Boosting pancreatic cancer chemotherapy by disrupting nerve–cancer crosstalk

Abstract

A preclinical study has developed a precision nano-intervention strategy targeting tumor-associated nerves to destroy nerve-fueled tumor growth in pancreatic cancer. In this strategy, Escherichia coli Nissle 1917-derived outer membrane vesicles (OMVs) are decorated with nerve-binding peptide for targeted delivery of co-loaded tropomyosin receptor kinase (Trk) inhibitors to tumor-associated nerves, thus precisely inhibiting nerve activity through the neurotrophin/Trk signaling pathway. Furthermore, the OMVs trigger M2-M1 switching, thus accelerating nerve injury. This nano-intervention strategy significantly enhances chemotherapy efficacy in pancreatic cancer.

Keywords

Cancer biology / Pharmaceutics / Biochemistry

References

[1] Banh RS, Biancur DE, Yamamoto K, Sohn ASW, Walters B, Kuljanin M, et al.: Neurons Release Serine to Support mRNA Translation in Pancreatic Cancer. Cell 2020, 183: 1202-1218.e25.

[2] Renz BW, Takahashi R, Tanaka T, Macchini M, Hayakawa Y, Dantes Z, et al.: β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer. Cancer Cell 2018, 33: 75-90.e7.

[3] Winkler F, Venkatesh HS, Amit M, Batchelor T, Demir IE, Deneen B, et al.: Cancer Neuroscience: State of the Field, Emerging Directions. Cell 2023, 186: 1689-1707.

[4] Silverman DA, Martinez VK, Dougherty PM, Myers JN, Calin GA, Amit M: Cancer-Associated Neurogenesis and Nerve-Cancer Cross-talk. Cancer Research 2021, 81: 1431-1440.

[5] Yaniv D, Mattson B, Talbot S, Gleber-Netto FO, Amit M: Targeting the Peripheral Neural-Tumour Microenvironment for Cancer Therapy. Nature Reviews Drug Discovery 2024, 23: 780-796.

[6] Eckerling A, Ricon-Becker I, Sorski L, Sandbank E, Ben-Eliyahu S: Stress and Cancer: Mechanisms, Significance and Future Directions. Nature Reviews Cancer 2021, 21: 767-785.

[7] Qin J, Liu J, Wei Z, Li X, Chen Z, Li J, et al.: Targeted Intervention in Nerve-Cancer Crosstalk Enhances Pancreatic Cancer Chemotherapy. Nature Nanotechnology 2024, 20: 311-324.

[8] Globig A-M, Zhao S, Roginsky J, Maltez VI, Guiza J, Avina-Ochoa N, et al.: The β1-Adrenergic Receptor Links Sympathetic Nerves to T Cell Exhaustion. Nature 2023, 622: 383-392.

[9] Li J, Kang R, Tang D: Cellular and Molecular Mechanisms of Perineural Invasion of Pancreatic Ductal Adenocarcinoma. Cancer Communications 2021, 41: 642-660.

[10] Zhao X, Zhao R, Nie G: Nanocarriers based on Bacterial Membrane Materials for Cancer Vaccine Delivery. Nature Protocols 2022, 17: 2240-2274.

[11] Neoptolemos JP, Kleeff J, Michl P, Costello E, Greenhalf W, Palmer DH: Therapeutic Developments in Pancreatic Cancer: Current and Future Perspectives. Nature Reviews Gastroenterology & Hepatology 2018, 15: 333-348.

[12] Chang A, Botteri E, Gillis RD, Löfling L, Le CP, Ziegler AI, et al.: Beta-blockade Enhances Anthracycline Control of Metastasis in Triple-negative Breast Cancer. Science Translational Medicine 2023, 15: eadf1147.

[13] Caroleo MC, Costa N, Bracci-Laudiero L, Aloe L: Human Monocyte/Macrophages Activate by Exposure to LPS Overexpress NGF and NGF Receptors. Journal of Neuroimmunology 2001, 113: 193-201.

[14] Li Y, Zhu T, Chen J, Liu K, Wei C, Fang Q, et al.: Dual-Targeted Engineered Bacterial Outer Membrane Vesicles for Hepatocellular Carcinoma Immunotherapy. Advanced Functional Materials 2024, 34: 2401355.

[15] Ho MY, Liu S, Xing B: Bacteria Extracellular Vesicle as Nanopharmaceuticals for Versatile Biomedical Potential. Nano Convergence 2024, 11: 28.

[16] Leach SD: Mouse Models of Pancreatic Cancer: The Fur is Finally Flying! Cancer Cell 2004, 5: 7-11.

[17] Mancusi R, Monje M: The Neuroscience of Cancer. Nature 2023, 618: 467-479.

[18] Zhao Z, Chen X, Dowbaj AM, Sljukic A, Bratlie K, Lin L, et al.: Organoids. Nature Reviews Methods Primers 2022, 2: 94.

[19] Chauhan VP, Martin JD, Liu H, Lacorre DA, Jain SR, Kozin SV, et al.: Angiotensin Inhibition Enhances Drug Delivery and Potentiates Chemotherapy by Decompressing Tumour Blood Vessels. Nature Communications 2013, 4: 2516.