bims-netuvo 2023-10-08 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2023–10–08
eleven papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute

Molecular Mechanisms of Intratumoral Nerve Recruitment and Perineural Invasion Elucidated with Spatial Transcriptomics and CRISPR Activation.
Transcriptome analyses reveal new insights on key determinants of perineural invasion in high-grade serous ovarian cancer.
Exploring the Link Between Pancreatic Neuroendocrine Tumors and Depression: A Case Study.
Honokiol: Treatment for malignant peripheral nerve sheath tumors.
Culture of attenuated Salmonella Typhimurium VNP20009 in animal-product-free media does not alter schwannoma growth control.
Peripheral Mechanism of Cancer-Induced Bone Pain.
Malignant Peripheral Nerve Sheath Tumors Activate Distinct Immunosuppressive Pathways Following Radiotherapy and are Associated with Immune Depletion In Vivo.
Gastric Schwannoma: A Rare Subepithelial Lesion of the Stomach.
In Silico Identification of Therapeutic Targets and Novel Drug Candidates for Malignant Peripheral Nerve Sheath Tumors.
Stress exhausts T cells.
Stress can be exhausting for T cells.

Int J Radiat Oncol Biol Phys. 2023 Oct 01. pii: S0360-3016(23)04370-5. [Epub ahead of print]117(2S): S21

Molecular Mechanisms of Intratumoral Nerve Recruitment and Perineural Invasion Elucidated with Spatial Transcriptomics and CRISPR Activation.

W L Hwang, J Su, C Shiau, P L Wang, J A Guo, N A Lester, J L Barth, H I Hoffman, A Aguirre, T S Hong, J Y Wo, D Ting, L Zheng, M Mino-Kenudson, T Jacks.

PURPOSE/OBJECTIVE(S): Perineural invasion (PNI) is an aggressive manifestation of tumor-nerve interactions associated with postoperative recurrence, metastasis, pain, and decreased survival. Hence, PNI is included in the staging criteria of several malignancies and often an indication for treatment intensification using adjuvant radiotherapy. However, the diverse molecular mechanisms underlying tumor-nerve crosstalk remain largely unknown-hindering the development of new therapies targeting this key pathological process. Moreover, prior studies were limited by a lack of cell-type information, spatial context, and/or a fragmented focus on a small number of pathways.
MATERIALS/METHODS: Using pancreatic ductal adenocarcinoma (PDAC) as an exemplar given the exceptionally high frequency of PNI in this malignancy, we performed the first comprehensive, cell-type specific, and spatially resolved whole-transcriptome analysis of human PDAC to identify molecular mediators of tumor-nerve crosstalk and PNI. We constructed 12 custom tissue microarrays (TMAs) derived from matched malignant regions with and without tumor-nerve proximity (n = 288 cores). We performed whole-transcriptome digital spatial profiling (DSP) to independently determine mRNA abundance from the malignant, fibroblast, and nerve compartments through optical sectioning.
RESULTS: We mapped malignant subtypes we previously identified onto the spatial data and found strong (p<0.0001) positive nerve associations with the mesenchymal, basaloid, and neural-like progenitor subtypes and a negative nerve association with the classical subtype. Numerous genes expressed by malignant cells were enriched (e.g., MMP2, PLXND1, NRP1) or depleted (e.g., SEMA3B) in association with radial distance from nerves, including recapitulation of prior literature. To functionally explore these candidate mediators of tumor-nerve crosstalk, we derived genetically-engineered murine organoids (KrasLSL-G12D/+; Trp53FL/FL; Rosa26-dCas9-VPR) and transduced them with guide RNAs to overexpress subtype-specific transcription factors or candidate genes from the spatial analysis. We quantified (1) cancer cell invasion through extracellular matrix using cultured dorsal root ganglia (DRG) sensory neurons as the chemoattractant, and (2) the role of cancer-intrinsic signaling on nerve recruitment/outgrowth by applying conditioned media or exogenous proteins to cultured DRG sensory neurons and tracking their growth with live imaging.
CONCLUSION: Our results suggest that the mechanisms enabling cancer cells to recruit nerves into the tumor microenvironment are distinct from those facilitating perineural invasion. This study has transformed our understanding of how cancer cells and the peripheral nervous system collaborate to promote tumor growth, survival, and dissemination, and is now guiding prioritization of therapeutic strategies that synergize with adjuvant radiotherapy in the burgeoning field of cancer neuroscience.

DOI: https://doi.org/10.1016/j.ijrobp.2023.06.244
Front Cell Dev Biol. 2023 ;11 1109710

Transcriptome analyses reveal new insights on key determinants of perineural invasion in high-grade serous ovarian cancer.

Zhen Zheng, Xiao Li, Guoqiang Chen, Jing Chen, Xiaolu Zhu, Yincheng Teng.

  Perineural invasion (PNI) is a pathological feature of many cancers associated with poor outcomes, metastases, and recurrence. In relation to ovarian cancer (OC), there is no information about PNI's role and mechanisms. Our study found that patients with PNI-positive symptoms had significantly shorter overall survival (OS) time than patients with PNI-negative symptoms. Multivariate analyses demonstrated that PNI represented a substantial independent prognostic factor in OC patients. At the transcriptome level, it is noteworthy that PNI positivity was negatively correlated with the degree of infiltration of immune killer cells in OC tumor tissues, including macrophage, central memory CD4 T-cell, natural killer cells, monocyte, and central memory CD4 T-cell. The results of this study revealed that TAS2Rs proteins were markedly upregulated in PNI-positive OC tissues and predicted poor prognoses. Moreover, Immunohistochemical analysis demonstrated that the TAS2R10 protein was associated with poor prognoses and PNI in OC. Consequently, we found for the first time that PNI was a powerful predictor of poor prognosis in OC and analyzed its expression pattern and some preliminary biochemical characterization, providing new clues for guiding clinical prevention and treatment of OC.

Keywords:  TAS2R receptor family proteins; neural invasion; ovarian cancer; transcriptome; tumor immune microenvironment

DOI:  https://doi.org/10.3389/fcell.2023.1109710
Cureus. 2023 Aug;15(8): e44363

Exploring the Link Between Pancreatic Neuroendocrine Tumors and Depression: A Case Study.

Nicole Ann E Villa, Gina Maria P Fiore, Eduardo D Espiridion.

  This case probes the potential temporal relationship between pancreatic neuroendocrine tumor (PNET) and depression. This patient has chronic symptoms of depression with no formal diagnosis until within a year of doctors suspecting her diagnosis of pancreatic cancer. An excisional biopsy confirmed a grade 1 neuroendocrine tumor (NET) in the pancreas, and postoperative psychiatric consultation confirmed continued elevated depression. This report presents an illustrative example of the ongoing research questions surrounding the relationship between the timing of a depression diagnosis and a PNET diagnosis. The depression-before-diagnosis relationship in pancreatic cancer patients is an observation that warrants further studies as depression could be a valuable early warning sign of pancreatic cancer.

Keywords:  depression; detection; neuroendocrine tumor; pancreatic cancer; pancreatic neuroendocrine cancer; temporal relationship

DOI:  https://doi.org/10.7759/cureus.44363
J Cancer Res Ther. 2023 Jul-Sep;19(5):19(5): 1485-1486

Honokiol: Treatment for malignant peripheral nerve sheath tumors.

Megha Rajeev Joshi.

DOI: https://doi.org/10.4103/jcrt.jcrt_1742_21
Hum Vaccin Immunother. 2023 Aug;19(2): 2262639

Culture of attenuated Salmonella Typhimurium VNP20009 in animal-product-free media does not alter schwannoma growth control.

Sherif G Ahmed, Giulia Oliva, Manlin Shao, John J Mekalanos, Gary J Brenner.

  Schwannomas are slow-growing benign peripheral nerve sheath tumors derived from Schwann-lineage cells that develop in association with NF2-related schwannomatosis (NF2) and schwannomatosis (NF3), as well as spontaneously. Individuals affected with NF2 and NF3 have multiple schwannomas with tumors arising throughout life. Surgical resection, the standard management, is limited in scope and efficacy and is itself associated with significant morbidity. We have previously shown that direct intratumoral injection of attenuated Salmonella Typhimurium (S. Typhimurium), strain VNP20009, showed a potent anti-tumor effect in preclinical NF-2 schwannoma models. The United States Federal Drug Administration (FDA) requires that bacterial products utilized in clinical trials be produced without exposure to animal-derived-products. In this context, we developed, characterized, and tested the antitumor efficacy of an attenuated S. Typhimurium serially passaged in animal-product-free media, naming it VNP20009-AF for "VNP20009-animal-product-free." Our in vitro data did not indicate any significant changes in the viability, motility, or morphology of VNP20009-AF, compared to its parental strain. In vivo efficacy data demonstrated that VNP20009-AF and VNP20009 controlled tumor growth to the same degree in both human NF2-schwannoma xenograft and murine-NF2 schwannoma allograft models. Together, these data support the use of VNP20009-AF for the translation of bacterial schwannoma therapy into clinical trials.

Keywords:  Salmonella Typhimurium (VNP20009); Schwannoma; animal-product-free; bacterial cancer therapy

DOI:  https://doi.org/10.1080/21645515.2023.2262639
Neurosci Bull. 2023 Oct 06.

Peripheral Mechanism of Cancer-Induced Bone Pain.

Yachen Yang, Wei Yang, Ruofan Zhang, Yanqing Wang.

  Cancer-induced bone pain (CIBP) is a type of ongoing or breakthrough pain caused by a primary bone tumor or bone metastasis. CIBP constitutes a specific pain state with distinct characteristics; however, it shares similarities with inflammatory and neuropathic pain. At present, although various therapies have been developed for this condition, complete relief from CIBP in patients with cancer is yet to be achieved. Hence, it is urgent to study the mechanism underlying CIBP to develop efficient analgesic drugs. Herein, we focused on the peripheral mechanism associated with the initiation of CIBP, which involves tissue injury in the bone and changes in the tumor microenvironment (TME) and dorsal root ganglion. The nerve-cancer and cancer-immunocyte cross-talk in the TME creates circumstances that promote tumor growth and metastasis, ultimately leading to CIBP. The peripheral mechanism of CIBP and current treatments as well as potential therapeutic targets are discussed in this review.

Keywords:  Cancer-induced bone pain; Immunocytes; Peripheral mechanism; Sensory nerve; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12264-023-01126-6
Int J Radiat Oncol Biol Phys. 2023 Oct 01. pii: S0360-3016(23)04600-X. [Epub ahead of print]117(2S): S168

Malignant Peripheral Nerve Sheath Tumors Activate Distinct Immunosuppressive Pathways Following Radiotherapy and are Associated with Immune Depletion In Vivo.

I Zhu, K Miller, K Mirchia, E Payne, J Pak, L Jacques, S E Braunstein, M Pekmezci, S J Liu, H Vasudevan.

PURPOSE/OBJECTIVE(S): Patients with neurofibromatosis type I, caused by NF1 loss, develop benign plexiform neurofibromas (pNF) in their peripheral nervous system (PNS). Malignant transformation of pNFs into malignant peripheral nerve sheath tumors (MPNSTs) occurs following CDKN2A/B and SUZ12 loss, a process associated with radiotherapy (RT). However, the molecular mechanisms underlying RT responses by different PNS cell types remain unclear. We hypothesized normal peripheral nerve cells, pNFs, and MPNSTs harbor distinct RT responses.
MATERIALS/METHODS: Patient derived NF1 WT immortalized peripheral nerve cells (iPNs), NF1 mutant pNF cells, and NF1/CDKN2AB/SUZ12 mutant MPNST cells were used to study RT responses in vitro. CRISPRi was used to assess the functional effects of candidate gene repression. In vitro viability was measured by cell counts. Transcriptomic signatures were measured by bulk RNA-sequencing and integrated with single-cell RNA sequencing (scRNA-seq) data from patient-derived pNF and MPNST resection specimens.
RESULTS: Radiation dose response curves revealed pNF cells (IC50 0.61 Gy) were more radiosensitive than MPNST cells (4.15 Gy). WT iPNs, NF1 deficient iPNs, and pNFs cells displayed no difference in cell viability (p = 0.67; t-test) following initiation of 2 Gy x 5 fractions, while MPNST cells were significantly more viable (p = 0.02; t-test). Principal component analysis of bulk RNA-sequencing data at 5 or 14 days following 2 Gy x 5 fractions revealed cell line of origin accounted for the greatest inter-sample variation (64.9% variance), with additional components separating samples based on radiation presence and timing. Using the most variable genes in PCA space to identify markers of RT response, iPNs and pNFs upregulated pro-apoptotic pathways (BAD, DAPK3) at 5 days post-radiation while MPNST cells alone upregulated pro-survival growth factor signaling). At 14 days post radiation, MPNST cells uniquely upregulated TGFβ signaling and interferon response circuits. Incorporation of scRNA-seq data revealed enrichment of growth factor signaling and TGFβ signatures in MPNSTs compared to pNF. Moreover, MPNST harbored significantly fewer immune cells than pNFs (p = 0.008, t-test), suggesting cell-autonomous signaling and crosstalk with the microenvironment are both critical to MPNST radioresistance.
CONCLUSION: Our data indicate additional genetic hits beyond NF1 loss may be required for RT-associated malignant transformation of pNFs and radioresistance in MPNSTs. Analysis of transcriptomic responses to RT suggests that upregulated growth factor signaling and TGFβ-associated immunosuppression are distinct features of MPNST. Future work will focus on CRISPRi screens to unbiasedly nominate functional modifiers of RT response in NF1/CDKN2AB deficient tumors, which may be broadly useful in cancer.

DOI: https://doi.org/10.1016/j.ijrobp.2023.06.269
Cureus. 2023 Sep;15(9): e44577

Gastric Schwannoma: A Rare Subepithelial Lesion of the Stomach.

Sameeta Kumari, Muhammad Ibrahim Saeed, Adeel Urrehman.

  Gastric schwannomas (GS) are rare, slow-growing, benign subepithelial (SE) lesions of the stomach. These are difficult to differentiate preoperatively from other types of SE lesions, as the gross appearance and clinical presentation are very similar especially the gastrointestinal stromal tumors (GISTs), which are the most common SE lesions of the stomach. We present the case of a 35-year-old Asian man with a one-month history of intermittent, right, upper quadrant pain and hematemesis. Preoperatively, intravenous contrast-enhanced computer tomography scan (CECT) showed a well-circumscribed lesion in the upper abdomen closer to the stomach's lesser curvature. Endoscopic ultrasound revealed an ulcerated subepithelial lesion and subsequent biopsy with a 22-gauge fine-needle biopsy (22G FNB) needle confirmed the diagnosis of GS. The patient underwent distal gastrectomy and a Bilroth 1 procedure. The postoperative biopsy was consistent with the initial one, therefore supporting the diagnosis of gastric schwannoma. Postoperatively, the recovery remained uneventful.

Keywords:  endoscopic ultrasound; gastric schwannoma; immune staining; subepithelial lesions; surgery

DOI:  https://doi.org/10.7759/cureus.44577
Front Biosci (Landmark Ed). 2023 Sep 24. 28(9): 214

In Silico Identification of Therapeutic Targets and Novel Drug Candidates for Malignant Peripheral Nerve Sheath Tumors.

Min Wei, Jianfeng Fan, Renjun Peng, Xiping Ding, Jian Xi, He Huang.

   BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are an aggressive form of sarcomas with a poor prognosis and limited treatment options. Therefore, new therapeutic targets are urgently needed to identify novel drugs.
METHODS: Based on the Gene Expression Omnibus database, an integrated analysis was performed to identify differentially expressed genes (DEGs) in MPNSTs compared to neurofibromas (NFs). Then functional enrichment analyses, protein-protein interaction (PPI) network construction, and hub gene selection were conducted. We explored DEG-guided repurposable drugs to treat MPNST based on the Library of Integrated Network-Based Cellular Signatures (LINCS) database. Furthermore, the binding affinity between predicted drug candidates and the MPNST-associated hub gene was calculated using molecular docking.
RESULTS: We identified 89 DEGs in common with all three MPNSTs datasets. In the PPI networks, twist family bHLH transcription factor 1 (Twist1) with higher node degrees was further evaluated as a therapeutic target. Cytochalasin-d, cabozantinib, everolimus, refametinib, and BGT-226 were extracted from the LINCS database, which showed lower normalized connectivity scores (-1.88, -1.81, -1.78, -1.76, and -1.72, respectively) and was considered as drug candidates. In addition, the results of molecular docking between the five drugs and Twist1 showed a binding affinity of -6.61, -7.03, -7.73, -3.94, and -7.07 kcal/mol, respectively.
CONCLUSIONS: Overall, our results describe the importance of Twist1 in MPNST pathogenesis. Everolimus was also found to be a potential therapeutic drug for MPNSTs.

Keywords:  everolimus; malignant peripheral nerve sheath tumors; molecular docking; twist family bHLH transcription factor 1

DOI:  https://doi.org/10.31083/j.fbl2809214
Sci Signal. 2023 Oct 03. 16(805): eadl0724

Stress exhausts T cells.

Amy E Baek.

Catecholamines associated with stress promote T cell exhaustion through the β1-adrenergic receptor.

DOI: https://doi.org/10.1126/scisignal.adl0724
Nat Rev Drug Discov. 2023 Oct 02.

Stress can be exhausting for T cells.

Kirsty Minton.



Keywords:  Cancer; Immunology; Therapeutics

DOI:  https://doi.org/10.1038/d41573-023-00157-y