bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2023–07–16
six papers selected by
Sergio Marchini, Humanitas Research
  1. Current Understanding on Why Ovarian Cancer Is Resistant to Immune Checkpoint Inhibitors.
  2. Circulating tumor DNA to drive treatment in metastatic colorectal cancer.
  3. Microsatellite instability states serve as predictive biomarkers for tumors chemotherapy sensitivity.
  4. Gene fusions during the early evolution of mesothelioma correlate with impaired DNA repair and Hippo pathways.
  5. The prognostic and biology of tumour-infiltrating lymphocytes in the immunotherapy of cancer.
  6. Cancer cell-specific cGAS/STING Signaling pathway in the era of advancing cancer cell biology.
  1. Int J Mol Sci. 2023 Jun 29. pii: 10859. [Epub ahead of print]24(13):
    Current Understanding on Why Ovarian Cancer Is Resistant to Immune Checkpoint Inhibitors.
    Anna Pawłowska, Anna Rekowska, Weronika Kuryło, Anna Pańczyszyn, Jan Kotarski, Iwona Wertel.
      The standard treatment of ovarian cancer (OC) patients, including debulking surgery and first-line chemotherapy, is unsatisfactory because of recurrent episodes in the majority (~70%) of patients with advanced OC. Clinical trials have shown only a modest (10-15%) response of OC individuals to treatment based on immune checkpoint inhibitors (ICIs). The resistance of OC to therapy is caused by various factors, including OC heterogeneity, low density of tumor-infiltrating lymphocytes (TILs), non-cellular and cellular interactions in the tumor microenvironment (TME), as well as a network of microRNA regulating immune checkpoint pathways. Moreover, ICIs are the most efficient in tumors that are marked by high microsatellite instability and high tumor mutation burden, which is rare among OC patients. The great challenge in ICI implementation is connected with distinguishing hyper-, pseudo-, and real progression of the disease. The understanding of the immunological, molecular, and genetic mechanisms of OC resistance is crucial to selecting the group of OC individuals in whom personalized treatment would be beneficial. In this review, we summarize current knowledge about the selected factors inducing OC resistance and discuss the future directions of ICI-based immunotherapy development for OC patients.
    Keywords:  PD-1/PD-L1; TIGIT; immune checkpoints; immunotherapy; microRNA; ovarian cancer; resistance
    DOI:  https://doi.org/10.3390/ijms241310859
  2. Clin Cancer Res. 2023 Jul 12. pii: CCR-23-0079. [Epub ahead of print]
    Circulating tumor DNA to drive treatment in metastatic colorectal cancer.
    Giorgio Patelli, Gianluca Mauri, Federica Tosi, Alessio Amatu, Katia Bencardino, Erica Bonazzina, Elio Gregory Pizzutilo, Federica Villa, Gabriele Calvanese, Alberto Giuseppe Agostara, Stefano Stabile, Silvia Ghezzi, Giovanni Crisafulli, Federica Di Nicolantonio, Silvia Marsoni, Alberto Bardelli, Salvatore Siena, Andrea Sartore-Bianchi.
      In the evolving molecular treatment landscape of metastatic colorectal cancer (mCRC), the identification of druggable alterations is pivotal to achieve the best therapeutic opportunity for each patient. Since the number of actionable targets is expanding, there is the need to timely detect their presence or emergence to guide the choice of different available treatment options. Liquid biopsy, through the analysis of circulating tumor DNA (ctDNA), has proven safe and effective as a complementary method to address cancer evolution while overcoming the limitations of tissue biopsy. Even though data are accumulating regarding the potential for ctDNA-guided treatments applied to targeted agents, still major gaps in knowledge exist as for their application to different areas of the continuum of care. In this review, we recapitulate how ctDNA information could be exploited to drive different targeted treatment strategies in mCRC patients, by refining molecular selection before treatment by addressing tumor heterogeneity beyond tumor tissue biopsy; longitudinally monitoring early-tumor response and resistance mechanisms to targeted agents, potentially leading to tailored, molecular-driven, therapeutic options; guiding the molecular triage towards rechallenge strategies with anti-EGFR agents suggesting the best time for retreatment; and providing opportunities for an "enhanced rechallenge" through additional treatments or combos aimed at overcoming acquired resistance. Besides, we discuss future perspectives concerning the potential role of ctDNA to fine-tune investigational strategies such as immuno-oncology.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-0079
  3. iScience. 2023 Jul 21. 26(7): 107045
    Microsatellite instability states serve as predictive biomarkers for tumors chemotherapy sensitivity.
    Taojun Ye, Anqi Lin, Zhengang Qiu, Shulu Hu, Chaozheng Zhou, Zaoqu Liu, Quan Cheng, Jian Zhang, Peng Luo.
      There is an urgent need for markers to predict the efficacy of different chemotherapy drugs. Herein, we examined whether microsatellite instability (MSI) status can predict tumor multidrug sensitivity and explored the underlying mechanisms. We downloaded data from several public databases. Drug sensitivity was compared between the high microsatellite instability (MSI-H) and microsatellite-stable/low microsatellite instability (MSS/MSI-L) groups. In addition, we performed pathway enrichment analysis and cellular chemosensitivity assays to explore the mechanisms by which MSI status may affect drug sensitivity and assessed the differences between drug-treated and control cell lines. We found that multiple MSI-H tumors were more sensitive to a variety of chemotherapy drugs than MSS/MSI-L tumors, and especially for CRC, chemosensitivity is enhanced through the downregulation of DDR pathways such as NHEJ. Additional DNA damage caused by chemotherapeutic drugs results in further downregulation of DDR pathways and enhances drug sensitivity, forming a cycle of increasing drug sensitivity.
    Keywords:  Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2023.107045
  4. Genes Chromosomes Cancer. 2023 Jul 08.
    Gene fusions during the early evolution of mesothelioma correlate with impaired DNA repair and Hippo pathways.
    Maymun Jama, Min Zhang, Charlotte Poile, Apostolos Nakas, Annabel Sharkey, Joanna Dzialo, Alan Dawson, Kudazyi Kutywayo, Dean A Fennell, Edward J Hollox.
      Malignant pleural mesothelioma (MPM), a rare cancer a long latency period (up to 40 years) between asbestos exposure and disease presentation. The mechanisms coupling asbestos to recurrent somatic alterations are poorly defined. Gene fusions arising through genomic instability may create novel drivers during early MPM evolution. We explored the gene fusions that occurred early in the evolutionary history of the tumor. We conducted multiregional whole exome sequencing (WES) of 106 samples from 20 patients undergoing pleurectomy decortication and identified 24 clonal nonrecurrent gene fusions, three of which were novel (FMO9P-OR2W5, GBA3, and SP9). The number of early gene fusion events detected varied from zero to eight per tumor, and presence of gene fusions was associated with clonal losses involving the Hippo pathway genes and homologous recombination DNA repair genes. Fusions involved known tumor suppressors BAP1, MTAP, and LRP1B, and a clonal oncogenic fusion involving CACNA1D-ERC2, PARD3B-NT5DC2, and STAB2-NT5DC2 fusions were also identified as clonal fusions. Gene fusions events occur early during MPM evolution. Individual fusions are rare as no recurrent truncal fusions event were found. This suggests the importance of early disruption of these pathways in generating genomic rearrangements resulting in potentially oncogenic gene fusions.
    Keywords:  evolution; gene fusion; genomics; mesothelioma; transcriptomics
    DOI:  https://doi.org/10.1002/gcc.23189
  5. Br J Cancer. 2023 Jul 14.
    The prognostic and biology of tumour-infiltrating lymphocytes in the immunotherapy of cancer.
    Yanbin Liu, Zhenjiang Liu, Yixiao Yang, Jun Cui, Jingwei Sun, Yarong Liu.
      Tumour immunotherapy has achieved remarkable clinical success in many different types of cancer in the past two decades. The outcome of immune checkpoint inhibitors in cancer patients has been linked to the quality and magnitude of T cell, NK cell, and more recently, B cell within the tumour microenvironment, suggesting that the immune landscape of a tumour is highly connected to patient response and prognosis. It is critical to understanding tumour immune microenvironments for identifying immune modifiers of cancer progression and developing cancer immunotherapies. The infiltration of solid tumours by immune cells with anti-tumour activity is both a strong prognostic factor and a therapeutic goal. Recent approaches and applications of new technologies, especially single-cell mRNA analysis in dissecting tumour microenvironments have brought important insights into the biology of tumour-infiltrating immune cells, revealed a remarkable degree of cellular heterogeneity and distinct patterns of immune response. In this review, we will discuss recent advances in the understanding of tumour infiltrated lymphocytes, their prognostic benefit, and predictive value for immunotherapy.
    DOI:  https://doi.org/10.1038/s41416-023-02321-y
  6. Eur J Cell Biol. 2023 Jul 06. pii: S0171-9335(23)00053-5. [Epub ahead of print]102(3): 151338
    Cancer cell-specific cGAS/STING Signaling pathway in the era of advancing cancer cell biology.
    Vijay Kumar, Caitlin Bauer, John H Stewart.
      Pattern-recognition receptors (PRRs) are critical to recognizing endogenous and exogenous threats to mount a protective proinflammatory innate immune response. PRRs may be located on the outer cell membrane, cytosol, and nucleus. The cGAS/STING signaling pathway is a cytosolic PRR system. Notably, cGAS is also present in the nucleus. The cGAS-mediated recognition of cytosolic dsDNA and its cleavage into cGAMP activates STING. Furthermore, STING activation through its downstream signaling triggers different interferon-stimulating genes (ISGs), initiating the release of type 1 interferons (IFNs) and NF-κB-mediated release of proinflammatory cytokines and molecules. Activating cGAS/STING generates type 1 IFN, which may prevent cellular transformation and cancer development, growth, and metastasis. The current article delineates the impact of the cancer cell-specific cGAS/STING signaling pathway alteration in tumors and its impact on tumor growth and metastasis. This article further discusses different approaches to specifically target cGAS/STING signaling in cancer cells to inhibit tumor growth and metastasis in conjunction with existing anticancer therapies.
    Keywords:  Cancer; Inflammation; NF-κB; STING; TIME; TME; Tumor; Type 1 IFNs; cGAS
    DOI:  https://doi.org/10.1016/j.ejcb.2023.151338
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