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Orthotopic Mouse Model of Colorectal Cancer
08:43

Orthotopic Mouse Model of Colorectal Cancer

Published on: December 4, 2007

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Reliance upon ancestral mutations is maintained in colorectal cancers that heterogeneously evolve during targeted

Mariangela Russo1, Simona Lamba2, Annalisa Lorenzato2,3

  • 1Candiolo Cancer Institute-FPO, IRCCS, 10060, Candiolo, Turin, Italy. mariangela.russo@ircc.it.

Nature Communications
|June 14, 2018
PubMed

Insights

Targeting the ancestral WNT pathway in colorectal cancer (CRC) can overcome drug resistance. Interfering with WNT signaling induces cell death in resistant models, offering a universal strategy against metastatic cancer relapse.

Area of Science:

  • Oncology
  • Cancer Biology
  • Genetics

Background:

  • Metastatic cancers often develop drug resistance due to heterogeneous genetic changes in cancer cell subclones.
  • Targeted therapies face limitations in eradicating all cancer cells, leading to relapse.
  • Colorectal cancer (CRC) serves as a model to study acquired drug resistance mechanisms.

Purpose of the Study:

  • To test if targeting a shared ancestral oncogenic event, like WNT pathway alterations, can overcome acquired drug resistance in colorectal cancer.
  • To investigate the subclonal architecture and evolutionary patterns in drug-resistant CRC populations.
  • To evaluate the therapeutic potential of modulating WNT signaling in overcoming treatment resistance.

Main Methods:

  • Phylogenetic analysis of CRC cell populations to understand subclonal architecture.
  • Functional and pharmacological modulation of the WNT signaling pathway.
  • Preclinical testing in CRC models from patients who relapsed during treatment.
  • Assessment of concomitant WNT and MAPK signaling blockade.

Main Results:

  • Phylogenetic analysis revealed complex subclonal architecture and parallel evolution in resistant CRC populations.
  • WNT pathway modulation induced cell death in preclinical CRC models, irrespective of resistance mechanisms.
  • Concomitant blockade of WNT and MAPK signaling inhibited the emergence of drug-resistant clones.
  • The WNT-APC pathway remains crucial throughout tumor evolution and relapse.

Conclusions:

  • Targeting the ancestral WNT pathway is a viable strategy to overcome acquired drug resistance in colorectal cancer.
  • WNT pathway inhibition demonstrates efficacy across diverse resistance mechanisms in preclinical models.
  • Combined WNT and MAPK pathway blockade may prevent the development of resistance.
  • The conserved reliance on the WNT-APC pathway offers a potential common therapeutic target for relapsed metastatic cancers.

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