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Manic Fringe deficiency imposes Jagged1 addiction to intestinal tumor cells

Erika López-Arribillaga1, Verónica Rodilla1, Carlota Colomer1

  • 1Cancer Research Program. CIBERONC. Institut Mar d'Investigacions Mèdiques, Hospital del Mar, Doctor Aiguader 88, 08003, Barcelona, Spain.

Nature Communications
|August 2, 2018
PubMed

Insights

Jagged1 activates Notch signaling in intestinal tumors, but not normal cells. Targeting Jagged1 with antibodies inhibits tumor growth, offering a potential therapy for colorectal cancer and FAP syndrome.

Area of Science:

  • Gastrointestinal Oncology
  • Cell Signaling
  • Cancer Therapeutics

Background:

  • Notch signaling is regulated by Delta ligands in normal intestinal stem cells.
  • Jagged1 (Jag1) activates Notch signaling specifically in intestinal adenomas with active β-catenin.

Purpose of the Study:

  • To investigate the divergent ligand-dependent Notch function in intestinal adenomas.
  • To explore the therapeutic potential of targeting Jag1 in colorectal cancer and Familial Adenomatous Polyposis (FAP) syndrome.

Main Methods:

  • Utilized the ApcMin/+ mouse model for in vivo studies.
  • Employed tumor spheroid cultures and patient-derived orthoxenografts (PDX).
  • Analyzed 239 human colorectal cancer patient samples for Jag1 and Manic Fringe (MFNG) expression.

Main Results:

  • Intestinal-specific Jag1 deletion or Jag1 antibody treatment prevented tumor initiation in mice.
  • Adenoma cells showed dependence on Jag1, correlated with the absence of MFNG.
  • High Jag1 in MFNG-negative human colorectal tumors predicted poor prognosis.
  • Jag1 antibody treatment reduced PDX tumor growth without impacting normal intestinal mucosa.

Conclusions:

  • Jag1 dependence in cancer is explained by the absence of MFNG.
  • Jag1-Notch1 interference demonstrates therapeutic benefit in a subset of colorectal cancer and FAP patients.
  • Targeting Jag1 represents a promising therapeutic strategy for specific cancer types.

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