P300, A New Player in Mechanosensitivity and Activation of Cancer-Associated Fibroblasts

See “P300 acetyltransferase mediates stiffness-induced activation of hepatic stellate cells into tumor-promoting myofibroblasts,” by Dou C, Liu Z, Tu K, et al, on page 2209. See “P300 acetyltransferase mediates stiffness-induced activation of hepatic stellate cells into tumor-promoting myofibroblasts,” by Dou C, Liu Z, Tu K, et al, on page 2209. The physical properties of the extracellular environment such as matrix composition and mechanics are key factors that determine cancer cell behavior.1Oudin M.J. Weaver V.M. Physical and chemical gradients in the tumor microenvironment regulate tumor cell invasion, migration, and metastasis.Cold Spring Harb Symp Quant Biol. 2016; 81: 189-205Crossref PubMed Scopus (106) Google Scholar, 2Nicolas-Boluda A. Silva A.K.A. Fournel S. et al.Physical oncology: new targets for nanomedicine.Biomaterials. 2018; 150: 87-99Crossref PubMed Scopus (26) Google Scholar Stiffening matrix is a result of a complex multidirectional interplay between stromal cells such as cancer-associated fibroblasts (CAF), infiltrating immune cells, and cancer cells. Fiber realignment and strain stiffening enable cancer cells to contract and break basement membranes, withdraw adhesions, and form invadosomes.3Ahmadzadeh H. Webster M.R. Behera R. et al.Modeling the two-way feedback between contractility and matrix realignment reveals a nonlinear mode of cancer cell invasion.Proc Natl Acad Sci U S A. 2017; 114: E1617-E1626Crossref PubMed Scopus (115) Google Scholar Cells can “sense” their environment, and respond by complex mechanotransductive pathways.4Chang T.T. Thakar D. Weaver V.M. Force-dependent breaching of the basement membrane.Matrix Biol. 2017; 57-58: 178-189Crossref PubMed Scopus (53) Google Scholar Extracellular physical signals are known to affect integrin subunit assembly and the recruitment of several cellular constituents such as focal adhesion kinase and associated Src, eventually leading to an increasing number and activity of invadosomes. Downstream activation of the RhoA GTPase ultimately controls actin cytoskeletal dynamics and invadopodia formation. Its effector, ROCK, is able to further increase matrix stiffness via a β-catenin–mediated transcriptional program. Matrix cross-linking also has a significant role in rigidity, and it was shown that the combined inhibition of lysyl oxidase 2 (LOXL2) and the transforming growth factor β receptor I had a potent inhibitory effect on collagen accumulation, softening the matrix.5Wei Y. Kim T.J. Peng D.H. et al.Fibroblast-specific inhibition of TGF-beta1 signaling attenuates lung and tumor fibrosis.J Clin Invest. 2017; 127: 3675-3688Crossref PubMed Scopus (108) Google Scholar The mechanical environment of tumor cells can strongly influence the response to chemotherapy or radiation therapy, and clinical outcomes. Integrin β1/focal adhesion kinase activation was central to hepatocyte growth factor-dependent ERK, AKT, STAT3, and cyclin D1 signals linking matrix stiffness to increased proliferative responses and chemoresistance.6Schrader J. Gordon-Walker T.T. Aucott R.L. et al.Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells.Hepatology. 2011; 53: 1192-1205Crossref PubMed Scopus (449) Google Scholar Changes in stiffness were observed to induce β1-integrin–dependent transcriptional programs that activate migration and angiogenesis-related genes. These signatures were correlated with worse survival in 9 different tumor types.7Velez D.O. Tsui B. Goshia T. et al.3D collagen architecture induces a conserved migratory and transcriptional response linked to vasculogenic mimicry.Nat Commun. 2017; 8: 1651Crossref PubMed Scopus (76) Google Scholar The matrix architecture and the mode of fiber alignment could also have an impact on outcomes. In a recent study, perpendicular fiber alignment (tumor-associated collagen signature-3) was a predictor of overall survival in breast cancer.8Esbona K. Yi Y. Saha S. et al.The presence of cyclooxygenase 2, tumor-associated macrophages, and collagen alignment as prognostic markers for invasive breast carcinoma patients.Am J Pathol. 2018; 188: 559-573Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar CAFs are key to controlling matrix deposition and dynamics. CAFs can elicit signals that align the fibronectin matrix, allowing the directional migration of cancer cells, and aligned fibronectin is a prominent feature of invasion sites in prostate and pancreatic carcinomas.9Erdogan B. Ao M. White L.M. et al.Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin.J Cell Biol. 2017; 216: 3799-3816Crossref PubMed Scopus (272) Google Scholar CAFs also produce an aberrant matrix, enabling invasion, with an increase in collagens IV, VI, VII, X, decorin, and laminin subunits.10Calvo F. Ege N. Grande-Garcia A. et al.Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts.Nat Cell Biol. 2013; 15: 637-646Crossref PubMed Scopus (835) Google Scholar, 11Affo S. Yu L.X. Schwabe R.F. The role of cancer-associated fibroblasts and fibrosis in liver cancer.Annu Rev Pathol. 2017; 12: 153-186Crossref PubMed Scopus (327) Google Scholar Thus, the question as to how CAFs become activated in the tumor environment is very relevant. In the liver, a common site of hematogenous metastases, hepatic stellate cells (HSCs) are thought to give rise to smooth muscle α-actin–positive CAFs. How does the stiffening matrix during metastatic invasion in the liver enable transdifferentiation of quiescent HSC into CAF/MF phenotypes? The study by Dou et al12Dou C. Liu Z. Tu K. et al.P300 acetyltransferase mediates stiffness-induced activation of hepatic stellate cells into tumor-promoting myofibroblasts.Gastroenterology. 2018; 154: 2209-2221Google Scholar highlights the novel role of the p300 acetyltransferase in durosensitivity and the epigenetic regulation of HSC plasticity. Increasing matrix rigidity induced the RhoA-Akt-p300 pathway, resulting in p300 nuclear translocation and the expression of smooth muscle α-actin and a panel of tumor-promoting factors, including CXCL12, CTGF, and PDGF A and B. P300 is a ubiquitous transcriptional regulator that plays a role in histone acetylation and chromatin remodeling, and an increase in p300 activity has been linked to a more aggressive phenotype in several cancers. By atomic force microscopy, the authors demonstrated that colorectal metastases in the liver were “stiffer” than the surrounding parenchyma, and that the expression of p300 was increased in both patient specimens and in mice. In quiescent HSC on soft matrix, p300 levels remained low owing to proteasomal degradation, whereas on stiff hydrogel matrix, both the protein levels and phosphorylation were induced, and p300 translocation to the nucleus was observed. RhoA, as described, is a critical “sensor” for increased matrix stiffness targeting Akt, leading to its phosphorylation. Because a stiff extracellular matrix could cause increased CAF migratory activity, it would be interesting to see whether the RhoA/p300 pathways could indeed be part of invadosome activation, and play a role in migration/invasiveness. The authors confirmed their findings in elegant in vivo studies. They used a tumor cell/conditioned medium co-implantation model where the deletion of p300 from HSC inhibited tumor growth, whereas seeding HSC grown on a hard matrix, enhanced it. Using a conditional knockout model deleting p300 from collagen-producing cells, both fibrosis (CCl4) and metastatic growth were decreased. Furthermore, C646, a selective small molecule inhibitor of p300, decreased colorectal metastases in mice. Intriguingly, p300 was induced not only in cancer-associated myofibroblasts, but also in metastatic tumor cells. This finding lends further credence to prior studies where metastatic progression was associated with increasing p300 activity, tumor cell survival, and proliferation.13Hu H. Zhu W. Qin J. et al.Acetylation of PGK1 promotes liver cancer cell proliferation and tumorigenesis.Hepatology. 2017; 65: 515-528Crossref PubMed Scopus (132) Google Scholar Recent studies demonstrated the role of Yes-associated protein in communicating mechanosensitive signals.14Foster C.T. Gualdrini F. Treisman R. Mutual dependence of the MRTF-SRF and YAP-TEAD pathways in cancer-associated fibroblasts is indirect and mediated by cytoskeletal dynamics.Genes Dev. 2017; 31: 2361-2375Crossref PubMed Scopus (116) Google Scholar Because p300 has been involved in Yes-associated protein acetylation, it would be worth exploring whether these pathways converge and p300 could indeed be a master regulator of mechanosensitive signals. Clinically, increasing liver stiffness is associated with a higher risk of hepatocellular carcinoma, and an increased proliferative response and chemoresistance at a molecular level. Thus, p300 activation could be a molecular “hot spot” in durosensitivity as it regulates a positive feedback loop between cancer cells and CAFs. Targeting p300 may open novel treatment approaches that could be used in combination with conventional chemotherapies. P300 Acetyltransferase Mediates Stiffness-Induced Activation of Hepatic Stellate Cells Into Tumor-Promoting MyofibroblastsGastroenterologyVol. 154Issue 8PreviewHepatic stellate cells (HSCs) contribute to desmoplasia and stiffness of liver metastases by differentiating into matrix-producing myofibroblasts. We investigated whether stiffness due to the presence of tumors increases activation of HSCs into myofibroblasts and their tumor-promoting effects, as well as the role of E1A binding protein p300, a histone acetyltransferase that regulates transcription, in these processes. Full-Text PDF