Cancer Cell: Zhang Zeda and others find 'survival signal' of prostate cancer resistance

The !-----and-!-----targeted treatment of tumors has made a remarkable breakthrough over the past 20 years.by finding key genes that drive tumors through high-throughput sequencing and large-scale functional genomics, and accurately "targeting" them, and then selectively killing tumor cells with smaller toxic side effects, has gradually become a standardized method of most cancer treatments.the effects and effective time of targeted therapy are often limited by the heterogeneity of the tumor itself and the complex interaction of tumor cells with the microenvironment around them, and the tumor microenvironment is often used as a "soil" to nourish tumor growth, further aiding the tumor cells by providing nutrients and survival signals.prostate cancer is one of the most high-risk tumors in men, with more than 1 million adult males diagnosed each year worldwide (WHO CancerReport 2020), and about 10-20% of progressive prostate cancers develop into deified, anti-aggressive prostate cancer resistant to traditional hormone therapy, 84% of which have metastasized at the time of diagnosis., although hormone therapy based on second-generation androgen receptor inhibitors greatly improved patients' progression-free and overall median survival, the five-year survival rate for advanced prostate cancer was still less than 30%.in recent years, large-scale clinical data show that the current strongest combination of hormone therapy still does not kill all tumor cells.only a very small number of patients receive a complete cure after hormone therapy.the vast majority of patients still have residual lesions, and these patients with residual lesions almost without exception will develop into defertilized prostate cancer, and eventually become incurable. finding and blocking signals to keep tumor cells aliveis of critical clinical significance for the complete remission and cure of patients with localprogression prostate cancer.Professor Charles Sawyers, Professor Jiang Xuejun and Dr. Philip Watson of memorial Sloan Kettering Cancer Research Center, in a joint article published in the journal Cancer Cell, Tumor Microenvironment-Derived NRG1 Promots Antiandrogen Antiandrogen In Prostate In Cancer identified growth factors secreted by fibroblasts in the prostate tumor microenvironment as a "survival signal" to protect prostate tumor cells and increase the risk of prostate cancer.the monme cell secretion of Fiber1 in the prostate tumor microenvironment during hormone therapy increases the resistance of prostate tumor cells, and the neutralizing antibodies of clinical efficacy can effectively block the survival signal, thus improving the effect of hormone therapy.the results were inspired by an unexpected discovery that the authors isolated a epidermal tumor cell line mixed with interstitial cells in patient-derived mouse heterogeneous tumors, and the unexpected finding that cancer cells were significantly more sensitive to androsteroid receptor inhibitors after removing mixed interstitial cells.suggestthat the presence of interstitial cells may protect tumor cells from the killing of androgen receptor inhibitors.the authors then demonstrated through a series of experimental methods, using a variety of tumor cells, organoids, and mouse isosome models, that the presence of interstitial cells, especially fibroblasts around tumors, can greatly promote the resistance of prostate tumors to hormone therapy.the cell lines isolated by isoprosis tumors are mixed with interstitial cells, and tumor cells are less resistant to drugs after the removal of interstitial cells.the authors have made a series of experimental explorations to find out why fibroblasts promote tumor cell resistance.first, the authors found that adding cultures that have grown fibroblasts to cancer cells can also protect them from androgen receptor inhibitors.this suggests that some "survival signal" that fibroblasts secrete into the environment can promote the resistance of tumor cells to drugs.the authors, with the guidance and help of Professor Jiang Xuejun of the Sloan Cancer Research Center, subdivided and analyzed the cytocell culture fluid through a series of biochemical, protein purification, and proteomics methods, eventually targeting a growth factor called Neuregulin 1 (NRG1).NRG1 is a family of epidermal growth factors that activate strains of growth and proliferation in cells by binding the receptor protein likinekine kinase HER2/HER3 on the cell surface.NRG family has important functions in neurodevelopment and heart regeneration, but its role in prostate tumors has not been previously reported.later, the authors conducted a series of functional experiments on NRG1 using genetic and pharmacological methods to confirm that NRG1, secreted by interstitial cells, has a role in promoting tumor cell resistance in many different cells, organs, and mouse models.it is worth mentioning that the survival signaling pathway mediated by NRG1-HER3 can be effectively cut off by neutralizing antibodies (YW538.24.71) with clinical efficacy, greatly reducing the tolerance of tumor cells to hormone therapy in mice.in turn provides a feasible solution for subsequent clinical studies.to study the molecular mechanisms of NRG1 molecules to promote tumor cell resistance, the authors conducted transcription altrusion stakes on cancer cells after the treatment of Vehicle, androgen receptor inhibitors (Enthroamines), NRG1 recombinant proteins, and Enthroamine and NRG1, and found that cancer cells activated by NRG1, although they increased resistance to androgen receptor inhibitors, remained blocked.findings suggest that NRG1's mechanism for promoting tumor cell resistance is not reactivated by global androgen signals, but that new mechanisms may exist. further transcription group analysisfound that NRG1 selectively reactivated a small number of downstream genes regulated by androgens, all of which, without exception, play an important role in amino acid and folic acid metabolism pathways.later, the authors worked with pathologists at Memorial Sloan Kettering Cancer Hospital to develop a clinically specific NRG1 immunohiscitis testforeable testforeed technology for the detection of NRG1 in a patient's tumor sample.using this technique, they found that the positive rate of NRG1 increased significantly in a sample of prostate cancer patients who had received the new assisted hormone therapy, suggesting that hormone therapy may be the cause of the increase in NRG1 in the tumor microenvironment of some patients.this hypothesis has been confirmed in multiple progenitor fibroblasts isolated from the patient's tumor, and the inhibition of androgen signals in in vitro culture environments can significantly increase the expression of NRG1 in fibroblasts.bioinformatics analysis of the Advanced Prostate Cancer Database (SU2C) showed a significant negative correlation between the activity of NRG1 in the tumor and the duration of non-progressive treatment in patients, further revealing that patients with high activity of NRG1 in the tumor developed faster resistance to hormone therapy.finally, the author found through the TCGA database and experimental models that the state of the cancer suppressor gene PTEN in tumor cells is a biomarker of NRG1 to promote drug resistance, and the expression of NRG1 was significantly higher in the tumor samples of PTEN wild type than the tumor samples of PTEN mutations/missing tumors.and NRG1 selectively promotes PTEN wild tumor cell resistance, which can be effectively blocked by NRG1-HER2/3 inhibitors. findings reveal that cutting off this "survival signal" in highly activated PTEN wild tumors with NRG1 signals can effectively reduce the resistance of tumor cells, thereby improving the effectiveness of hormone therapy. .