bims-ovdlit 2022-03-27 papers

Issue of 2022–03–27
six papers selected by
Lara Paracchini, Humanitas Research

Cancers (Basel). 2022 Mar 10. pii: 1420. [Epub ahead of print]14(6):

PARP Inhibitors Resistance: Mechanisms and Perspectives.

Elena Giudice, Marica Gentile, Vanda Salutari, Caterina Ricci, Lucia Musacchio, Maria Vittoria Carbone, Viola Ghizzoni, Floriana Camarda, Francesca Tronconi, Camilla Nero, Francesca Ciccarone, Giovanni Scambia, Domenica Lorusso.

PolyADP-ribose polymerase (PARP) inhibitors (PARPis) represent the first clinically approved drugs able to provoke "synthetic lethality" in patients with homologous recombination-deficient (HRD) tumors. Four PARPis have just received approval for the treatment of several types of cancer. Besides, another three additional PARPis underlying the same mechanism of action are currently under investigation. Despite the success of these targeted agents, the increasing use of PARPis in clinical practice for the treatment of different tumors raised the issue of PARPis resistance, and the consequent disease relapse and dismal prognosis for patients. Several mechanisms of resistance have been investigated, and ongoing studies are currently focusing on strategies to address this challenge and overcome PARPis resistance. This review aims to analyze the mechanisms underlying PARPis resistance known today and discuss potential therapeutic strategies to overcome these processes of resistance in the future.

Keywords: BRCA; DNA damage repair; PARP inhibitor resistance; homologous recombination; ovarian cancer; polyADP-ribose polymerase (PARP) inhibitor; replication fork

DOI: https://doi.org/10.3390/cancers14061420

Nat Biotechnol. 2022 Mar 21.

Spatial charting of single-cell transcriptomes in tissues.

Runmin Wei, Siyuan He, Shanshan Bai, Emi Sei, Min Hu, Alastair Thompson, Ken Chen, Savitri Krishnamurthy, Nicholas E Navin.

Single-cell RNA sequencing methods can profile the transcriptomes of single cells but cannot preserve spatial information. Conversely, spatial transcriptomics assays can profile spatial regions in tissue sections, but do not have single-cell resolution. Here, we developed a computational method called CellTrek that combines these two datasets to achieve single-cell spatial mapping through coembedding and metric learning approaches. We benchmarked CellTrek using simulation and in situ hybridization datasets, which demonstrated its accuracy and robustness. We then applied CellTrek to existing mouse brain and kidney datasets and showed that CellTrek can detect topological patterns of different cell types and cell states. We performed single-cell RNA sequencing and spatial transcriptomics experiments on two ductal carcinoma in situ tissues and applied CellTrek to identify tumor subclones that were restricted to different ducts, and specific T cell states adjacent to the tumor areas. Our data show that CellTrek can accurately map single cells in diverse tissue types to resolve their spatial organization.

DOI: https://doi.org/10.1038/s41587-022-01233-1

Curr Oncol. 2022 Mar 21. 29(3): 2132-2140

Risk-Reducing Options for High-Grade Serous Gynecologic Malignancy in BRCA1/2.

Lauren Clarfield, Laura Diamond, Michelle Jacobson.

Ovarian cancer (OC) is the leading cause of death among women with gynecologic malignancy. Breast Cancer Susceptibility Gene 1 (BRCA 1) and Breast Cancer Susceptibility Gene 2 (BRCA 2) germline mutations confer an estimated 20 to 40 times increased risk of OC when compared to the general population. The majority of BRCA-associated OC is identified in the late stage, and no effective screening method has been proven to reduce mortality. Several pharmacologic and surgical options exist for risk-reduction of gynecologic malignancy in BRCA 1/2 mutation carriers. This review summarizes up-to-date research on pharmacologic risk-reducing interventions, including the oral contraceptive pill, acetylsalicylic acid/nonsteroidal anti inflammatory drugs (ASA/NSAID) therapy, and denosumab, and surgical risk-reducing interventions, including risk-reducing bilateral salpingo-oophorectomy, salpingectomy with delayed oophorectomy, and hysterectomy at the time of risk-reducing bilateral salpingo-oophorectomy.

Keywords: BRCA 1; BRCA 2; breast neoplasms; contraceptives; endometrial neoplasms; genes; genetic predisposition to disease; germ-line mutation; hysterectomy; oral; ovarian neoplasms; salpingo-oophorectomy

DOI: https://doi.org/10.3390/curroncol29030172

Front Oncol. 2022 ;12 798680

CAF-Associated Paracrine Signaling Worsens Outcome and Potentially Contributes to Chemoresistance in Epithelial Ovarian Cancer.

Michael Wessolly, Elena Mairinger, Sabrina Borchert, Agnes Bankfalvi, Pawel Mach, Kurt Werner Schmid, Rainer Kimmig, Paul Buderath, Fabian Dominik Mairinger.

Background: High-grade serous ovarian cancer (HGSOC) is the predominant and deadliest form of ovarian cancer. Some of its histological subtypes can be distinguished by frequent occurrence of cancer-associated myofibroblasts (CAFs) and desmoplastic stroma reaction (DSR). In this study, we want to explore the relationship between therapy outcome and the activity of CAF-associated signaling pathways in a homogeneous HGSOC patient collective. Furthermore, we want to validate these findings in a general Epithelial ovarian cancer (EOC) cohort.
Methods: The investigation cohort consists of 24 HGSOC patients. All of them were treated with platinum-based components and clinical follow-up was available. The validation cohort was comprised of 303 patients. Sequencing data (whole transcriptome) and clinical data were extracted from The Cancer Genome Atlas (TCGA). RNA of HGSOC patients was isolated using a Maxwell RSC instrument and the appropriate RNA isolation kit. For digital expression analysis a custom-designed gene panel was employed. All genes were linked to various DSR- and CAF- associated pathways. Expression analysis was performed on the NanoString nCounter platform. Finally, data were explored using the R programming environment (v. 4.0.3).
Result: In total, 15 CAF-associated genes were associated with patients' survival. More specifically, 6 genes (MMP13, CGA, EPHA3, PSMD9, PITX2, PHLPP1) were linked to poor therapy outcome. Though a variety of different pathways appeared to be associated with therapy failure, many were related to CAF paracrine signaling, including MAPK, Ras and TGF-β pathways. Similar results were obtained from the validation cohort.
Discussion: In this study, we could successfully link CAF-associated pathways, as shown by increased Ras, MAPK and PI3K-Akt signaling to therapy failure (chemotherapy) in HGSOC and EOCs in general. As platinum-based chemotherapy has been the state-of-the-art therapy to treat HGSOC for decades, it is necessary to unveil the reasons behind resistance developments and poor outcome. In this work, CAF-associated signaling is shown to compromise therapy response. In the validation cohort, CAF-associated signaling is also associated with therapy failure in general EOC, possibly hinting towards a conserved mechanism. Therefore, it may be helpful to stratify HGSOC patients for CAF activity and consider alternative treatment options.

Keywords: cancer-associated fibroblasts; chemoresistance; epithelial ovarian cancer; high-grade serous ovarian cancer; tumor microenvironment

DOI: https://doi.org/10.3389/fonc.2022.798680

Int J Mol Sci. 2022 Mar 11. pii: 3042. [Epub ahead of print]23(6):

Single-Cell RNA Sequencing with Spatial Transcriptomics of Cancer Tissues.

Rashid Ahmed, Tariq Zaman, Farhan Chowdhury, Fatima Mraiche, Muhammad Tariq, Irfan S Ahmad, Anwarul Hasan.

Single-cell RNA sequencing (RNA-seq) techniques can perform analysis of transcriptome at the single-cell level and possess an unprecedented potential for exploring signatures involved in tumor development and progression. These techniques can perform sequence analysis of transcripts with a better resolution that could increase understanding of the cellular diversity found in the tumor microenvironment and how the cells interact with each other in complex heterogeneous cancerous tissues. Identifying the changes occurring in the genome and transcriptome in the spatial context is considered to increase knowledge of molecular factors fueling cancers. It may help develop better monitoring strategies and innovative approaches for cancer treatment. Recently, there has been a growing trend in the integration of RNA-seq techniques with contemporary omics technologies to study the tumor microenvironment. There has been a realization that this area of research has a huge scope of application in translational research. This review article presents an overview of various types of single-cell RNA-seq techniques used currently for analysis of cancer tissues, their pros and cons in bulk profiling of transcriptome, and recent advances in the techniques in exploring heterogeneity of various types of cancer tissues. Furthermore, we have highlighted the integration of single-cell RNA-seq techniques with other omics technologies for analysis of transcriptome in their spatial context, which is considered to revolutionize the understanding of tumor microenvironment.

Keywords: intratumor heterogeneity; single-cell RNA sequencing techniques; spatial transcriptomics

DOI: https://doi.org/10.3390/ijms23063042