Arrest-associated transcriptional programmes outweigh apoptosis-associated programmes in treatment-naive pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a cancer fueled by mutant KRAS, and RAS inhibitors have been shown to extend survival in patients with metastatic disease after previous treatment. However, it remains unclear whether treatment shrinks the tumor or simply halts its growth, as the balance between apoptosis and arrest can vary.

Researchers sought to investigate the balance between these two programs in untreated PDAC, and its relationship to tumor subtype, TGM2 expression, tissue organization, survival, and drug sensitivity.

Utilizing a transcriptional contrast between genes associated with apoptosis and those linked to resistance to apoptosis or cell-cycle arrest, the researchers analyzed 52,999 malignant cells from 18 untreated patients in the Hwang atlas. In every patient, the contrast favored the arrest-associated side, with 86.3% of informative cells falling on that side, although the proportion varied depending on the threshold chosen.

This pattern was consistent in the Steele atlas, where the arrest-associated side comprised 71.6% of cells on average, ranging from 37.1% to 90.8%.

In the discovery cohort, tumors with higher basal-like scores tended to have fewer cells on the arrest-side, while TGM2 expression was modestly higher on this side in both cohorts. However, the contrast did not correlate with drug sensitivity in bulk tumors or patient survival. In conclusion, untreated PDAC cells exhibit a consistent transcriptional bias toward anti-apoptotic and cell-cycle-arrest programs, but the implications of this bias for treatment response require further investigation.