bims-tumhet 2023-06-25 papers

Issue of 2023‒06‒25
four papers selected by
Sergio Marchini
Humanitas Research

Clin Cancer Res. 2023 Jun 22. pii: CCR-23-0563. [Epub ahead of print]

Assessment of Homologous Recombination Deficiency in Ovarian Cancer.

Accurately assessing homologous recombination deficiency to use as predictive biomarker is an area of intense research in ovarian cancer. Validated assays have demonstrated utility in determining maintenance therapy following platinum sensitive chemotherapy. Novel functional assays promise the potential to reflect HRD in real time and predict response to PARP inhibitors.

DOI: https://doi.org/10.1158/1078-0432.CCR-23-0563

Clin Cancer Res. 2023 Jun 20. pii: CCR-22-3815. [Epub ahead of print]

The prognostic effect of immune cell infiltration depends on molecular subtype in Endometrioid Ovarian Carcinomas.

PURPOSE: Endometrioid ovarian carcinoma (ENOC) is the second most-common type of ovarian carcinoma, comprising 10-20% of cases. Recently, the study of ENOC has benefitted from comparisons to endometrial carcinomas (EC) including defining ENOC with four prognostic molecular subtypes. Each subtype suggests differential mechanisms of progression, though tumor initiating events remain elusive. There is evidence that the ovarian microenvironment may be critical to early lesion establishment and progression. However, while immune infiltrates have been well studied in high-grade serous ovarian carcinoma, studies in ENOC are limited.EXPERIMENTAL DESIGN: We report on 210 ENOC, with clinical follow-up and molecular subtype annotation. Using multiplex immunohistochemistry and immunofluorescence, we examine the prevalence of T cell lineage, B cell lineage, macrophages, and populations with PD-1 or PD-L1 across subtypes of ENOC.
RESULTS: Immune cell infiltrates in tumor epithelium and stroma showed higher densities in ENOC subtypes with known high mutation burden (POLEmut and MMRd). While molecular subtypes were prognostically significant, immune infiltrates were not (OS p>0.2). Analysis by molecular subtype revealed that immune cell density was prognostically significant in only the no specific molecular subtype (NSMP) subtype, where immune infiltrates lacking B cells (TILB minus) had inferior outcome (DSS HR:4.0 CI 1.1-14.7, p<0.05). Similar to EC, molecular subtype stratification was generally superior to immune response in predicting outcomes.
CONCLUSIONS: Subtype stratification is critical for better understanding of ENOC, in particular the distribution and prognostic significance of immune cell infiltrates. The role of B cells in the immune response within NSMP tumors warrants further study.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-3815

Genomics. 2023 Jun 21. pii: S0888-7543(23)00115-5. [Epub ahead of print] 110671

Spatial transcriptomics: Technologies, applications and experimental considerations.

Ye Wang, Bin Liu, Gexin Zhao, YooJin Lee, Anton Buzdin, Xiaofeng Mu, Joseph Zhao, Hong Chen, Xinmin Li.

The diverse cell types of an organ have a highly structured organization to enable their efficient and correct function. To fully appreciate gene functions in a given cell type, one needs to understand how much, when and where the gene is expressed. Classic bulk RNA sequencing and popular single cell sequencing destroy cell structural organization and fail to provide spatial information. However, the spatial location of gene expression or of the cell in a complex tissue provides key clues to comprehend how the neighboring genes or cells cross talk, transduce signals and work together as a team to complete the job. The functional requirement for the spatial content has been a driving force for rapid development of the spatial transcriptomics technologies in the past few years. Here, we present an overview of current spatial technologies with a special focus on the commercially available or currently being commercialized technologies, highlight their applications by category and discuss experimental considerations for a first spatial experiment.

Keywords: 10× Visium; BMKMANU S1000; CosMx SMI; GeoMx DSP; MERFISH; RNA sequencing; Spatial transcriptomics; Stereo-seq; Xienum

DOI: https://doi.org/10.1016/j.ygeno.2023.110671

Front Cell Dev Biol. 2023 ;11 1209136

Whole-Genome Doubling as a source of cancer: how, when, where, and why?

Natalia Sanz-Gómez, María González-Álvarez, Javier De Las Rivas, Guillermo de Cárcer.

Chromosome instability is a well-known hallmark of cancer, leading to increased genetic plasticity of tumoral cells, which favors cancer aggressiveness, and poor prognosis. One of the main sources of chromosomal instability are events that lead to a Whole-Genome Duplication (WGD) and the subsequently generated cell polyploidy. In recent years, several studies showed that WGD occurs at the early stages of cell transformation, which allows cells to later become aneuploid, thus leading to cancer progression. On the other hand, other studies convey that polyploidy plays a tumor suppressor role, by inducing cell cycle arrest, cell senescence, apoptosis, and even prompting cell differentiation, depending on the tissue cell type. There is still a gap in understanding how cells that underwent WGD can overcome the deleterious effect on cell fitness and evolve to become tumoral. Some laboratories in the chromosomal instability field recently explored this paradox, finding biomarkers that modulate polyploid cells to become oncogenic. This review brings a historical view of how WGD and polyploidy impact cell fitness and cancer progression, and bring together the last studies that describe the genes helping cells to adapt to polyploidy.

Keywords: aneuploidy; chromosomal instability; endoreduplication; mitotic slippage; oncogene; polyploidy; whole-genome doubling

DOI: https://doi.org/10.3389/fcell.2023.1209136