Mois : octobre 2024

Researchers publishing in Aging Cell have investigated the biology of skin cells taken from people who don’t produce the senescence-related compound p16.

A necessary evil

The aging community has published a lot of papers on p16INK4a (p16) and its SASP-associated dangers, as excessive SASP production is a key driver of aging. However, p16 is a protein that must be coded for by the genome, so what happens if a mutation deprives that gene (CDKN2A) of function? There is already a name for this condition: familial melanoma syndrome (FMS) [1], and it leads to both melanoma and pancreatic cancer [2].

The relationship beween senescence and cancer is well-known. While excessive amounts of senescence can drive cancer, it serves a protective function under normal circumstances [3]. As cellular senescence is highly heterogenous, the removal of one of its compounds affects some cells more than others. As expected, correlating with its associated cancers, CDKN2A mutations primarily affect the skin.

While previous work has been done to investigate what such mutations do, that research is somewhat dated [4]. These researchers decided to take a modern look at the problem, investigating skin cells taken from people with CDKN2A mutations and seeing how they behave.

The benefits of less p16 don’t outweigh the risks

This study used cells derived from 16 patients aged 18 to 68 recruited in London. The majority of these patients had missense mutations that reduced the binding ability of the created proteins. These cells did not produce no p16 at all; rather, compared to healthy controls, the number of p16-expressing cells was the same, but the amount of this protein in each cell was significantly reduced. While there were only three male patients, there were no sex differences discovered. Unlike the control group, older people with these FMS mutations did not have more p16 than similar younger people did.

Pigment-producing melanocytes were found to be more prone to DNA damage than skin fibroblasts in both the control and FMS groups. Interestingly, the FMS group had slightly less senescence-related DNA damage than the control group, as measured by the co-location of the damage marker H2AX with telomeres. This was particularly noticeable in the melanocytes. Also interestingly, cellular proliferation, as measured by the marker ki67, was not different in skin cells between the groups.

Dermal fibroblasts could be driven senescent by chemicals or radiation. Under both methods, this senescence occurred through the p21 pathway in the FMS group, while the control group used p16. However, melanocytes were not able to produce as much p21; they are more reliant on the p16 pathway, which corroborates previous research [5].

When left to replicate themselves into senescence, fibroblasts derived from FMS patients did go senescent over time, but they divided more and for longer, even when the cells were derived from older people. Replicative senescence occurred in all of the normal cells in less than a year; all of the FMS cells took longer than a year to become senescent. The cells still accumulated some DNA damage as measured by H2AX; it simply did not stop them from proliferating as quickly.

This was accompanied by less immune activity. The number of active immune cells, including lymphocytes and T cells, was significantly less in the skin of FMS patients than in the control group. These immune cells, isolated and examined, were found to behave similarly; it was the lack of SASP expression that discouraged them from appearing in the skin at normal levels in the FMS group.

In total, while a lack of p16 appears to have significant benefits, none of them outweigh the increased risk of cancer. Therefore, anyone developing a therapy that involves affecting the SASP, or anyone seeking a drug that reduces the SASP, should keep research such as this in mind.

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Literature

[1] Potrony, M., Badenas, C., Aguilera, P., Puig-Butille, J. A., Carrera, C., Malvehy, J., & Puig, S. (2015). Update in genetic susceptibility in melanoma. Annals of translational medicine, 3(15).

[2] Mize, D. E., Bishop, M., Resse, E., & Sluzevich, J. (2009). Cancer Syndromes.

[3] Campisi, J. (2013). Aging, cellular senescence, and cancer. Annual review of physiology, 75(1), 685-705.

[4] Sviderskaya, E. V., Gray-Schopfer, V. C., Hill, S. P., Smit, N. P., Evans-Whipp, T. J., Bond, J., … & Bennett, D. C. (2003). p16/cyclin-dependent kinase inhibitor 2A deficiency in human melanocyte senescence, apoptosis, and immortalization: possible implications for melanoma progression. Journal of the National Cancer Institute, 95(10), 723-732.

[5] Sviderskaya, E. V., Hill, S. P., Evans-Whipp, T. J., Chin, L., Orlow, S. J., Easty, D. J., … & Bennett, D. C. (2002). p16Ink4a in melanocyte senescence and differentiation. Journal of the National Cancer Institute, 94(6), 446-454.

A new study describes a novel anti-cancer vaccine based on antigen-producing bacteria that can tackle solid and metastatic cancers [1].

Invading an invader

Years ago, scientists discovered that bacteria can colonize tumors [2]. Some bacteria are drawn to the tumor microenvironment due to factors such as necrotic tissue, hypoxia, and nutrient availability. For example, Clostridium species prefer anaerobic conditions and have been explored in tumor-targeting therapies. Salmonella and E. coli strains have also shown an affinity for tumors [3].

This led to the idea of a microbial anti-cancer vaccine: using tumor-targeting bacteria to improve an organism’s immune response to cancer. However, this task has proven to be difficult. In a new study published in Nature, researchers from Columbia University report creating a sophisticated bacterial vector that is effective against solid tumors, which are considered particularly tough targets.

Takes out cancer, including metastatic

It takes several mutations to turn a healthy cell into a cancerous one. The products of those mutations, which might include full-length mutated proteins and truncated protein chains, can elicit an immune response (become antigens).

The researchers identified several such “neoantigens” in a type of colorectal carcinoma and genetically engineered E. coli to produce them in large quantities. Mice were then inoculated with cancer cells. After tumors developed, the bacterial vaccine was injected directly into the tumor microenvironment.

The bacteria readily colonized the tumors but not healthy tissues. As expected, tumor antigens produced by the bacteria elicited a strong, multi-faceted immune response. A single injection effectively prevented tumor growth, with three out of seven mice exhibiting a complete response (full tumor eradication).

The researchers then complicated the task: the mice were inoculated with cancer cells on both sides of the body, leading to the appearance of two tumors. Only one tumor was treated with the bacterial vaccine to see if this could produce a systemic response.

As the researchers hoped, the treatment produced a sustained systemic immune response. The bacteria were only found in the treated tumors, but the untreated tumors also came under attack by the immune system.

Injecting a drug directly into the tumor can be complicated, so the researchers tried intravenous delivery. They found that the bacteria were quickly cleared away from healthy tissues but successfully colonized the tumor and produced results comparable to intratumoral administration.

Another tough test was metastases. Metastatic (stage 4) cancers are virtually incurable. In this study, lung metastases were created by injecting carcinoma cells into the bloodstream. After the engraftment, the bacterial vaccine was also injected intravenously. Amazingly, all the treated animals survived past day 50 of the experiment, while all the animals in the other groups succumbed to cancer much earlier.

The researchers then tackled a more aggressive tumor cell type (B16F10 melanoma). Of course, they had to engineer a new strain of bacteria carrying melanoma-specific antigens. The treatment produced strong results with localized tumors, blocking their growth almost completely. With metastatic melanoma, the survival rate was 60% in the treatment group versus zero in the control group.

A bespoke treatment

According to the authors, their modified bacteria “recruit and activate dendritic cells, stimulate both neoantigen-specific and broad adaptive immunity, and reduce immunosuppression within the tumor microenvironment.” The researchers also predict that their system might produce a synergistic effect when combined with other treatments.

The new therapy would have to be tailored not only to a specific type of cancer but to each patient. “The time to treatment will first depend on how long it takes to sequence the tumor,” said Tal Danino, associate professor of biomedical engineering at Columbia’s School of Engineering and a leading author on the study. “Then we just need to make the bacterial strains, which can be quite fast. Bacteria can be simpler to manufacture than some other vaccine platforms.”

However, there’s an upside to that level of personalization. Since the vaccine is based on several tumor-specific antigens, the cancer will hardly be able to evade it by rapidly mutating. “Because our platform allows us to deliver so many different neoantigens, it theoretically becomes difficult for tumor cells to lose all those targets at once and avoid the immune response,” said another leading author, Nicholas Arpaia, associate professor of microbiology and immunology at Columbia University’s Vagelos College of Physicians and Surgeons.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Yes I will donate

Literature

[1] Redenti, A., Im, J., Redenti, B., Li, F., Rouanne, M., Sheng, Z., Sun, W., Gurbatri, C. R., Huang, S., Komaranchath, M., Jang, Y., Hahn, J., Ballister, E. R., Vincent, R. L., Vardoshivilli, A., Danino, T., & Arpaia, N. (2024). Probiotic neoantigen delivery vectors for precision cancer immunotherapy. Nature, 1-9.

[2] Yu, Y. A., Zhang, Q., & Szalay, A. A. (2008). Establishment and characterization of conditions required for tumor colonization by intravenously delivered bacteria. Biotechnology and bioengineering, 100(3), 567-578.

[3] Pawelek, J. M., Low, K. B., & Bermudes, D. (1997). Tumor-targeted Salmonella as a novel anticancer vector. Cancer research, 57(20), 4537-4544.

In Aging Cell, researchers have identified a receptor in the brain that appears to be responsible for cognitive problems after surgery, particularly in older people.

Surgery can cause cognitive problems

Neurological symptoms such as postoperative cognitive dysfunction [1] and postoperative delirium [2] are common after surgery, particularly when the surgery is intensive or the patient is older. These symptoms, known collectively as postoperative neurocognitive disorders (pNCDs), have been associated with inflammation but are largely poorly understood.

This research is focused on Nogo-66 receptor 1 (NgR1), a receptor that naturally restricts neuroplasticity [3], the ability of neurons to change shape and form new memories. Previous research has implied that it is a core reason why childhood trauma is difficult to forget for adults [4]. Other work has found that this protein instigates the spread of the disease in Alzheimer’s model mice [5] and that it interacts with amyloid beta [6].

The brains of healthy organisms can learn when and how to become more plastic [7]. This metaplasticity is regulated in part by receptors known as AMPARs, which are composed of four separate subunits [8]. Actin, specifically the ratio of F-actin to G-actin, affects how neurons grow and develop, regulates the function of AMPARs, and is key to neuroplasticity [9]. These researchers, therefore, hypothesized that NgR1 has effects in this area.

An increase in anxiety

In the first experiment, aged mice (20-22 months) were anaesthetized and had their abdominal regions opened (laparotomy). Compared to the control group, these mice had consistently greater levels of NgR1 in the hippocampus for a week, but this did not hold true for other brain regions. Its co-receptors, which are necessary for its function, were also similarly upregulated.

This was accompanied by several behavioral changes. Mice that had been subjected to surgery had increases in marble burying and grooming behaviors, and when given a choice between closed and open areas, spend less time in open areas than mice not subjected to surgery. This represents increased anxiety and fear memory. However, when a peptide known to be antagonistic to NgR1 (NEP1-40) was also administered to block its function, these behavioral changes were diminished to be indistinguishable from a control group given no surgery at all.

Potential protection on multiple levels

This behavioral protection was accompanied by protection for the synapses as well. In mice given surgery, PSD95, a marker of synaptic activity, was significantly reduced. However, mice given NEP1-40 with the surgery did not have this marker reduced. As expected, NEP1-40 reduced both NgR1 and the related compound NogoA.

The researchers found that this chemical protection has physical effects. Many aspects of CA1 pyramidal neurons in the hippocampus, including total length, intersections, and branching, were affected neither by surgery nor by NEP1-40. However, these neurons’ dendrites were significantly affected; the number of thin and stubby dendritic spines was unchanged, but the surgical group had fewer mature and healthy spines than the control group. NEP1-40 also reversed this change.

This was found to be directly related to changes to the F-actin/G-actin ratio, a benefit that was recapitulated in a cellular experiment. Multiple enzymes and proteins related to actin, both downstream and upstream, were affected by surgery and restored by NEP1-40. Likewise, AMPAR activity, specifically in the expressions of Glu1 and Glu2, was reduced by surgery and restored by NEP1-40. Calcium responses were found to be similarly affected.

Neuroplasticity is a long-known problem in the world of aging, not just in the context of surgery and trauma but in the learning ability of older people more generally. If NgR1 can be affected by interventions, it may be possible to restore some degree of learning and memory retention to older people, particularly those recovering from serious injuries. Much more work will need to be done, including drug discovery, to determine if this is the case.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Yes I will donate

Literature

[1] Alam, A., Hana, Z., Jin, Z., Suen, K. C., & Ma, D. (2018). Surgery, neuroinflammation and cognitive impairment. EBioMedicine, 37, 547-556.

[2] Jin, Z., Hu, J., & Ma, D. (2020). Postoperative delirium: perioperative assessment, risk reduction, and management. British journal of anaesthesia, 125(4), 492-504.

[3] Akbik, F. V., Bhagat, S. M., Patel, P. R., Cafferty, W. B., & Strittmatter, S. M. (2013). Anatomical plasticity of adult brain is titrated by Nogo Receptor 1. Neuron, 77(5), 859-866.

[4] Bhagat, S. M., Butler, S. S., Taylor, J. R., McEwen, B. S., & Strittmatter, S. M. (2016). Erasure of fear memories is prevented by Nogo Receptor 1 in adulthood. Molecular psychiatry, 21(9), 1281-1289.

[5] Wang, J., Qin, X., Sun, H., He, M., Lv, Q., Gao, C., … & Liao, H. (2021). Nogo receptor impairs the clearance of fibril amyloid‐β by microglia and accelerates Alzheimer’s‐like disease progression. Aging Cell, 20(12), e13515.

[6] Zhao, Y., Sivaji, S., Chiang, M. C., Ali, H., Zukowski, M., Ali, S., … & Wills, Z. P. (2017). Amyloid beta peptides block new synapse assembly by nogo receptor-mediated inhibition of T-type calcium channels. Neuron, 96(2), 355-372.

[7] Toyoizumi, T., Kaneko, M., Stryker, M. P., & Miller, K. D. (2014). Modeling the dynamic interaction of Hebbian and homeostatic plasticity. Neuron, 84(2), 497-510.

[8] Diering, G. H., & Huganir, R. L. (2018). The AMPA receptor code of synaptic plasticity. Neuron, 100(2), 314-329.

[9] Gu, J., Lee, C. W., Fan, Y., Komlos, D., Tang, X., Sun, C., … & Zheng, J. Q. (2010). ADF/cofilin-mediated actin dynamics regulate AMPA receptor trafficking during synaptic plasticity. Nature neuroscience, 13(10), 1208-1215.