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Spontaneously evolved progenitor niches escape Yap oncogene addiction in advanced pancreatic ductal adenocarcinomas

Shigekazu Murakami1, Shannon M White1, Alec T McIntosh1

  • 1Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.

Nature Communications
|March 16, 2023
PubMed

Insights

Lineage plasticity allows pancreatic cancer to regrow after Yap inhibition by reactivating pluripotent transcription factors. Targeting Brd4 with BET inhibitors synergizes with Yap inhibitors to block tumor growth.

Area of Science:

  • Oncology
  • Cancer Biology
  • Molecular Biology

Background:

  • Lineage plasticity contributes to tumor heterogeneity and treatment resistance.
  • Pancreatic Ductal Adenocarcinoma (PDAC) often exhibits resistance to therapies targeting oncogenic drivers.

Purpose of the Study:

  • To investigate the role of lineage plasticity in PDAC relapse after oncogenic driver elimination.
  • To identify molecular mechanisms driving resistance and potential therapeutic targets.

Main Methods:

  • Utilized an inducible genetic engineered mouse model of PDAC.
  • Performed transcriptomic and immunohistochemistry analysis on PDAC tumors.
  • Conducted Comprehensive Cut&Tag analysis and chemical-genetic screening.

Main Results:

  • PDAC tumors relapsed spontaneously after Yap inhibition due to lineage plasticity.
  • PDAC cells reactivated pluripotent transcription factors (PTFs), reducing Yap dependency.
  • PTFs formed a distinct core transcriptional regulatory circuitry (CRC) with Jun, independent of TGFb-induced EMT.
  • Brd4 was identified as an epigenetic gatekeeper for the PTF-Jun CRC.

Conclusions:

  • Lineage plasticity is a key mechanism for PDAC relapse and therapeutic resistance.
  • The PTF-Jun CRC offers a novel therapeutic vulnerability in Yap-dependent PDAC.
  • Combined BET and Yap inhibition demonstrates strong synergistic effects in blocking PDAC growth.

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