bims-ovdlit 2022-11-27 papers

Issue of 2022–11–27
five papers selected by
Lara Paracchini, Humanitas Research

Eur J Cancer. 2022 Oct 27. pii: S0959-8049(22)01308-9. [Epub ahead of print]178 91-113

Methylation biomarkers for early cancer detection and diagnosis: Current and future perspectives.

Joe Ibrahim, Marc Peeters, Guy Van Camp, Ken Op de Beeck.

The increase in recent scientific studies on cancer biomarkers has brought great new insights into the field. Moreover, novel technological breakthroughs such as long read sequencing and microarrays have enabled high throughput profiling of many biomarkers, while advances in bioinformatic tools have made the possibility of developing highly reliable and accurate biomarkers a reality. These changes triggered renewed interest in biomarker research and provided tremendous opportunities for enhancing cancer management and improving early disease detection. DNA methylation alterations are known to accompany and contribute to carcinogenesis, making them promising biomarkers for cancer, namely due to their stability, frequency and accessibility in bodily fluids. The advent of newer minimally invasive experimental methods such as liquid biopsies provide the perfect setting for methylation-based biomarker development and application. Despite their huge potential, accurate and robust biomarkers for the conclusive diagnosis of most cancer types are still not routinely used, hence a strong need for sustained research in this field is still needed. This review provides a brief exposition of current methylation biomarkers for cancer diagnosis and early detection, including markers already in clinical use as well as various upcoming ones. It also outlines how recent big data and novel technologies will revolutionise the next generation of cancer tests in supplementing or replacing currently existing invasive techniques.

Keywords: Biomarkers; Cancer; Diagnosis; Early detection; Methylation

DOI: https://doi.org/10.1016/j.ejca.2022.10.015

Nat Methods. 2022 Nov 24.

Image-seq: spatially resolved single-cell sequencing guided by in situ and in vivo imaging.

Christa Haase, Karin Gustafsson, Shenglin Mei, Shu-Chi Yeh, Dmitry Richter, Jelena Milosevic, Raphaël Turcotte, Peter V Kharchenko, David B Sykes, David T Scadden, Charles P Lin.

Tissue function depends on cellular organization. While the properties of individual cells are increasingly being deciphered using powerful single-cell sequencing technologies, understanding their spatial organization and temporal evolution remains a major challenge. Here, we present Image-seq, a technology that provides single-cell transcriptional data on cells that are isolated from specific spatial locations under image guidance, thus preserving the spatial information of the target cells. It is compatible with in situ and in vivo imaging and can document the temporal and dynamic history of the cells being analyzed. Cell samples are isolated from intact tissue and processed with state-of-the-art library preparation protocols. The technique therefore combines spatial information with highly sensitive RNA sequencing readouts from individual, intact cells. We have used both high-throughput, droplet-based sequencing as well as SMARTseq-v4 library preparation to demonstrate its application to bone marrow and leukemia biology. We discovered that DPP4 is a highly upregulated gene during early progression of acute myeloid leukemia and that it marks a more proliferative subpopulation that is confined to specific bone marrow microenvironments. Furthermore, the ability of Image-seq to isolate viable, intact cells should make it compatible with a range of downstream single-cell analysis tools including multi-omics protocols.

DOI: https://doi.org/10.1038/s41592-022-01673-2

Front Cell Dev Biol. 2022 ;10 1042734

Fallopian tube secreted protein affects ovarian metabolites in high grade serous ovarian cancer.

Tova M Bergsten, Sarah E Levy, Katherine E Zink, Hannah J Lusk, Melissa R Pergande, Stephanie M Cologna, Joanna E Burdette, Laura M Sanchez.

High grade serous ovarian cancer (HGSOC), the most lethal histotype of ovarian cancer, frequently arises from fallopian tube epithelial cells (FTE). Once transformed, tumorigenic FTE often migrate specifically to the ovary, completing the crucial primary metastatic step and allowing the formation of the ovarian tumors after which HGSOC was originally named. As only the fimbriated distal ends of the fallopian tube that reside in close proximity to the ovary develop precursor lesions such as serous tubal intraepithelial carcinomas, this suggests that the process of transformation and primary metastasis to the ovary is impacted by the local microenvironment. We hypothesize that chemical cues, including small molecules and proteins, may help stimulate the migration of tumorigenic FTE to the ovary. However, the specific mediators of this process are still poorly understood, despite a recent growth in interest in the tumor microenvironment. Our previous work utilized imaging mass spectrometry (IMS) to identify the release of norepinephrine (NE) from the ovary in co-cultures of tumorigenic FTE cells with an ovarian explant. We predicted that tumorigenic FTE cells secreted a biomolecule, not produced or produced with low expression by non-tumorigenic cells, that stimulated the ovary to release NE. As such, we utilized an IMS mass-guided bioassay, using NE release as our biological marker, and bottom-up proteomics to demonstrate that a secreted protein, SPARC, is a factor produced by tumorigenic FTE responsible for enhancing release of ovarian NE and influencing primary metastasis of HGSOC. This discovery highlights the bidirectional interplay between different types of biomolecules in the fallopian tube and ovarian microenvironment and their combined roles in primary metastasis and disease progression.

Keywords: SPARC; fallopian tube; imaging mass spectrometry (IMS); ovarian cancer; proteomics; tumor micro environment

DOI: https://doi.org/10.3389/fcell.2022.1042734

Nat Commun. 2022 Nov 23. 13(1): 7182

Reversion mutations in germline BRCA1/2-mutant tumors reveal a BRCA-mediated phenotype in non-canonical histologies.

Yonina R Murciano-Goroff, Alison M Schram, Ezra Y Rosen, Helen Won, Yixiao Gong, Anne Marie Noronha, Yelena Y Janjigian, Zsofia K Stadler, Jason C Chang, Soo-Ryum Yang, Diana Mandelker, Kenneth Offit, Michael F Berger, Mark T A Donoghue, Chaitanya Bandlamudi, Alexander Drilon.

The association between loss of BRCA1/2 and a homologous recombination deficiency phenotype is lineage dependent. In BRCA-associated cancers such as breast, ovarian, pancreas and prostate, this phenotype confers sensitivity to PARP inhibitors and platinum-therapies. Somatic reversion mutations restoring BRCA1/2 function mediate resistance, and have exclusively been reported in BRCA-associated tumors. In this study, we analyze matched tumor and normal sequencing from 31,927 patients and identify 846 (2.7%) patients with germline BRCA1/2 variants across 43 different cancer types, including 11 with somatic reversion mutations. While nine are in BRCA-associated tumors, we find two reversion mutations in non-BRCA-associated histologies, namely lung and esophagogastric adenocarcinomas. Both were detected following platinum therapy. Whole exome sequencing confirms the homologous recombination deficiency phenotype of these tumors. While reversion mutations arise in all BRCA-associated cancer types, here we show that reversion mutations arising post-platinum in non-BRCA associated histologies, while rare, may indicate BRCA1/2 mediated tumorigenesis.

DOI: https://doi.org/10.1038/s41467-022-34109-8

Int J Mol Sci. 2022 Nov 08. pii: 13687. [Epub ahead of print]23(22):

Nanobodies for the Early Detection of Ovarian Cancer.

Lan-Huong Tran, Geert-Jan Graulus, Cécile Vincke, Natalia Smiejkowska, Anne Kindt, Nick Devoogdt, Serge Muyldermans, Peter Adriaensens, Wanda Guedens.

Ovarian cancer ranks fifth in cancer-related deaths among women. Since ovarian cancer patients are often asymptomatic, most patients are diagnosed only at an advanced stage of disease. This results in a 5-year survival rate below 50%, which is in strong contrast to a survival rate as high as 94% if detected and treated at an early stage. Monitoring serum biomarkers offers new possibilities to diagnose ovarian cancer at an early stage. In this study, nanobodies targeting the ovarian cancer biomarkers human epididymis protein 4 (HE4), secretory leukocyte protease inhibitor (SLPI), and progranulin (PGRN) were evaluated regarding their expression levels in bacterial systems, epitope binning, and antigen-binding affinity by enzyme-linked immunosorbent assay and surface plasmon resonance. The selected nanobodies possess strong binding affinities for their cognate antigens (KD~0.1-10 nM) and therefore have a pronounced potential to detect ovarian cancer at an early stage. Moreover, it is of utmost importance that the limits of detection (LOD) for these biomarkers are in the pM range, implying high specificity and sensitivity, as demonstrated by values in human serum of 37 pM for HE4, 163 pM for SLPI, and 195 pM for PGRN. These nanobody candidates could thus pave the way towards multiplexed biosensors.

Keywords: early-stage cancer detection; epithelial ovarian cancer; human epididymis protein 4; nanobodies; progranulin; secretory leukocyte protease inhibitor

DOI: https://doi.org/10.3390/ijms232213687