Women’s health, at the cellular level

Women’s health is the area of medicine that focuses on diagnosing and treating conditions unique to women only, such as ovarian cancer, endometriosis, and menopause, as well as those that disproportionately affect them, like osteoporosis and rheumatoid arthritis. It also includes diseases that manifest differently in women compared to men—most notably heart disease, which, due to a historical focus on men, is often misdiagnosed in women.

Despite increasing awareness of women’s health issues, as we move further into the 21st century, this field of medicine is still severely lacking funding and attention. A clear indicator is the number of new drug approvals: between 2009 and 2023, the US FDA approved 599 drugs, of which only 43 (~7%) targeted women-specific conditions (Young, 2024).

This time we would like to highlight one of the most common conditions that affect women – uterine fibroids, or leiomyomas. These benign tumors form in the tissues of the uterus, specifically, the myometrium (the muscle layer in the middle of the uterine wall) and adversely affect the endometrium (the inner epithelial layer) (Narwal et al., 2024). Leiomyomas are the most common tumors in women; by age 50, an estimated 70-80% of women have at least one such tumor (fibroid). While many cases are asymptomatic, given their prevalence, fibroids can cause negative effects, such as excessive menstrual bleeding leading to anemia, infertility, and pregnancy complications. Clinically symptomatic tumors make up 20-25% of all uterine fibroid cases, affecting 15-20% of all women of reproductive age. Yet, as of last year, there were no therapeutics specifically targeting this extremely frequent condition (based on Goad et al., 2022, and Young 2024). Instead, many patients must undergo extreme surgical treatment, such as hysterectomy (surgery to remove the uterus) (Buyukcelebi et al., 2024).

Leiomyomas and genetic mutations

However, research into uterine leiomyomas has been progressing, supported by the developing technologies in molecular biology and sequencing. In 2013, a whole genome sequencing study of uterine fibroids was published in The New England Journal of Medicine (Mehine et al., 2013). It found evidence that multiple fibroids often develop from a single cell undergoing complex chromosomal rearrangements (multiple intrachromosomal breaks which then rearrange incorrectly). While such rearrangements are typically associated with advanced cancer stages and poor prognosis, no direct link between fibroids and uterine cancers, which are rare, has been established (Mehine et al., 2013).

A distinct group of leiomyomas (70% of cases) contain somatic mutations in one specific gene, which encodes a transcription mediator protein (MED12). This group is also characterized by a relatively small number of chromosomal aberrations (Mehine et al., 2013). Using single-cell RNA sequencing, Goad et al. (2022) found that uterine fibroids (leiomyomas) that contain smooth muscle cells (SMC) with MED12 mutations also contain SMCs with wild type MED12 gene, indicating that these tumors are more heterogenous in their cellular composition than previously thought. The study also observed upregulation of genes linked to ECM (extracellular matrix) metabolism and muscle structure development in leiomyomas compared to healthy myometrium.Hormone-responsive genes were also upregulated in a distinct group of SMCs inside fibroids. Presence of estrogen and progesterone is known to increase MED12-mutated leiomyoma growth, and the aforementioned SMC cluster may be responsible. Finally, this study also identified distinct fibroblast and lymphatic endothelial cell populations present in these tumors, underlying their heterogeneity (Goad et al., 2022).

Multi-omics in uterine fibroids research

Scientists have also started utilizing multi-omics approaches to gain better understanding of uterine fibroids. For instance, George et al. (2019) published a study wherein they investigated DNA methylation profiles, transcriptomes and performed whole exome sequencing of leiomyoma cells. They found evidence that changes in gene expression, driven by differential DNA methylation, play a role in fibroid development and growth. Their study highlighted similarities in gene expression between fibroid cells and cervical stromal cells, suggesting that the transformation of myometrial cells into a cervical-stroma-like phenotype is involved in the development of the disease (George et al.,2019).

Buyukcelebi et al. (2024) used a multi-omics approach to investigate genetic variants and gene targets associated with leiomyomas. They identified risk loci and potentially causal single nucleotide polymorphisms from existing genome-wide association data and performed an integrated analysis of epigenetic, transcriptomic, and chromatin association profiles.

The integration of multi-omics data helped narrow down gene targets from the identified risk loci, which are often present in non-coding regulatory DNA regions. The scientists also performed locus-specific epigenetic editing and measured changes in the expression of any associated genes. This revealed complex regulatory networks, including cross-talk between distant genes, e.g., manipulating the promoter of ESR1 gene affected the expression of SYNE1 gene, which are nowhere near each other. This research is particularly important given that genetic and racial background is one of the main risk factors of uterine fibroids: family members of a patient have 2.5-fold greater risk to develop leiomyomas; African-American women have a higher risk and tend to present with more severe cases than white women (Khan et al., 2024).

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While there is still much work to do to remedy the unmet medical needs in women’s healthcare, it appears that powers that be are starting to give it more attention (Young, 2024). Meanwhile, utilizing developing single-cell analysis and multi-omics technologies to deepen our understanding of specific health conditions, such as uterine fibroids, can pave the way to the development of new therapeutics. Further research is still required, both in terms of gaining more knowledge and continuing to develop better technologies for single-cell multi-omics analysis. To help drive innovation in this field, Atrandi Biosciences has introduced the Semi-Permeable Capsule (SPC) technology, which can be used to develop ultra-high throughput molecular biology methodologies and single-cell multi-omics analysis workflows.

?? Find out more here: Semi–Permeable Capsules | Atrandi.com

References:

1. Buyukcelebi et al. Nat Comm 2024; 15: 1169 https://doi.org/10.1038/s41467-024-45382-0
2. George et al. Cell Rep 2019; 29: 4069 https://doi.org/10.1016/j.celrep.2019.11.077
3. Goad et al. Hum Reprod 2022; 37: 2334 https://doi.org/10.1093/humrep/deac183
4. Khan et al. Mol Hum Reprod 2024; 30: gaae004 https://doi.org/10.1093/molehr/gaae004
5. Mehine et al. N Engl J Med 2013; 369: 43 https://doi.org/10.1056/NEJMoa1302736
6. Narwal et al. "A Systematic Review on Uterine Leiomyoma: From Pathogenomics to Therapeutics." 2024. https://doi.org/10.5772/intechopen.1002877
7. Young. J Med Chem 2024; 67: 8473 https://doi.org/10.1021/acs.jmedchem.4c01135