Metabolic diversity is the molecular basis determining fitness for breast cancer brain metastases

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Metabolic diversity is the molecular basis determining fitness for breast cancer brain metastases

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Cell Metabolism | Metabolic diversity is the molecular basis determining fitness for breast cancer brain metastases.

The incidence of brain metastases in breast cancer patients varies significantly by disease subtype.

For example, HER2+ and triple-negative (TN) breast cancers have a higher risk of brain metastases than ER+/PR+ breast cancers.

In addition, brain metastases from HER2+ breast cancer can be classified into three types: synchronous ( S-BM) , latent (Lat) and occult (M-BM) according to the time of appearance of metastases [1] .

Why do the same type of breast cancer have different metastatic characteristics? The molecular basis for this is still unclear.

Recently, a research team led by Professor Srinivas Malladi from the University of Texas Southwestern Medical Center published a research article entitled Metabolic diversity within breast cancer brain-tropic cells determines metastatic fitness in Cell Metabolism , revealing the metabolic diversity of breast cancer. Sex is the molecular basis that determines their fitness for brain metastases .

The authors orthotopically transplanted two breast cancer patient-derived HER2+ cells (HCC1954 and SKBR3) into nude mice , and obtained HCC1954 with the same genotype but different brain metastases (S-BM, M- BM and Lat) and SKBR3 (M-BM and Lat) cell lines.

With such a cellular tool, the authors embarked on a follow-up mechanistic investigation.

First, by performing RNA sequencing on HCC1954-derived S-BM, M-BM and Lat cell lines, the authors found that the metabolic profiles of Lat and M-BM were significantly different from S-BM.

Through metabolite analysis, the authors found that S-BM and M-BM with strong metastatic ability excreted lactate higher than Lat, while Lat and M-BM excreted Glutamate higher than S-BM.

Further, the authors used labeled 13 C6 glucose and 13 C5 glutamine to analyze the metabolic flux of these three types of cells, and the results again proved that these cells metabolized Glucose and Glutamine in a very different way, specifically: S with strong transfer ability -BM and M-BM were more able to utilize Glucose and produce lactate, while M-BM and Lat were more able to utilize Glutamine and excrete Glutamate .

Extracellular lactate can not only be utilized by tumors as an energy substance, but also can reshape the tumor microenvironment to help tumor metastasis [2] .

Therefore, to explore whether exogenous lactate is sufficient to promote tumor brain metastasis, the authors treated nude mice transplanted with HCC1954 and SKBR3-derived Lat cells by intraperitoneal injection of PBS, lactate, and sodium lactate.

The results showed that lactate and sodium lactate treatment resulted in significant brain metastases. , and reduced overall survival in tumor-bearing mice.

Furthermore, the authors found that NK cells in the periphery and metastases of tumor-bearing mice were significantly reduced in the lactate-treated group, suggesting that exogenous lactate helps latent breast cancer cells evade immune surveillance mediated by NK cells .

So how does lactate help tumors evade immune surveillance mediated by NK cells? Through functional studies, the authors found that lactate inhibits the ability of NK cells to aggregate and kill.

The results of in vitro cell killing experiments also showed that compared with Lat cells, S-BM and M-BM had stronger resistance to NK cell killing, and exogenous addition of lactate or the use of S-BM and M-BM cells Media treatment of Lat cells enhanced their resistance to NK cells.

Thus, these experimental results suggest that latent tumor cells (Lat) are equilibrated under NK cell-mediated immune surveillance, but lactate production by brain metastatic tumor cells (S-BM and M-BM) limits NK cell function and thus Evade innate immune surveillance.

So could inhibition of lactate production limit brain metastases from highly aggressive breast cancer? To test this conjecture, the authors used Oxamate (an analog of Pyruvate, which can inhibit the activity of LDH) to treat and knock down the level of LDHA protein to suppress the lactate production capacity of the tumor, respectively.

The results showed that both treatments can inhibit S -Brain metastases in BM and M-BM, but the authors also noticed an interesting phenomenon: the degree of response of S-BM was significantly higher than that of M-BM cells .

Through further mechanism studies , the authors found that the original M-BM has a stronger ability to cope with oxidative stress (compared with M-BM, S-BM and Lat cells have higher GSH/GSSG levels and lower ROS levels) , Thus, it has stronger resistance to the inhibition of LDHA.

The above experimental results suggest that the stronger anti-oxidative stress ability of S-BM and Lat cells may be related to their metastatic latency, and the authors found that the cystine/glutamate antiporter xCT is a key factor in S-BM and Lat cells. highly expressed, and this finding is also consistent with this previously observed phenotype of stronger metabolism of Glutamine, which excretes Glutamate.

Next, by knocking down xCT in S-BM and Lat cells, the authors found that intracellular ROS levels were significantly elevated and brain metastases of the tumors were significantly reduced. These experimental results suggest that xCT mediates breast cancer latency .

Finally, based on these findings, the authors investigated the therapeutic effect of xCT in combination with a HERT2 inhibitor for latent brain metastases.

The results showed that the xCT inhibitor Erastatin significantly sensitized S-BM and Lat to the HERT2 inhibitors lapatinib and tucatinib.

Taken together, this work demonstrates that metabolic diversity is the molecular basis for different metastatic characteristics of HER2+ breast cancer cells. More importantly, this discovery is expected to help clinically develop more precise treatment plans for cancer patients with S-BM, Lat or M-BM brain metastases.

Reference:

https://doi.org/10.1016/j.cmet.2021.12.001

Metabolic diversity is the molecular basis determining fitness for breast cancer brain metastases

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