REVIEWS AND COMMENTARY on literature in general medicine and biology
The staff of THE REPRODUCTIVE TIMES here offers commentaries on recently published articles, primarily chosen for educational values (in the positive but also in the negative), for clinical purposes, and for their potential translational values to clinical medicine when addressing basic science in reproductive medicine and biology. Today we address some basic science issues.
The first human organoids with an immune compartment
Before there were artificial human embryos, there were organoids originating from adult stem cells. They are, however, basically only epithelial structures, while organs are multilayered and multicompartmental, also including—among others—immune cells which, of course, play crucially important roles. Now Swiss investigators reported a first intestinal immune-organoid which allowed them to identify the Rho pathway as a new target for mitigation of immunotherapy-associated intestinal inflammation (1). The authors correctly concluded that such models could be used to study tissue-resident immune responses in the context of tumorigenesis, infectious diseases, and autoimmune diseases. Interestingly, they forgot to mention what is likely, at least for reproductive biology, the most interesting application: embryo implantation in the endometrium, which for far too long has been viewed as an endocrine process, while it really should be viewed as an immunological process.
Reference
1. Recaldin et al., Nature 2024;633:165173
A newly discovered cancer mechanism with potential to improve immunotherapy of cancers
Scientists at Tel Aviv University in Israel discovered unexpectedly a previously unknown cancer mechanism that prevents the immune system from attacking tumors. Once they reverse the mechanism, the immune system is stimulated, and attacks cancer cells and eliminates them (1). The investigators discovered that skin-specific, UV-induced suppression of T-cell killing activity is mediated by an upregulation of Ly6ahigh T-cell subpopulation. These cells – independently of the UV effects – are in the tumor microenvironment induced by chronic type-1 interferon and treatment with anti-Ly6a antibody enhanced the antitumor cytotoxic activity of T cells and reprogrammed their mitochondrial metabolism via the Erk/cMyk axis. In mice resistant to anti-PF1 therapy treatment with the Ly6a antibody inhibited tumor growth.
Reference
1. Maliah et al., Nt Commun 2024;15:8354
Extrachromosomal DNAs (ecDNAs) with surprising capabilities in cancer
Investigators from Stanford University (and collaborators) published a rather astonishing series of three papers in Nature magazine (1-3), demonstrating that extrachromosomal DNAs (ecDNAs)—also described as “small DNA circles”—are major drivers of cancer development (see figure below) (4).
In their first paper the authors attempted to determine the prevalence and the clinical relevance (i.e., prognostic potential) of ecDNAs in thousands of cancers. In the process they discovered a new non-Mendelian method of inheritance that contradicts pretty much everything we used to believe about inheritance and, in the future, should lead to new therapies for cancer which target those small DNA circles. As the authors also noted, some clinical trials are already underway.
On the left, ecDNAs that link together to enhance cancer cell growth tend to be inherited together by daughter cells after cell division. On the right, in contrast, ecDNAs that are inherited randomly give more genetic variability but may be less likely to spur tumor growth (Emily Moskal, Stanford Medicine, Conger K, November 6, 2024).
ecDNA was in 2017 for the first time demonstrated to play a major role in cancer cell survival and proliferation. In the first of the three recent papers, the investigators found 17.1% of cancers contain ecDNAs. And their presence indicated metastatic spread and poorer clinical outcomes. The surprise was, however, that some ecDNAs did not encode cancer causing genes directly but contained enhancer sequences which activate genes on other ecDNAs and in the process link ecDNA circles. In other words, ecDNAs have to work together to enhance cancer growth.
The second paper investigated what happens to ecDNAs when cancer cells divide and another surprising finding was that daughter cancer cells may have ecDNAs and others may not. In practical terms this provides a survival mechanism for the cancer because at least some populations of cells will have the right combination of ecDNAs to allow those cells to escape standard cancer treatments and – by doing so – establish drug resistance. This finding, of course is completely contradictory to the widely accepted Mendelian rule of independent assortment.
The third paper in the series addressed a possible new treatment approach toward cancer, considering what was learned about ecDNAs before and attempted to exploit a vulnerability if ecDNAs-containing cancer cells which is the cancer cells’ dependency on excessive transcription of copying DNA into RNA. Excessive transcription occurs—as note in the first paper—because of the interconnections between ecDNAs. If that process can be interrupted, cancer cells die. The interruption was achieved by blocking a checkpoint protein (CHK1) which is essential for cell division and, indeed, led to cancer cell death. Consequently, CHK1 blockers are already in clinical trials.
References
1. Bailey et al., Nature 2024;635:193-200
2. King et al., Nature 2024;635:201-209
3. Tang et al., Nature 2024;635: 210-218
4. Conger K. Stanford Medicine. November 6, 2024. https://med.stanford.edu/news/all-news/2024/11/ecdna-cancer.html