Poster Presentation 38th Lorne Cancer Conference 2026

Translational reprogramming disrupts mitosis to drive SMAD4-deficient oesophageal adenocarcinoma (#217)

Julia Milne 1 2 3 , Ka Meng Wu 1 , Sasha Witts 1 , Eric Kusnadi 1 2 , Kenji Fujihara 1 2 , Sandra Brosda 4 , Katherine Papastratos 1 2 , Maree Pechlivanis 1 , Anna Trigos 1 2 , Metta Jana 1 , Paul McMillan 1 , Thomas Jackson 1 , Niko Thio 1 , Karen Montgomery 1 , Carlos Cabalag 1 2 , Jovana Gotovac 1 2 , Luc Furic 1 2 , Andrew Barbour 4 , Kaylene Simpson 1 2 5 , David Liu 1 6 , Cuong Duong 1 6 , Wayne Phillips 1 2 6 , Nicholas Clemons 1 2 3
  1. Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VICTORIA, Australia
  2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VICTORIA, Australia
  3. Astex Pharmaceuticals, UK, Cambridge, United Kingdom
  4. The University of Queensland, Brisbane, Queensland, Australia
  5. Victorian Centre for Functional Genomics (VCFG), Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  6. Department of Surgery (St. Vincent's Hospital), University of Melbourne, Parkville, Victoria, Australia

Oesophageal adenocarcinoma (OAC) develops from a precursor lesion named Barrett’s oesophagus; a progression that can be mapped by increasing genomic instability. We have previously shown that SMAD4 loss induces tumourigenesis and increased copy number alterations (CNA) in Barrett’s oesophagus cells with an existing TP53 mutation. The observed CNA increase was especially pronounced in the resultant SMAD4-deficient tumour cells, suggesting that accumulation of mitotic errors occurs in these cells throughout their oncogenic progression. However, such an effect cannot be explained by our current understanding of canonical SMAD4 signalling. Thus, in this study, we aimed to delineate the role of SMAD4 in maintaining chromosomal stability in OAC.

Our multi-omics (RNA-sequencing, proteomics and reverse-phase protein array) approach detected both deregulated translation and mitosis signatures in SMAD4-deficient cells. Using live cell imaging, we demonstrated that TP53-mutant SMAD4-deficient cells exhibit significantly more mitotic errors than TP53-mutant only cells, particularly chromosome segregation defects, which frequently result in chromosomal instability (CIN). Consistent with this, analysis of TCGA data demonstrated that CIN was more prevalent in tumours with both SMAD4 and TP53 mutation than either mutation alone. Further biochemical analyses revealed an increase in cap-dependent translation in these cells, and a decrease in internal ribosome entry site (IRES)-mediated translation. IRES-mediated translation is essential for synthesis of many important mitotic proteins, including a mitosis-specific isoform of a cell cycle kinase. Polysome sequencing showed decreased translation (but not transcription) of this kinase in SMAD4-deficient cells. Ectopic expression of the mitosis-specific isoform of this kinase rescued the mitotic errors that arose as a consequence of SMAD4 loss.

In sum, we present a model where translational reprogramming disrupts mitosis, inducing CIN and potentially driving OAC tumourigenesis in response to loss of SMAD4. This represents a novel mechanism of tumourigenesis in OAC and previously a previously unknown role of SMAD4 in maintaining chromosomal integrity.