HGF/MET and CD44 in intestinal cancer: Partners in tumorigenesis and therapy resistance

Research output: ThesisThesis: Research University of Amsterdam, graduation University of Amsterdam

Abstract

Curative therapeutic options for metastatic colorectal cancer (mCRC) are limited and tumors almost invariably escape these treatment regimens and become therapy resistant. A major event in CRC initiation is mutational activation of the WNT signaling pathway resulting in constitutive WNT target-gene transcription, driving malignant transformation. Two direct WNT target genes are CD44 and MET. Elevated expression levels of both CD44 and MET are strongly correlated with reduced disease free and overall survival after surgery for CRC. The functional role of CD44, including its distinct splice variants, and of MET, during intestinal homeostasis and in tumor initiation, progression, and metastasis is currently poorly understood. In this work we elucidate this role and the collaborative function of CD44 in MET signaling, under homeostatic conditions and in cancer initiation and outgrowth.
CD44 is exclusively expressed on the cycling cells in the intestine and intestinal stem cells express a specific CD44 splice variant. This unique Cd44v4-10 variant supports adenoma development in ApcMin/+ mice, establishing a functional role for this Cd44v4-v10 splice variant in cancer initiation. Furthermore, Cd44v4-10 supports the outgrowth of stem cells into fully organized organoids when stimulated with Met ligand hepatocyte growth factor (HGF). Met deficiency in vivo result in strongly reduced adenoma initiation, in both an acute and a stochastic tumor model.
CRC patients with an unmutated EGFR signaling pathway initially benefit from EGFR inhibition treatments. However, normal and APC mutant human stem cells expand on HGF into organoids, even in the presence of EGFR inhibition (and vice versa). CRC patients may escape from EGFR inhibition by co-opting HGF/MET signaling, implying that EGFR inhibition should (upfront) be complemented with a treatment targeting the CD44v/HGF/MET signaling complex.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • University of Amsterdam
Supervisors/Advisors
  • Pals, Steven T., Supervisor
  • Spaargaren, Marcel, Co-supervisor
Award date29 Oct 2021
Print ISBNs9789464168129
Publication statusPublished - 2021

Cite this