bims-tumhet 2023-10-22 papers

Issue of 2023–10–22
five papers selected by
Sergio Marchini, Humanitas Research

Int J Cancer. 2023 Oct 20.

Natural resistance to cancer: A window of hope.

Mohammad Masoudi, Parisa Torabi, Robert L Judson-Torres, Reza Khodarahmi, Sharif Moradi.

As healthcare systems are improving and thereby the life expectancy of human populations is increasing, cancer is representing itself as the second leading cause of death. Although cancer biologists have put enormous effort on cancer research so far, we still have a long way to go before being able to treat cancers efficiently. One interesting approach in cancer biology is to learn from natural resistance and/or predisposition to cancer. Cancer-resistant species and tissues are thought-provoking models whose study shed light on the inherent cancer resistance mechanisms that arose during the course of evolution. On the other hand, there are some syndromes and factors that increase the risk of cancer development, and revealing their underlying mechanisms will increase our knowledge about the process of cancer formation. Here, we review natural resistance and predisposition to cancer and the known mechanisms at play. Further insights from these natural phenomena will help design future cancer research and could ultimately lead to the development of novel cancer therapeutic strategies.

Keywords: carcinogenesis; lifespan; malignancy; resistance to cancer; tumor

DOI: https://doi.org/10.1002/ijc.34766

Nat Commun. 2023 Oct 16. 14(1): 6505

Molecular landscape and functional characterization of centrosome amplification in ovarian cancer.

High-grade serous ovarian carcinoma (HGSOC) is characterised by poor outcome and extreme chromosome instability (CIN). Therapies targeting centrosome amplification (CA), a key mediator of chromosome missegregation, may have significant clinical utility in HGSOC. However, the prevalence of CA in HGSOC, its relationship to genomic biomarkers of CIN and its potential impact on therapeutic response have not been defined. Using high-throughput multi-regional microscopy on 287 clinical HGSOC tissues and 73 cell lines models, here we show that CA through centriole overduplication is a highly recurrent and heterogeneous feature of HGSOC and strongly associated with CIN and genome subclonality. Cell-based studies showed that high-prevalence CA is phenocopied in ovarian cancer cell lines, and that high CA is associated with increased multi-treatment resistance; most notably to paclitaxel, the commonest treatment used in HGSOC. CA in HGSOC may therefore present a potential driver of tumour evolution and a powerful biomarker for response to standard-of-care treatment.

DOI: https://doi.org/10.1038/s41467-023-41840-3

Front Oncol. 2023 ;13 1268127

Nora Sahnane, Laura Libera, Sofia Facchi, Ileana Carnevali, Susanna Ronchi, Chiara Albeni, Antonella Cromi, Jvan Casarin, Fausto Sessa, Maria Grazia Tibiletti.

Introduction: BRCA1 methylated (BRCA1met) epithelial ovarian cancer (EOC) is a recently defined and not well-investigated subset of neoplasms. To date, no studies have focused on the transcriptional profiles of BRCA1met cases, and, as a matter of fact, we still do not know if this subset of EOCs is similar, and to what extent, to BRCA1 mutated (BRCA1mut) cases.
Methods: We compared a group of 17 BRCA1met cases against 10 BRCA1mut cases using a subset of carefully selected 17 BRCAwt EOCs as a control group.
Results: First, BRCA1met cases showed a downregulation of the relative transcript, while this association was not observed for BRCA1mut EOCs. The BRCA1met group exhibited a general upregulation of homologous recombination (HR)-related genes, as well as BRCA1mut. Overall, BRCA1met had a different gene expression profile, characterized by diffuse downregulation, whereas BRCA1mut showed a general upregulation (p < 0.0001). Both BRCA1-defective groups showed a slightly activated immune response mediated by interferon (IFN) gamma pathways.
Discussion: In conclusion, even if the expression profile of many genes related to DNA damage and repair system is shared between BRCA1mut and BRCA1met EOCs supporting that BRCA1met EOCs may benefit from PARPi therapies, our data demonstrate that BRCA1mut and BRCA1met EOCs show different expression profiles, suggesting a different mechanism of carcinogenesis that can be reflected in different responses to therapies and disease recovery.

Keywords: BRCA1 methylation; EOC; NanoString®; PARPi therapy; gene expression profiles

DOI: https://doi.org/10.3389/fonc.2023.1268127

Chromosome Res. 2023 Oct 21. 31(4): 31

Permission to pass: on the role of p53 as a gatekeeper for aneuploidy.

Joana F Marques, Geert J P L Kops.

Aneuploidy-the karyotype state in which the number of chromosomes deviates from a multiple of the haploid chromosome set-is common in cancer, where it is thought to facilitate tumor initiation and progression. However, it is poorly tolerated in healthy cells: during development and tissue homeostasis, aneuploid cells are efficiently cleared from the population. It is still largely unknown how cancer cells become, and adapt to being, aneuploid. P53, the gatekeeper of the genome, has been proposed to guard against aneuploidy. Aneuploidy in cancer genomes strongly correlates with mutations in TP53, and p53 is thought to prevent the propagation of aneuploid cells. Whether p53 also participates in preventing the mistakes in cell division that lead to aneuploidy is still under debate. In this review, we summarize the current understanding of the role of p53 in protecting cells from aneuploidy, and we explore the consequences of functional p53 loss for the propagation of aneuploidy in cancer.

Keywords: Aneuploidy; Cancer; Chromosomal instability; p53

DOI: https://doi.org/10.1007/s10577-023-09741-9

Mol Cell. 2023 Oct 19. pii: S1097-2765(23)00749-9. [Epub ahead of print]83(20): 3582-3587

The crosstalk between DNA repair and immune responses.

Karlene A Cimprich, Guo-Min Li, Sandra Demaria, Nelson O Gekara, Shan Zha, Qianming Chen.

In recent years, increasing evidence has highlighted the profound connection between DNA damage repair and the activation of immune responses. We spoke with researchers about their mechanistic interplays and the implications for cancer and other diseases.

DOI: https://doi.org/10.1016/j.molcel.2023.09.022