bims-tumhet 2024-09-01 papers

bims-tumhet

Biomed News

on Tumor Heterogeneity

Issue of 2024‒09‒01
eight papers selected by
Sergio Marchini, Humanitas Research

Cracking the Codes behind Cancer Cells' Immune Evasion.
Epigenetic regulation in ovarian cancer.
IMPRESS: Improved methylation profiling using restriction enzymes and smMIP sequencing, combined with a new biomarker panel, creating a multi-cancer detection assay.
Epigenetic contribution to cancer.
Application of single cell sequencing technology in ovarian cancer research (review).
PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma.
Liquid Biopsy in the Clinical Management of Cancers.
Spatiotemporal omics for biology and medicine.

Int J Mol Sci. 2024 Aug 15. pii: 8899. [Epub ahead of print]25(16):

Cracking the Codes behind Cancer Cells' Immune Evasion.

Nikita Mundhara, Pritam Sadhukhan.

  Immune evasion is a key phenomenon in understanding tumor recurrence, metastasis, and other critical steps in tumor progression. The tumor microenvironment (TME) is in constant flux due to the tumor's ability to release signals that affect it, while immune cells within it can impact cancer cell behavior. Cancer cells undergo several changes, which can change the enrichment of different immune cells and modulate the activity of existing immune cells in the tumor microenvironment. Cancer cells can evade immune surveillance by downregulating antigen presentation or expressing immune checkpoint molecules. High levels of tumor-infiltrating lymphocytes (TILs) correlate with better outcomes, and robust immune responses can control tumor growth. On the contrary, increased enrichment of Tregs, myeloid-derived suppressor cells, and M2-like anti-inflammatory macrophages can hinder effective immune surveillance and predict poor prognosis. Overall, understanding these immune evasion mechanisms guides therapeutic strategies. Researchers aim to modulate the TME to enhance immune surveillance and improve patient outcomes. In this review article, we strive to summarize the composition of the tumor immune microenvironment, factors affecting the tumor immune microenvironment (TIME), and different therapeutic modalities targeting the immune cells. This review is a first-hand reference to understand the basics of immune surveillance and immune evasion.

Keywords:  cancer biology; cancer immunology; immune evasion; immunotherapy; targeted therapy

DOI:  https://doi.org/10.3390/ijms25168899
Int Rev Cell Mol Biol. 2024 ;pii: S1937-6448(24)00045-5. [Epub ahead of print]387 77-98

Epigenetic regulation in ovarian cancer.

Hue Vu Thi, Anh-Dao Ngo, Dinh-Toi Chu.

  Ovarian cancer is one of the diseases that have the highest mortality rate for women, especially women over 50 years old. In the future, incidence and mortality rates are predicted to extend in countries with low HDI. Instability in the structure and function of genetic factors has long been known as a cause of cancer, including ovarian cancer. Besides understanding gene mutations, epigenetic alterations have emerged as another aspect leading to the pathogenesis of ovarian neoplasm. The development and progression of this fatal disease have been found to be associated with abnormalities of epigenetic regulation. DNA methylation, histone modification, and non-coding RNAs-based gene silencing are processes of interest in developing ovarian carcinoma and are also new targets for cancer detection or treatment.

Keywords:  DNA methylation; Epigenetic regulation; Histone modification; Ovarian cancer; Ovarian cancer diagnosis; Ovarian cancer therapy

DOI:  https://doi.org/10.1016/bs.ircmb.2024.03.006
Br J Cancer. 2024 Aug 24.

IMPRESS: Improved methylation profiling using restriction enzymes and smMIP sequencing, combined with a new biomarker panel, creating a multi-cancer detection assay.

Janah Vandenhoeck, Isabelle Neefs, Thomas Vanpoucke, Joe Ibrahim, Arvid Suls, Dieter Peeters, Anne Schepers, Alexander Hoischen, Erik Fransen, Marc Peeters, Guy Van Camp, Ken Op de Beeck.

BACKGROUND: Despite the worldwide progress in cancer diagnostics, more sensitive diagnostic biomarkers are needed. The methylome has been extensively investigated in the last decades, but a low-cost, bisulfite-free detection method for multiplex analysis is still lacking.METHODS: We developed a methylation detection technique called IMPRESS, which combines methylation-sensitive restriction enzymes and single-molecule Molecular Inversion Probes. We used this technique for the development of a multi-cancer detection assay for eight of the most lethal cancer types worldwide. We selected 1791 CpG sites that can distinguish tumor from normal tissue based on DNA methylation. These sites were analysed with IMPRESS in 35 blood, 111 tumor and 114 normal samples. Finally, a classifier model was built.
RESULTS: We present the successful development of IMPRESS and validated it with ddPCR. The final classifier model discriminating tumor from normal samples was built with 358 CpG target sites and reached a sensitivity of 0.95 and a specificity of 0.91. Moreover, we provide data that highlight IMPRESS's potential for liquid biopsies.
CONCLUSIONS: We successfully created an innovative DNA methylation detection technique. By combining this method with a new multi-cancer biomarker panel, we developed a sensitive and specific multi-cancer assay, with potential use in liquid biopsies.

DOI: https://doi.org/10.1038/s41416-024-02809-1
Int Rev Cell Mol Biol. 2024 ;pii: S1937-6448(24)00088-1. [Epub ahead of print]387 1-25

Epigenetic contribution to cancer.

Songhua Quan, Hao Huang.

  Epigenetics has transformed our understanding of cancer by revealing how changes in gene activity, which do not alter the DNA itself, can initiate and progress the disease. These changes include adjustments in DNA methylation, histone configuration, and non-coding RNA activity. For instance, DNA methylation can inactivate genes that typically protect against cancer, leading to broader genomic instability. Histone modifications can alter how tightly DNA is wound, influencing which genes are active or silenced; while non-coding RNAs can interfere with the messages that direct protein production, impacting cancer-related processes. Unlike genetic mutations, which are permanent and irreversible, epigenetic changes provide a malleable target for therapeutic intervention, allowing potentially reversible adjustments to gene expression patterns. This flexibility is essential in the complex landscape of cancer where static genetic solutions may be insufficient. Additionally, epigenetics bridges the gap between genetic predispositions and environmental influences on cancer, offering a comprehensive framework for understanding how lifestyle factors and external exposures impact cancer risk and progression. The integration of epigenetics into cancer research not only enhances our understanding of the disease but also opens innovative avenues for intervention that were previously unexplored in traditional genetic-focused studies. Technologies like advanced sequencing and precise epigenetic modification are paving the way for early cancer detection and more personalized treatment approaches, highlighting the critical role of epigenetics in modern cancer care.

Keywords:  Cancer; DNA methylation; Epigenetics; Hitone modification; RNA methylaiton

DOI:  https://doi.org/10.1016/bs.ircmb.2024.05.003
Funct Integr Genomics. 2024 Aug 28. 24(5): 144

Application of single cell sequencing technology in ovarian cancer research (review).

Qiqolei Yuan, Nengyuan Lv, Qianying Chen, Siyi Shen, Yahui Wang, Jinyi Tong.

  Ovarian cancer is a malignant tumor of ovary. It has the characteristics of difficult early diagnosis, poor late curative effect and high recurrence rate. It is the biggest disease that seriously threatens women's health. Single cell sequencing technology refers to sequencing the genetic information carried by it at the single cell level to obtain the gene sequence, transcript, protein and epigenetic expression profile information of a certain cell type and conduct integrated analysis. It has unique advantages in the study of tumor occurrence and evolution, and can provide new methods for the study of ovarian cancer. This paper reviews the single cell sequencing technology and its application in ovarian cancer.

Keywords:  Heterogeneity; Ovarian cancer; Single cell sequencing

DOI:  https://doi.org/10.1007/s10142-024-01432-w
Cancer Res. 2024 Aug 26.

PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma.

Sarah Spear, Olivia Le Saux, Hasan B Mirza, Nayana Iyer, Katie Tyson, Fabio Grundland Freile, Josephine B Walton, Chloe Woodman, Sheba Jarvis, Darren P Ennis, Carmen Aguirre Hernandez, Yuewei Xu, Pavlina Spiliopoulou, James D Brenton, Ana P Costa-Pereira, David P Cook, Barbara C Vanderhyden, Hector C Keun, Evangelos Triantafyllou, James N Arnold, Iain A McNeish.

High-grade serous ovarian carcinoma (HGSC) remains a disease of poor prognosis that is unresponsive to current immune checkpoint inhibitors. Although PI3K pathway alterations, such as PTEN loss, are common in HGSC, attempts to target this pathway have been unsuccessful. We hypothesized that aberrant PI3K pathway activation may alter the HGSC immune microenvironment and present a targeting opportunity. Single-cell RNA sequencing identified populations of resident macrophages specific to Pten-null omental tumors in murine models, which were confirmed by flow cytometry. These macrophages derived from peritoneal fluid macrophages and had a unique gene expression program, marked by high expression of the enzyme heme oxygenase-1 (HMOX1). Targeting resident peritoneal macrophages prevented the appearance of HMOX1hi macrophages and reduced tumor growth. Furthermore, direct inhibition of HMOX1 extended survival in vivo. RNA sequencing identified IL33 in Pten-null tumor cells as a likely candidate driver leading to the appearance of HMOX1hi macrophages. Human HGSC tumors also contained HMOX1hi macrophages with a corresponding gene expression program. Moreover, the presence of these macrophages correlated with activated tumoral PI3K/mTOR signaling and poor overall survival in HGSC patients. In contrast, tumors with low numbers of HMOX1hi macrophages were marked by increased adaptive immune response gene expression. These data suggest targeting HMOX1hi macrophages as a potential therapeutic strategy for treating poor prognosis HGSC.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-3890
Int J Mol Sci. 2024 Aug 06. pii: 8594. [Epub ahead of print]25(16):

Liquid Biopsy in the Clinical Management of Cancers.

Ho-Yin Ho, Kei-See Kasey Chung, Chau-Ming Kan, Sze-Chuen Cesar Wong.

  Liquid biopsy, a noninvasive diagnosis that examines circulating tumor components in body fluids, is increasingly used in cancer management. An overview of relevant literature emphasizes the current state of liquid biopsy applications in cancer care. Biomarkers in liquid biopsy, particularly circulating tumor DNA (ctDNA), circulating tumor RNAs (ctRNA), circulating tumor cells (CTCs), extracellular vesicles (EVs), and other components, offer promising opportunities for early cancer diagnosis, treatment selection, monitoring, and disease assessment. The implementation of liquid biopsy in precision medicine has shown significant potential in various cancer types, including lung cancer, colorectal cancer, breast cancer, and prostate cancer. Advances in genomic and molecular technologies such as next-generation sequencing (NGS) and digital polymerase chain reaction (dPCR) have expanded the utility of liquid biopsy, enabling the detection of somatic variants and actionable genomic alterations in tumors. Liquid biopsy has also demonstrated utility in predicting treatment responses, monitoring minimal residual disease (MRD), and assessing tumor heterogeneity. Nevertheless, standardizing liquid biopsy techniques, interpreting results, and integrating them into the clinical routine remain as challenges. Despite these challenges, liquid biopsy has significant clinical implications in cancer management, offering a dynamic and noninvasive approach to understanding tumor biology and guiding personalized treatment strategies.

Keywords:  cancers; clinical management; liquid biopsy

DOI:  https://doi.org/10.3390/ijms25168594
Cell. 2024 Aug 22. pii: S0092-8674(24)00834-1. [Epub ahead of print]187(17): 4488-4519

Spatiotemporal omics for biology and medicine.

Longqi Liu, Ao Chen, Yuxiang Li, Jan Mulder, Holger Heyn, Xun Xu.

The completion of the Human Genome Project has provided a foundational blueprint for understanding human life. Nonetheless, understanding the intricate mechanisms through which our genetic blueprint is involved in disease or orchestrates development across temporal and spatial dimensions remains a profound scientific challenge. Recent breakthroughs in cellular omics technologies have paved new pathways for understanding the regulation of genomic elements and the relationship between gene expression, cellular functions, and cell fate determination. The advent of spatial omics technologies, encompassing both imaging and sequencing-based methodologies, has enabled a comprehensive understanding of biological processes from a cellular ecosystem perspective. This review offers an updated overview of how spatial omics has advanced our understanding of the translation of genetic information into cellular heterogeneity and tissue structural organization and their dynamic changes over time. It emphasizes the discovery of various biological phenomena, related to organ functionality, embryogenesis, species evolution, and the pathogenesis of diseases.

DOI: https://doi.org/10.1016/j.cell.2024.07.040