Mois : avril 2024

Scientists have identified the proteins FOXF1 and its downstream target FZD4 as potential targets for treating lung cancer. Upregulating them helps to normalize vasculature in the tumor area and suppresses this lethal type of cancer [1].

Lung cancer and vasculature

Lung cancer remains one of the deadliest diseases in the world, accounting for 22% of all cancer deaths. Medicine’s successes against it have been limited, especially against non-small cell lung cancer, a particular type with a five-year survival rate of only 20%. All of this makes developing better treatment strategies imperative.

Lung cancer’s success hinges on the ability of cancer cells to reprogram healthy lung endothelial cells (EC) into tumor-associated endothelial cells (TECs). The latter form leaky, structurally and functionally abnormal blood vessels that promote tumor growth [2]. Cancer cells achieve this by secreting various factors such as vascular endothelial growth factor (VEGF). Normalizing tumor vasculature morphology improves the efficacy of anti-cancer therapies [3]. However, the exact mechanism of how tumor cells change vasculature is not fully understood.

Going down the pathway

In this study, the researchers identified a protein named FOXF1 as decreasing in human and murine endothelial cells associated with non-small cell lung cancer (NSCLC). FOXF1 was expressed by a majority of healthy endothelial cells but only by 5%-10% of tumor-associated ones. Analyzing the Cancer Genome Atlas showed that in a large sample of NSCLC patients, FOXF1 levels were significantly associated with survival.

In line with these results, deletion of the Foxf1 gene promoted tumor growth and metastasis in two mouse models of lung cancer and caused cancer-associated structural abnormalities in the lung vasculature.

Overexpression of FOXF1 specific to endothelial cells had the opposite effect. 28 days after mice were inoculated with lung cancer cells, tumors were much smaller in mice with FOXF1 overexpression, and they exhibited virtually no metastases.

The researchers were able to show that FOXF1 does its thing via the canonical Wnt/β-catenin signaling pathway, a mediator of endothelial cells’ proliferation and survival, eventually downregulating another protein, FZD4, by directly binding to the promoter of the gene coding for it. Just like with FOXF1, higher levels of FZD4 in lung cancer patients were associated with better chances of survival.

Nanoparticle administration effective in mice

Finally, the researchers administered FZD4 intravenously, with the help of nanoparticles carrying FZD4-coding DNA plasmids, to FOXF1-deficient mice with lung cancer. The treatment was found to be safe and did not change the histological appearance of endothelial cells in other organs. In lungs, on the other hand, nanoparticles were detected in 70% of cells.

In treated mice, tumor size was decreased to the levels observed in controls with normal FOXF1 expression. The researchers, however, did not investigate the effect of FZD4 administration on mice without a FOXF1 knockout, which would arguably be more clinically relevant. Still, this study is potentially very good news for lung cancer patients.

“We have identified the novel protein FOXF1 that stabilizes blood vessels inside the lung tumors, decreases intertumoral hypoxia and prevents lung cancer metastases,” explained Tanya Kalin, MD, PhD, professor of Child Health and Internal Medicine at the University of Arizona College of Medicine and the senior author of this study. “Since targeting the FOXF1/FZD4 signaling using gene therapy had efficiently decreased lung cancer progression and normalized tumor blood vessels, our next step will be to develop a pharmacological approach to activate this signaling pathway and to move this therapy into clinical trials.”

FOXF1 was highly expressed in normal lung vasculature but was decreased in TEC within non-small cell lung cancers (NSCLC). Low FOXF1 correlated with poor overall survival of NSCLC patients. In mice, endothelial-specific deletion of FOXF1 decreased pericyte coverage, increased vessel permeability and hypoxia, and promoted lung tumor growth and metastasis. Endothelial-specific overexpression of FOXF1 normalized tumor vessels and inhibited the progression of lung cancer. FOXF1 deficiency decreased Wnt/β-catenin signaling in TECs through direct transcriptional activation of Fzd4. Restoring FZD4 expression in FOXF1-deficient TECs through endothelial-specific nanoparticle delivery of Fzd4 cDNA rescued Wnt/β-catenin signaling in TECs, normalized tumor vessels and inhibited the progression of lung cancer. Altogether, FOXF1 increases tumor vessel stability, and inhibits lung cancer progression by stimulating FZD4/Wnt/β-catenin signaling in TECs. Nanoparticle delivery of FZD4 cDNA has promise for future therapies in NSCLC.

Literature

[1] Bian, F., Goda, C., Wang, G., Lan, Y. W., Deng, Z., Gao, W., … & Kalin, T. V. (2024). FOXF1 promotes tumor vessel normalization and prevents lung cancer progression through FZD4. EMBO Molecular Medicine, 1-28.

[2] Dumanskiy, Y. V., Stoliarova, O. Y., Syniachenko, O. V., & Iegudina, E. D. (2015). Endothelial dysfunction of vessels at lung cancer. Experimental oncology, (37,№ 4), 277-280.

[3] Martin, J. D., Seano, G., & Jain, R. K. (2019). Normalizing function of tumor vessels: progress, opportunities, and challenges. Annual review of physiology, 81, 505-534.

In Aging Cell, researchers have published evidence that downregulating a key aspect of lipid metabolism harms mitochondrial function, but only in cells taken from younger people.

Fat regulation at the cellular level

Perilipins (PLINs) are proteins that regulate the use of fats (lipids) within cells. This paper focuses on PLIN2, which has previously been investigated in the context of aging [1] and plays a significant role in lipid metabolism [2]. PLIN2 plays a role in diabetes [3] and has been investigated in cancer, although its role varies by the cancer type [4].

Most pertinent to this study, PLIN2 plays a role in the maintenance of mitochondria. Downregulating it in pancreatic beta cells, which produce insulin, has been shown to impair that critical function and harm mitochondria, particularly their ability to metabolize oxygen [5]. On the other hand, it also plays a role in mitochondrially mediated cellular senescence under stress conditions [6], and it increases with age in skeletal muscle and brain cells. These researchers have previously associated it with sarcopenia [7].

To determine its roles in mitochondrial dysfunction and cellular senescence, the researchers tested it on cells taken from older and younger cohorts, and their findings were surprising.

Same amount, different processing

Six people between the ages of 25 and 34 along with five people between 63 and 78 were recruited for this study. These participants had dermal fibroblasts extracted and cultivated, and then some of the cells were subjected to RNA that silenced most expression of PLIN2, PLIN3, or the related factor GDF15; this silencing did not affect the cells’ viability.

Interestingly, these cells, unlike brain cells, do not have significantly different amounts of PLIN2 or PLIN3 between older and younger people. Instead, the researchers found that fatty acid accumulation causes increased expression of PLIN2.

In fibroblasts that had their PLIN2 expression knocked down, multiple other gene expressions related to lipid handling were affected. However, PLIN3 did not seem to have a similar effect. Knocking down PLIN2 significantly decreased the accumulation of lipids within these cells.

While this may seem beneficial, the researchers were able to confirm previous research demonstrating its negative mitochondrial effects [5], impairing respiration in general. This was only significant in cells taken from younger people; cells from older people trended towards worse respiration, but to a much lesser degree. Analyzing gene expression, the researchers found that younger and older cells had entirely different strategies for dealing with PLIN2 knockdown: the younger cells increased mitochondrial turnover, while the older ones increased mitochondrial fusion.

The role of GDF15

Both older and younger cells expressed markers of mitochondrial stress with PLIN2 knockdown, most notably of GDF15, which older cells expressed more of than younger cells did. GDF15 expression was also found to be associated with an increase in cellular senescence. Further experiments involving knocking down both PLIN2 and GDF15 found that cellular senescence was reduced to the level of cells without any RNA knockdowns at all, demonstrating that it is indeed the cause in this case.

Differences were also found between younger and older cells when GDF15 was knocked down. Similarly to PLIN2, genes that were significantly downregulated along with GDF15 knockdown in younger people’s cells were not significantly affected in those of older people.

The researchers note that many of their findings are limited and somewhat murky; while the effects of these knockdowns on younger cells are largely clear, the effects on older cells are less so. Further research will have to be conducted to determine what biochemical changes have occurred with age and what might be able to be done about them.

Literature

[1] Conte, M., Franceschi, C., Sandri, M., & Salvioli, S. (2016). Perilipin 2 and age-related metabolic diseases: a new perspective. Trends in Endocrinology & Metabolism, 27(12), 893-903.

[2] Xu, S., Zou, F., Diao, Z., Zhang, S., Deng, Y., Zhu, X., … & Liu, P. (2019). Perilipin 2 and lipid droplets provide reciprocal stabilization. Biophysics Reports, 5, 145-160.

[3] Ji, J., Petropavlovskaia, M., Khatchadourian, A., Patapas, J., Makhlin, J., Rosenberg, L., & Maysinger, D. (2019). Type 2 diabetes is associated with suppression of autophagy and lipid accumulation in β‐cells. Journal of cellular and molecular medicine, 23(4), 2890-2900.

[4] Hayakawa, M., Taylor, J. N., Nakao, R., Mochizuki, K., Sawai, Y., Hashimoto, K., … & Harada, Y. (2023). Lipid droplet accumulation and adipophilin expression in follicular thyroid carcinoma. Biochemical and biophysical research communications, 640, 192-201.

[5] Mishra, A., Liu, S., Promes, J., Harata, M., Sivitz, W., Fink, B., … & Imai, Y. (2021). Perilipin 2 downregulation in β cells impairs insulin secretion under nutritional stress and damages mitochondria. JCI insight, 6(9).

[6] Che, L., Huang, J., Lin, J. X., Xu, C. Y., Wu, X. M., Du, Z. B., … & Lin, Y. C. (2023). Aflatoxin B1 exposure triggers hepatic lipotoxicity via p53 and perilipin 2 interaction-mediated mitochondria-lipid droplet contacts: An in vitro and in vivo assessment. Journal of Hazardous Materials, 445, 130584.

[7] Conte, M., Vasuri, F., Trisolino, G., Bellavista, E., Santoro, A., Degiovanni, A., … & Salvioli, S. (2013). Increased Plin2 expression in human skeletal muscle is associated with sarcopenia and muscle weakness. PLoS One, 8(8), e73709.

Berlin’s event landscape is growing: Longevity Week will take place in the German capital for the first time from May 6-12, 2024. The opening event will take place on May 6th at the Langenbeck-Virchow-Haus in Berlin Mitte near the Charité hospital. A total of 15 events will be organised throughout the city.

Speakers include, among others, Prof. Eric Verdin, CEO of the renowned Buck Institute; Michael Greve from Kizoo Technology Capital; and Dr. Ina Czyborram, Senator for Science, Health, and Care of the State of Berlin.

Longevity Week is organised by a consortium of founders, doctors and longevity experts. The aim of Longevity Week is to broaden public understanding of the trend and its potentials, helping to establish Berlin as the capital of longevity in the medium term.

Longevity Week Berlin sets new standards as a pioneering format that unites the different areas of the growing global trend. It aims to create an open platform that provides information in the areas of nutrition and lifestyle, research & medicine and technology and takes the dialogue between stakeholders from society, business and politics to a new level. With this in mind, Longevity Week aims to become the leading platform for the longevity scene.

Longevity Week is the result of an initiative by doctor and entrepreneur Guido Axmann, healthtech investor Joachim Rautter (Peppermint Venture Partners) and the founder of cryogenics start-up Tomorrow Biosis, Dr. Emil Kendziorra. Other initiators include the physician and entrepreneur Dr. Andrea Gartenbach; Christina Hanck, founder of everlabs; as well as investor Judith Müller.

“Berlin has the potential to become a pioneering city and an important centre for longevity worldwide. The city has one of the best medical facilities in the world and is characterised by an ecosystem that promotes and generates innovation. It is therefore time to create a specific theme week that not only facilitates an intensive dialogue between the players and covers a wide range of topics, but also looks beyond national borders,” says Guido Axmann, initiator of Longevity Week Berlin.

Christina Hanck, co-initiator, adds: “Although humanity is getting older and older, more and more of us are struggling with chronic diseases in old age. With this event, we want to show that the pursuit of a healthy and longer life is not exclusive and merely an expensive hobby of tech billionaires from Silicon Valley. With Longevity Week Berlin, we are committed to making knowledge and innovations on this topic accessible to everyone and turning longevity into a lifestyle.”

The entire program can be found on the Longevity Week here and on the website.

About the Longevity Week

Longevity Week was launched in 2024 and is an open platform that educates along the lines of nutrition and lifestyle, research & medicine and technology and takes the exchange between players from society, business and politics to a new level. With this in mind, the initiators of Longevity Week are striving to become the leading platform for the longevity scene and to establish Berlin as the centre of this development.

It is the result of an initiative by the doctor and entrepreneur Guido Axmann, the health investor Joachim Rautter (Peppermint Venture Partners) and the founder of the cryogenics start-up Tomorrow Biosis, Dr Emil Kendziorra. The other initiators include the physician Dr Andrea Gartenbach, the founder Christina Hanck and the investor Judith Müller.

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stanij.wicaz@redgertcomms.com