EMBO Mol Med. Huang shengcong and others found the "King of Cancer" treatment of new ideas.

As one of the most malignant tumors, pancreatic cancer is known as "the king of cancer" for its extremely low survival rate.advanced pancreatic cancer is well tolerated to most treatments including chemotherapy, radiotherapy and immunotherapy.so far, the therapeutic effect of pancreatic cancer is unsatisfactory [1].therefore, scientists all over the world and many large pharmaceutical enterprises have taken the tackling of pancreatic cancer as the focus of their efforts.in many other types of malignant tumors, anti transforming growth factor beta (TGF β) therapy has been regarded as an effective method to improve chemotherapy, radiotherapy and immunotherapy.especially in recent years, with the rise of tumor immunotherapy, anti TGF β therapy has shown a powerful function to enhance the efficacy of immunotherapy [2,3].therefore, many research groups and drug research and development enterprises actively explore and develop anti TGF - β pathway drugs.however, due to the complex function of TGF β pathway in pancreatic cancer, anti TGF β therapy has failed to show the efficacy in animal experiments or clinical studies.one of the most significant features of pancreatic cancer is its special tumor microenvironment.the tumor is filled with a large number of stromal cells, including tumor associated fibroblasts, immune suppressor myeloid cells and lymphocytes [4].these stromal cells have been considered as the biggest "accomplices" in the progression of pancreatic cancer.in the whole process of tumor progression, TGF β pathway is involved in the functional regulation of tumor cells and various stromal cells [5].TGF β pathway can improve the tumor promoting function of many stromal cells.however, in pancreatic cancer cells with epithelial characteristics, the classic TGF β signaling pathway (mediated by its receptor TGF β R1 / R2 and downstream Smad proteins including Smad2, Smad3 and Smad4) is considered as a pathway to inhibit tumor cell growth [5,6].therefore, TGF β signaling pathway has the function of promoting and inhibiting cancer.this leads to the side effects of anti TGF β therapy on the growth of pancreatic cancer cells.on October 14, 2019, Professor brekken from Texas Southwest Medical Center cooperated with Eli Lilly (the first author was Dr. Huang Huo Cong) to publish an article targeting TGF β R2 mutants exposures in pancreatic in EMBO molecular medicine Cancer reported a new idea of anti TGF β therapy in pancreatic cancer. by using mouse specific anti TGF β R2 monoclonal antibody, the research group identified interleukin-6 (IL-6) as the tumor matrix factor mainly stimulated by TGF β. then, through single cell sequencing and other technologies, we found that tumor associated fibroblasts (CAF) are stromal cells that secrete IL-6 mainly regulated by TGF β. the research group further found that the IL-6 signal can promote the growth of tumor cells through STAT3 signal, and induce the immunosuppressive environment in tumor together with TGF β. therefore, anti TGF β therapy can significantly inhibit the secretion of this fibroblast signal, thereby reducing the activation of STAT3 in tumor cells and reversing the microenvironment of immunosuppression. however, the anti TGF β therapy failed to prolong the survival time of animals due to its stimulating effect on epithelial tumor cells. in pancreatic cancer patients, nearly 50% of tumors have loss of function mutations in the members of the classic TGF β signaling pathway (including tgfbr2 and Smad4 mutations) [7,8]. the researchers hypothesized that in this part of tumor mutants, tumor cells would lose the proteins that mediate the complete classic TGF β signaling pathway. Therefore, in this case, anti TGF β therapy should be able to escape the side effects of stimulating tumor cell growth. in order to simulate this mutant tumor, the researchers used CRISPR technology to establish a pancreatic cancer model with tgfbr2 function loss mutation, and found that anti TGF β therapy can inhibit the tumor matrix promoting signal in this type of tumor, without side effects of stimulating tumor cell growth, and ultimately significantly prolong the survival time of animals. in conclusion, this study reveals the principle of anti TGF β therapy in pancreatic cancer, and the importance of accurate treatment according to the specific tumor mutation of patients in the future. Rahib L, Smith BD, aizenberg R, Rosenzweig AB, Fleshman JM, matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thymoid, liver, and pancreas cancers in the United States. Cancer res. 2014; 74 (11): 2913-21.2. Mariathasan s, Turley SJ, nickles D, Castiglioni A, Yuen K, Wang Y, et al. TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554(7693):544-8.3. Tauriello DVF, Palomo-Ponce S, Stork D, Berenguer-Llergo A, Badia-Ramentol J, Iglesias M, et al. TGFbeta drives immune evasion in genetically reconstituted colon cancer metastasis. Nature. 2018;554(7693):538-43.4. Feig C, Gopinathan A, Neesse A, Chan DS, Cook N, Tuveson DA. The pancreas cancer microenvironment. Clin Cancer Res. 2012;18(16):4266-76.5. Massague J. TGFbeta in Cancer. Cell. 2008; 134(2):215-30.6. Massague J. TGFbeta signalling in context. Nat Rev Mol Cell Biol. 2012;13(10):616-30.7. Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science. 1996;271(5247):350-3.8. Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518(7540):495-501.