bims-tumhet 2023-08-27 papers

Issue of 2023–08–27
seven papers selected by
Sergio Marchini, Humanitas Research

Cells. 2023 Aug 10. pii: 2042. [Epub ahead of print]12(16):

Tsai-Ying Chen, Li You, Jose Angelito U Hardillo, Miao-Ping Chien.

Spatial transcriptomic technologies enable measurement of expression levels of genes systematically throughout tissue space, deepening our understanding of cellular organizations and interactions within tissues as well as illuminating biological insights in neuroscience, developmental biology and a range of diseases, including cancer. A variety of spatial technologies have been developed and/or commercialized, differing in spatial resolution, sensitivity, multiplexing capability, throughput and coverage. In this paper, we review key enabling spatial transcriptomic technologies and their applications as well as the perspective of the techniques and new emerging technologies that are developed to address current limitations of spatial methodologies. In addition, we describe how spatial transcriptomics data can be integrated with other omics modalities, complementing other methods in deciphering cellar interactions and phenotypes within tissues as well as providing novel insight into tissue organization.

Keywords: NGS-based spatial profiling; image-guided spatially resolved single cell sequencing; imaging-based spatial profiling; probe-based spatial profiling; spatial omics technologies

DOI: https://doi.org/10.3390/cells12162042

Cold Spring Harb Perspect Med. 2023 Aug 21. pii: a041337. [Epub ahead of print]

Early Detection of Ovarian Cancer.

Naoko Sasamoto, Kevin M Elias.

The risk of death from ovarian cancer is highly associated with the clinical stage at diagnosis. Efforts to implement screening for ovarian cancer have been largely unsuccessful, due to the low prevalence of the disease in the general population and the heterogeneity of the various cancer types that fall under the ovarian cancer designation. A practical test for early detection will require both high sensitivity and high specificity to balance reducing the number of cancer deaths with minimizing surgical interventions for false positive screens. The technology must be cost-effective to deliver at scale, widely accessible, and relatively noninvasive. Most importantly, a successful early detection test must be effective not only at diagnosing ovarian cancer but also in reducing ovarian cancer deaths. Stepwise or multimodal approaches among the various areas under investigation will likely be required to make early detection a reality.

DOI: https://doi.org/10.1101/cshperspect.a041337

Ann Oncol. 2023 Aug 10. pii: S0923-7534(23)00797-4. [Epub ahead of print]

Newly diagnosed and relapsed epithelial ovarian cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.

ESMO Guidelines Committee

Keywords: diagnosis; epithelial ovarian cancer; follow-up; guideline; surgery; treatment

DOI: https://doi.org/10.1016/j.annonc.2023.07.011

Gynecol Oncol. 2023 Aug 23. pii: S0090-8258(23)00372-4. [Epub ahead of print]177 20-31

Overall survival and patient-reported outcome results from the placebo-controlled randomized phase III IMagyn050/GOG 3015/ENGOT-OV39 trial of atezolizumab for newly diagnosed stage III/IV ovarian cancer.

OBJECTIVE: To determine the impact on overall survival (OS) and patient-reported outcomes (PROs) of combining atezolizumab with standard therapy for newly diagnosed stage III/IV ovarian cancer.
METHODS: The placebo-controlled double-blind randomized phase III IMagyn050/GOG 3015/ENGOT-OV39 trial (NCT03038100) assigned eligible patients to 3-weekly atezolizumab 1200 mg or placebo for 22 cycles with platinum-based chemotherapy and bevacizumab. Coprimary endpoints were progression-free survival (already reported) and OS in the PD-L1-positive and intent-to-treat (ITT) populations, tested hierarchically. Prespecified PRO analyses focused on disease-related abdominal pain and bloating symptoms (European Organisation for Research and Treatment of Cancer QLQ-OV28), functioning, and health-related quality of life (HRQoL) (QLQ-C30).
RESULTS: After 38 months' median follow-up, the OS hazard ratio in the PD-L1-positive population was 0.83 (95% CI, 0.66-1.06; p = 0.13); median OS was not estimable with atezolizumab versus 49.2 months with placebo. The hazard ratio for OS in the ITT population was 0.92 (95% CI, 0.78-1.09; median 50.5 versus 46.6 months, respectively). At week 9, similar proportions of patients in both arms of the neoadjuvant cohort showed ≥10-point improvement from baseline in abdominal pain and bloating, functioning, and HRQoL. In the primary surgery cohort, similar proportions of patients in each arm had improved, stable, or worsened physical and role function and HRQoL from baseline over time. Neither cohort showed differences between arms in treatment-related symptoms or overall side-effect bother.
CONCLUSIONS: Incorporation of atezolizumab into standard therapy for newly diagnosed ovarian cancer does not significantly improve efficacy or impose additional treatment burden for patients.
CLINICALTRIALS: gov registration: NCT03038100.

Keywords: Immune checkpoint blockade; Ovarian cancer; Overall survival; PD-L1; Patient-reported outcomes

DOI: https://doi.org/10.1016/j.ygyno.2023.06.018

Nature. 2023 Aug 23.

Non-cell-autonomous cancer progression from chromosomal instability.

Chromosomal instability (CIN) is a driver of cancer metastasis1-4, yet the extent to which this effect depends on the immune system remains unknown. Using ContactTracing-a newly developed, validated and benchmarked tool to infer the nature and conditional dependence of cell-cell interactions from single-cell transcriptomic data-we show that CIN-induced chronic activation of the cGAS-STING pathway promotes downstream signal re-wiring in cancer cells, leading to a pro-metastatic tumour microenvironment. This re-wiring is manifested by type I interferon tachyphylaxis selectively downstream of STING and a corresponding increase in cancer cell-derived endoplasmic reticulum (ER) stress response. Reversal of CIN, depletion of cancer cell STING or inhibition of ER stress response signalling abrogates CIN-dependent effects on the tumour microenvironment and suppresses metastasis in immune competent, but not severely immune compromised, settings. Treatment with STING inhibitors reduces CIN-driven metastasis in melanoma, breast and colorectal cancers in a manner dependent on tumour cell-intrinsic STING. Finally, we show that CIN and pervasive cGAS activation in micronuclei are associated with ER stress signalling, immune suppression and metastasis in human triple-negative breast cancer, highlighting a viable strategy to identify and therapeutically intervene in tumours spurred by CIN-induced inflammation.

DOI: https://doi.org/10.1038/s41586-023-06464-z

NAR Cancer. 2023 Sep;5(3): zcad043

The dynamic process of covalent and non-covalent PARylation in the maintenance of genome integrity: a focus on PARP inhibitors.

Adèle Beneyton, Louis Nonfoux, Jean-Philippe Gagné, Amélie Rodrigue, Charu Kothari, Nurgul Atalay, Michael J Hendzel, Guy G Poirier, Jean-Yves Masson.

Poly(ADP-ribosylation) (PARylation) by poly(ADP-ribose) polymerases (PARPs) is a highly regulated process that consists of the covalent addition of polymers of ADP-ribose (PAR) through post-translational modifications of substrate proteins or non-covalent interactions with PAR via PAR binding domains and motifs, thereby reprogramming their functions. This modification is particularly known for its central role in the maintenance of genomic stability. However, how genomic integrity is controlled by an intricate interplay of covalent PARylation and non-covalent PAR binding remains largely unknown. Of importance, PARylation has caught recent attention for providing a mechanistic basis of synthetic lethality involving PARP inhibitors (PARPi), most notably in homologous recombination (HR)-deficient breast and ovarian tumors. The molecular mechanisms responsible for the anti-cancer effect of PARPi are thought to implicate both catalytic inhibition and trapping of PARP enzymes on DNA. However, the relative contribution of each on tumor-specific cytotoxicity is still unclear. It is paramount to understand these PAR-dependent mechanisms, given that resistance to PARPi is a challenge in the clinic. Deciphering the complex interplay between covalent PARylation and non-covalent PAR binding and defining how PARP trapping and non-trapping events contribute to PARPi anti-tumour activity is essential for developing improved therapeutic strategies. With this perspective, we review the current understanding of PARylation biology in the context of the DNA damage response (DDR) and the mechanisms underlying PARPi activity and resistance.

DOI: https://doi.org/10.1093/narcan/zcad043

Cancer Rep (Hoboken). 2023 Aug 21. e1858

Omentum provides a special cell microenvironment for ovarian cancer.

Zeying Li, Xiaoling Fang, Sixue Wang.

BACKGROUND: Ovarian cancer seriously threatens women's health because of its poor prognosis and high mortality. Due to the lack of efficient early detection and screening methods, when patients seek doctors' help with complaints of abdominal distension, back pain and other nonspecific signs, the clinical results always hint at the widespread metastasis of disease. When referring to the metastasis of this disease, the omentum always takes precedence.
RECENT FINDINGS: The distinguishing feature of the omentum is adipose tissue, which satisfies the energy demand of cancer cells and supplies a more aggressive environment for ovarian cancer cells. In this review, we mainly focus on three important cell types: adipocytes, macrophages, and mesenchymal stem cells. Besides, several mechanisms underlying cancer-associated adipocytes (CAA)-facilitated ovarian cancer cell development have been revealed, including their capacities for storing lipids and endocrine function, and the release of hormones, growth factors, and adipokines. Blocking the reciprocity among cancer cells and various cells located on the omentum might contribute to ovarian cancer therapy. The inhibition of hormones, growth factors and adipokines produced by adipocytes will be a novel therapeutic strategy. However, a sufficient number of trials has not been performed. In spite of this, the therapeutic potential of metformin and the roles of exercise in ovarian cancer will be worth mentioning.
CONCLUSION: It is almost impossible to overcome completely ovarian cancer at the moment. What we can do is trying our best to improve these patients' prognoses. In this process, adipocytes may bring promising future for the therapy of ovarian cancer.

Keywords: adipocyte; exercise; metformin; omentum; ovarian cancer

DOI: https://doi.org/10.1002/cnr2.1858