Poster Presentation 37th Lorne Cancer Conference 2025

Validating ATF3 as a new therapeutic target to eradicate metastatic and chemotherapy-resistant triple negative breast cancer (#272)

Anton Westacott 1 2 3 , Shabarni Gupta 1 3 , Alexander Corr 3 , Ryan Chai 2 3 , Xingzhi Sun 4 , Betty Gration 3 5 , Elizabeth Driscoll 5 , Georgia McCaughan 3 5 , Rachel Dear 1 2 3 , Tri Giang Phan 2 3 , Smita Krishnaswamy 4 6 , Peter I Croucher 2 3 , Christine L Chaffer 1 2 3
  1. The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW
  2. St Vincent’s Clinical School, UNSW Medicine, University of New South Wales, Darlinghurst, NSW, Australia
  3. Garvan Institute of Medical Research, Sydney, NSW, Australia
  4. Department of Computer Science, Yale University, New Haven, CT, USA
  5. Department of Haematology, St Vincent’s Hospital, Darlinghurst, NSW, Australia
  6. Department of Genetics, Yale University, New Haven, CT, USA

Triple negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer. When the disease metastasises to distant organs, such as the bone, patients face only a 12% chance of surviving beyond five years1,2. An essential pathway for cancer cells to disseminate and seed to distant organs is the cell plasticity program, mesenchymal-to-epithelial transition (MET)3,4. By gaining a deeper understanding of the molecular pathways that drive MET, we can uncover new therapeutic targets to inhibit the metastatic colonisation and outgrowth of TNBC cells.

To this end we developed Trajectory Net5, a neural ODE network to model single cell state trajectories. Applied to our in-vitro TNBC tumoursphere model system, we defined causative gene regulatory networks that drive the MET. Newly, this identified activating transcription factor 3 (ATF3) as a causative MET transcription factor. ATF3 plays a key role in modulating metabolism6, immunity7 and oncogenesis8,9 however it’s role in cancer cell plasticity and driving the MET has yet to be defined. We have shown that knocking down ATF3 expression leads to a significant change in expression of cell state plasticity markers, CDH1 and ZEB1. Moreover, we performed single cell RNA sequencing on disseminated cancer cells isolated from the bone of a patient with metastatic TNBC. Excitingly, these disseminated cancer cells showed a significant increase in ATF3 expression, and in the ATF3-dependent gene regulatory network. This data matches with our pre-clinical models of metastatic dissemination, revealing a decrease in ATF3 expression when cells undergo MET. Together, our data suggests that ATF3 could be a critical driver of the metastatic cancer cell state. By targeting ATF3 it may offer a promising new approach to eradicate metastatic and chemotherapy-resistant TNBC.

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  8. Yin, X., Dewille, J. W., & Hai, T. (2008). A potential dichotomous role of ATF3, an adaptive-response gene, in cancer development. Oncogene, 27(15), 2118–2127. https://doi.org/10.1038/sj.onc.1210861
  9. Hasim, M. S., Nessim, C., Villeneuve, P. J., Vanderhyden, B. C., & Dimitroulakos, J. (2018). Activating Transcription Factor 3 as a Novel Regulator of Chemotherapy Response in Breast Cancer. Translational oncology, 11(4), 988–998. https://doi.org/10.1016/j.tranon.2018.06.001