Figure 5 from ATM Regulates Differentiation of Myofibroblastic Cancer-Associated Fibroblasts and Can Be Targeted to Overcome Immunotherapy Resistance
Year: 2025
Type: other
Abstract: Targeting ATM in myofibroblasts reduces their intratumoral accumulation and slows tumor growth. A and F, qRT-PCR showing shRNA ATM knockdown in HFFF2 (A) or TGFβ1-treated MLF (myoMLF; F) prior to injection in mice (ntr = 3; SD shown). B, G, C, and H, Tumor growth curves (B and G) and AUC histograms (C and H) following coinjection of tumor cells with shCTR or shATM fibroblasts (5PT cells + HFFF2, B and C; TC-1 cells + myoMLF, G and H). Data from single experiments are presented; mouse numbers = 3–8 (B and G). Two-way ANOVA is used for AUC analysis of three individual experiments for both 5PT (C) and TC-1 models (H). D and I, Representative SMA IHC from the experiments shown in B and G, respectively. E and J, Quantification of SMA staining (ntr = FoV = 3) from the experiments shown in B (E) and G (J). K, L,P, and Q, Mice injected with either TC-1 ± myoMLF (K and L) or MC38 ± TGFβ1-treated MCF (myoMCF; P and Q) were treated with ATM inhibitor AZD0156 for the duration of the experiment (mouse number = 5–8); tumor growth curves (K and P); AUC analysis of two experiments relative to K (two-way ANOVA; L); AUC analysis of the single experiment shown in P (homoscedastic Student t test; Q). M, N, R, and S, Representative images and quantification of SMA IHC of mouse tumors in K and P, respectively (ntr = FoV = 3). O, Overall survival of TC-1 + myoMLF mice treated daily with AZD0156 at days 15–28 (mouse number = 11–12; Mantel–Cox log-rank test is shown; see also Supplementary Fig. S5K and S5L). Homoscedastic Student t test is shown in the figure and refers to the control unless otherwise highlighted. Scale bars, 200 μm. ns, nonsignificant; *, P ≤ 0.05; **, P ≤ 0.01; ****, P ≤ 0.0001.
Authors: Massimiliano Mellone, Klaudia Piotrowska, Giulia Venturi, Lija James, Aleksandra Bzura, Maria A. Lopez, Sonya James, Chuan Wang, Matthew J. Ellis, Christopher J. Hanley, Josephine F. Buckingham, Kerry L. Cox, Gareth Hughes, Viia Valge-Archer, Emma V. King, Stephen A. Beers, Vincent Jaquet, George D.D. Jones, Natalia Savelyeva, Emre Sayan, Jason L. Parsons, Stephen Durant, Gareth J. Thomas
Language: English
Topic: TGF-β signaling in diseases
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4416587861