. The next question to investigate is obviously how exactly changes in nutritional status affect macrophages.
The research results of Dr. Li’s team show that there is a complex and sophisticated amino acid sensing system on the lysosomal membrane of macrophages.
To put it simply, when the level of amino acids in the cell is high, it will be sensed by GATOR1, and this system will recruit the transcription factor TFEB/TFE3 to the lysosome, resulting in the inability of the transcription factor to enter the nucleus, and the signal level of mTORC1 will decrease.
Phage cells are at a competitive disadvantage; when the level of amino acids in macrophages is low, it will be sensed by another protein called FLCN, which will cause the system to release TFEB/TFE3, and the transcription factors will enter the nucleus smoothly, enhancing the signal level of mTORC1, so that Macrophages are at a competitive advantage .
Schematic diagram of the control mechanism
Subsequent studies also found that under low-protein diet (LP) conditions, the phagocytic ability of macrophages in MYC-PyMT tumors was also enhanced, and it was this phagocytic function of macrophages that drove the activation of mTORC1 and the activation of macrophages. Growth/proliferation of phagocytes and antineoplastic effects .
Schematic representation of amino acid effects on competition
Overall, Dr. Li’s team revealed the effect of nutrition on the competition between cancer cells and macrophages, and to some extent revealed the mechanism of low-protein diet anti-cancer.
Most importantly, this study discovered a new anti-cancer mechanism of innate immune cells, which can transform tumor-associated macrophages into anti-cancer weapons, which undoubtedly provides a new target for macrophage-based new cancer immunotherapy.
Of course, this study still leaves some questions, such as what is the mechanism of the different effects of the LP diet on cancer cells and macrophages, and so on. The answers to these questions will help advance our understanding of the anti-cancer mechanisms of low-protein diets, and perhaps discover new anti-cancer targets.
Looking forward to the follow-up research by scientists.
references:
[1]. Zhang X, Li S, Malik I, et al. Reprogramming tumor-associated macrophages to outcompete cancer cells. Nature. 2023. doi:10.1038/s41586-023-06256-5
[2].Di Giacomo S, Sollazzo M, de Biase D, et al. Human Cancer Cells Signal Their Competitive Fitness Through MYC Activity. Sci Rep. 2017;7(1):12568. doi:10.1038/s41598-017-13002 -1
The anti-cancer mechanism of low-protein diet has been found
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