Abstract B026: APOBEC3 Promotes Squamous Differentiation Via IL1A/AP-1 Signaling

Andrew S. Truong,Michael S. Sturdivant,Mi Zhou,Wolfgang A. Beckabir, John Raupp,Ujjawal Manocha, Elliot D. Toomer,Ibardo A. Zambrano,Hung-Jui Tan, Marc A. Bjurlin,Angela B. Smith,Tracy L. Rose,Matthew I. Milowsky, Sara E. Wobker,Kathryn H. Gessner,Jeffrey S. Damrauer,William Y. Kim

Clinical Cancer Research（2024）

1University of North Carolina at Chapel Hill

Cited 0|Views22

Abstract

Abstract The APOBEC family of cytidine deaminase enzymes catalyze the conversion of cytosine to uracil in ssDNA and RNA substrates. The resulting C to U transition has been noted in the innate immune response to viral infection, and somatic hypermutation. However, APOBEC family members APOBEC3A (hA3A) and APOBEC3B (hA3B) have been implicated as drivers of the APOBEC3 mutational signatures in numerous cancer types. Notably, approximately 70% of single nucleotide variant mutations in bladder cancer can be attributed to APOBEC3 induced mutagenesis. Studies have implicated various APOBEC3 family members to be drivers of tumorigenesis, disease progression, and therapeutic resistance. To investigate APOBEC3’s role in bladder cancer, we have generated a novel, cre-inducible, pten and p53 knockout, to overexpress mouse Apobec3(mA3) in Upk3a+ cells (UPPA), compared to a model that does not overexpress mA3 (UPP). Apobec3 expression was shown to accelerate bladder tumor formation, indicated by a shorter median time of tumor latency in the UPPA model (43.3 weeks) compared to the UPP model (53.6 weeks). While both tumor models had presence of squamous differentiation, the extensiveness was more profound in the UPPA tumors. Transcriptional analysis of UPP and UPPA tumors, via scRNA sequencing, revealed an enrichment of squamous gene expression in the UPPA tumors. Utilizing mouse syngeneic bladder cancer cell lines and normal bladder urothelial cells, we overexpressed mA3 in a doxycycline inducible manner. Overexpression of mA3 was shown to prevent luminal differentiation. Additionally, mA3 overexpression resulted in the increase of IL-1a production. IL-1a production was sufficient to drive squamous differentiation in BBN963 and normal bladder urothelial cells. Blocking cFOS and IL-1R, individually, prevented expression of squamous genes. These results suggest that DNA damage induced by mA3 is sufficient to drive squamous differentiation via signaling through IL-1a resulting in AP-1 transcription factor activation. We then analyzed bladder cancer samples from The Cancer Genome Atlas and found that hA3A was the only APOBEC family member to be significantly associated with squamous gene expression. Interestingly, hA3A expression was enriched in the basal/squamous consensus subtype. To further interrogate the potential of hA3A being a driver of squamous differentiation in bladder cancer, we have also generated doxycycline inducible expression of hA3A and hA3B in syngeneic bladder cancer cell lines. Targeting IL-1a in various autoimmune diseases has resulted in FDA approval of antibodies targeting IL-1a and IL-1R. Given the clinical utility of targeting IL-1a, it is plausible to target this signaling axis for therapeutic benefit in bladder cancers with ongoing hA3A activity. In aggregate, our work demonstrates the promotion of an aggressive tumor state, driven by APOBEC mutagenesis and implicates hA3A as a possible driver of squamous differentiation in urothelial carcinoma. Citation Format: Andrew S. Truong, Michael S. Sturdivant, Mi Zhou, Wolfgang A. Beckabir, John Raupp, Ujjawal Manocha, Elliot D. Toomer, Ibardo A. Zambrano, Hung-Jui Tan, Marc A. Bjurlin, Angela B. Smith, Tracy L. Rose, Matthew I. Milowsky, Sara E. Wobker, Kathryn H. Gessner, Jeffrey S. Damrauer, William Y. Kim. APOBEC3 promotes squamous differentiation via IL1A/AP-1 signaling [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr B026.

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【要点】：研究揭示了APOBEC3通过IL1A/AP-1信号通路促进膀胱癌细胞鳞状分化的机制，并将hA3A作为潜在的鳞状分化驱动因子。

【方法】：通过建立新型Cre诱导的PTEN和p53敲除小鼠模型，在Upk3a+细胞中过表达小鼠Apobec3(mA3)，并通过单细胞RNA测序分析基因表达差异。

【实验】：实验中，研究人员在UPPA模型中观察到膀胱肿瘤形成速度加快，鳞状分化的程度更明显。通过对小鼠同基因膀胱癌细胞系和正常膀胱尿路上皮细胞过表达mA3，发现mA3过表达抑制了管腔分化，并增加了IL-1a的产生。此外，通过分析来自癌症基因组图谱的膀胱癌样本，发现hA3A与鳞状基因表达显著相关。实验结果还表明，针对IL-1a的治疗可能有潜在的膀胱癌治疗价值。