1. Non-Canonical Activin A Signaling Stimulates Context-Dependent and Cellular-Specific Outcomes in CRC to Promote Tumor Cell Migration and Immune Tolerance.
- Author
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Wiley, Mark B, Bauer, Jessica, Mehrotra, Kunaal, Zessner-Spitzenberg, Jasmin, Kolics, Zoe, Cheng, Wenxuan, Castellanos, Karla, Nash, Michael G, Gui, Xianyong, Kone, Lyonell, Maker, Ajay V, Qiao, Guilin, Reddi, Deepti, Church, David N, Kerr, Rachel S, Kerr, David J, Grippo, Paul J, and Jung, Barbara
- Subjects
activin A ,colorectal cancer ,digital spatial profiling ,metastasis ,tumor microenvironment ,Cancer ,Digestive Diseases ,Colo-Rectal Cancer ,Good Health and Well Being ,Oncology and Carcinogenesis - Abstract
We have shown that activin A (activin), a TGF-β superfamily member, has pro-metastatic effects in colorectal cancer (CRC). In lung cancer, activin activates pro-metastatic pathways to enhance tumor cell survival and migration while augmenting CD4+ to CD8+ communications to promote cytotoxicity. Here, we hypothesized that activin exerts cell-specific effects in the tumor microenvironment (TME) of CRC to promote anti-tumoral activity of immune cells and the pro-metastatic behavior of tumor cells in a cell-specific and context-dependent manner. We generated an Smad4 epithelial cell specific knockout (Smad4-/-) which was crossed with TS4-Cre mice to identify SMAD-specific changes in CRC. We also performed IHC and digital spatial profiling (DSP) of tissue microarrays (TMAs) obtained from 1055 stage II and III CRC patients in the QUASAR 2 clinical trial. We transfected the CRC cells to reduce their activin production and injected them into mice with intermittent tumor measurements to determine how cancer-derived activin alters tumor growth in vivo. In vivo, Smad4-/- mice displayed elevated colonic activin and pAKT expression and increased mortality. IHC analysis of the TMA samples revealed increased activin was required for TGF-β-associated improved outcomes in CRC. DSP analysis identified that activin co-localization in the stroma was coupled with increases in T-cell exhaustion markers, activation markers of antigen presenting cells (APCs), and effectors of the PI3K/AKT pathway. Activin-stimulated PI3K-dependent CRC transwell migration, and the in vivo loss of activin lead to smaller CRC tumors. Taken together, activin is a targetable, highly context-dependent molecule with effects on CRC growth, migration, and TME immune plasticity.
- Published
- 2023