bims-tumhet 2023-04-09 papers

Issue of 2023–04–09
five papers selected by
Sergio Marchini, Humanitas Research

Nat Commun. 2023 Apr 07. 14(1): 1958

Homologous recombination deficiency derived from whole-genome sequencing predicts platinum response in triple-negative breast cancers.

The high frequency of homologous recombination deficiency (HRD) is the main rationale of testing platinum-based chemotherapy in triple-negative breast cancer (TNBC), however, the existing methods to identify HRD are controversial and there is a medical need for predictive biomarkers. We assess the in vivo response to platinum agents in 55 patient-derived xenografts (PDX) of TNBC to identify determinants of response. The HRD status, determined from whole genome sequencing, is highly predictive of platinum response. BRCA1 promoter methylation is not associated with response, in part due to residual BRCA1 gene expression and homologous recombination proficiency in different tumours showing mono-allelic methylation. Finally, in 2 cisplatin sensitive tumours we identify mutations in XRCC3 and ORC1 genes that are functionally validated in vitro. In conclusion, our results demonstrate that the genomic HRD is predictive of platinum response in a large cohort of TNBC PDX and identify alterations in XRCC3 and ORC1 genes driving cisplatin response.

DOI: https://doi.org/10.1038/s41467-023-37537-2

J Immunother Cancer. 2023 Apr;pii: e006170. [Epub ahead of print]11(4):

Cancer cell genotype associated tumor immune microenvironment exhibits differential response to therapeutic STING pathway activation in high-grade serous ovarian cancer.

Noor Shakfa, Deyang Li, Gwenaelle Conseil, Elizabeth D Lightbody, Juliette Wilson-Sanchez, Ali Hamade, Stephen Chenard, Natasha A Jawa, Brian J Laight, Afrakoma Afriyie-Asante, Kathrin Tyryshkin, Martin Koebel, Madhuri Koti.

BACKGROUND: High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy characterized by resistance to chemotherapy and high rates of recurrence. HGSC tumors display a high prevalence of tumor suppressor gene loss. Given the type 1 interferon regulatory function of BRCA1 and PTENgenes and their associated contrasting T-cell infiltrated and non-infiltrated tumor immune microenvironment (TIME) states, respectively, in this study we investigated the potential of stimulator of interferon genes (STING) pathway activation in improving overall survival via enhancing chemotherapy response, specifically in tumors with PTEN deficiency.
METHODS: Expression of PTEN protein was evaluated in tissue microarrays generated using pretreatment tumors collected from a cohort of 110 patients with HGSC. Multiplex immunofluorescence staining was performed to determine spatial profiles and density of selected lymphoid and myeloid cells. In vivo studies using the syngeneic murine HGSC cell lines, ID8-Trp53 -/-; Pten -/- and ID8-Trp53 -/-; Brca1 -/-, were conducted to characterize the TIME and response to carboplatin chemotherapy in combination with exogenous STING activation therapy.
RESULTS: Patient tumors with absence of PTEN protein exhibited a significantly decreased disease specific survival and intraepithelial CD68+ macrophage infiltration as compared with intact PTEN expression. In vivo studies demonstrated that Pten-deficient ovarian cancer cells establish an immunosuppressed TIME characterized by increased proportions of M2-like macrophages, GR1+MDSCs in the ascites, and reduced effector CD8+ cytotoxic T-cell function compared with Brca1-deficient cells; further, tumors from mice injected with Pten-deficient ID8 cells exhibited an aggressive behavior due to suppressive macrophage dominance in the malignant ascites. In combination with chemotherapy, exogenous STING activation resulted in longer overall survival in mice injected with Pten-deficient ID8 cells, reprogrammed intraperitoneal M2-like macrophages derived from Pten-deficient ascites to M1-like phenotype and rescued CD8+ cytotoxic T-cell activation.
CONCLUSIONS: This study reveals the importance of considering the influence of cancer cell intrinsic genetic alterations on the TIME for therapeutic selection. We establish the rationale for the optimal incorporation of interferon activating therapies as a novel combination strategy in PTEN-deficient HGSC.

Keywords: Genital Neoplasms, Female; Immunomodulation; Immunotherapy; Interferon Inducers; Tumor Microenvironment

DOI: https://doi.org/10.1136/jitc-2022-006170

Bioinformatics. 2023 Apr 02. pii: btad165. [Epub ahead of print]

STGRNS: An interpretable Transformer-based method for inferring gene regulatory networks from single-cell transcriptomic data.

Jing Xu, Aidi Zhang, Fang Liu, Xiujun Zhang.

MOTIVATION: Single-cell RNA-sequencing (scRNA-seq) technologies provide an opportunity to infer cell-specific gene regulatory networks (GRNs) which is an important challenge in systems biology. Although numerous methods have been developed for inferring GRNs from scRNA-seq data, it is still a challenge to deal with cellular heterogeneity.
RESULTS: To address this challenge, we developed an interpretable transformer-based method namely STGRNS for inferring GRNs from scRNA-seq data. In this algorithm, gene expression motif (GEM) technique was proposed to convert gene pairs into contiguous sub-vectors which can be used as input for the transformer encoder. By avoiding missing phase-specific regulations in a network, GEM can improve the accuracy of GRN inference for different types of scRNA-seq data. To assess the performance of STGRNS, we implemented the comparative experiments with some popular methods on extensive benchmark datasets including 21 static and 27 time-series scRNA-seq dataset. All the results show that STGRNS is superior to other comparative methods. In addition, STGRNS was also proved to be more interpretable than "black box" deep learning methods which are well-known for the difficulty to explain the predictions clearly.
AVAILABILITY: The source code and data are available at https://github.com/zhanglab-wbgcas/STGRNS.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

DOI: https://doi.org/10.1093/bioinformatics/btad165

Genes Dis. 2023 Jan;10(1): 76-88

Targeting RAS-RAF-MEK-ERK signaling pathway in human cancer: Current status in clinical trials.

Yanlin Song, Zhenfei Bi, Yu Liu, Furong Qin, Yuquan Wei, Xiawei Wei.

Molecular target inhibitors have been regularly approved by Food and Drug Administration (FDA) for tumor treatment, and most of them intervene in tumor cell proliferation and metabolism. The RAS-RAF-MEK-ERK pathway is a conserved signaling pathway that plays vital roles in cell proliferation, survival, and differentiation. The aberrant activation of the RAS-RAF-MEK-ERK signaling pathway induces tumors. About 33% of tumors harbor RAS mutations, while 8% of tumors are driven by RAF mutations. Great efforts have been dedicated to targeting the signaling pathway for cancer treatment in the past decades. In this review, we summarized the development of inhibitors targeting the RAS-RAF-MEK-ERK pathway with an emphasis on those used in clinical treatment. Moreover, we discussed the potential combinations of inhibitors that target the RAS-RAF-MEK-ERK signaling pathway and other signaling pathways. The inhibitors targeting the RAS-RAF-MEK-ERK pathway have essentially modified the therapeutic strategy against various cancers and deserve more attention in the current cancer research and treatment.

Keywords: Clinical trials; Molecular target therapy; RAS–RAF–MEK–ERK signaling pathway

DOI: https://doi.org/10.1016/j.gendis.2022.05.006