Related Experiment Video

Updated: May 28, 2025

In vitro Organoid Culture of Primary Mouse Colon Tumors
07:33

In vitro Organoid Culture of Primary Mouse Colon Tumors

Published on: May 17, 2013

35.0K

Oncofetal reprogramming drives phenotypic plasticity in WNT-dependent colorectal cancer

Slim Mzoughi1,2, Megan Schwarz3,4,5, Xuedi Wang6

  • 1Center for OncoGenomics and Innovative Therapeutics (COGIT), Center for Therapeutics Discovery, Department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. slim.mzoughi@mssm.edu.

Nature Genetics
|February 10, 2025
PubMed

Insights

Targeting cancer stem cells (CSCs) in colorectal cancer (CRC) is key, but resistance persists. Oncofetal reprogramming drives plasticity and drug tolerance in CRC, suggesting new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gastroenterology

Background:

  • Targeting cancer stem cells (CSCs) is vital for effective colorectal cancer (CRC) treatment.
  • Mechanisms of resistance to LGR5+ CSC depletion in WNT-driven CRC are not fully understood.

Purpose of the Study:

  • To investigate the mechanisms underlying CSC plasticity and drug resistance in CRC.
  • To identify novel therapeutic targets for overcoming treatment resistance in CRC.

Main Methods:

  • Analysis of mutant intestinal stem cell (SC) identity and phenotypic plasticity.
  • Investigation of oncofetal (OnF) reprogramming pathways involving YAP, AP-1, and retinoid X receptor.
  • Assessment of the correlation between OnF program activity and resistance to chemotherapy (FOLFIRI).

Main Results:

  • Mutant intestinal stem cells exhibit plasticity, transitioning through a spectrum of phenotypes.
  • Oncofetal reprogramming, driven by YAP and AP-1, initiates this plasticity and promotes lineage infidelity.
  • Deregulation of retinoid X receptor after APC loss creates a sustained OnF 'memory'.
  • An active OnF program is associated with resistance to FOLFIRI, indicating its role in drug tolerance.

Conclusions:

  • Oncogenic reprogramming and stem cell plasticity are key drivers of therapeutic resistance in colorectal cancer.
  • Targeting the oncofetal program in conjunction with standard chemotherapy may improve treatment efficacy and durability in CRC.

More Related Videos

Discovery of Driver Genes in Colorectal HT29-derived Cancer Stem-Like Tumorspheres06:52

Discovery of Driver Genes in Colorectal HT29-derived Cancer Stem-Like Tumorspheres

Published on: July 22, 2020

6.5K
Author Spotlight: Reprogramming Cancer Cells to iPSCs to Study Disease Progression and Treatment Targets07:08

Author Spotlight: Reprogramming Cancer Cells to iPSCs to Study Disease Progression and Treatment Targets

Published on: February 2, 2024

708

Related Concept Videos

Canonical Wnt Signaling Pathway02:54

Canonical Wnt Signaling Pathway

The gene encoding the main signaling molecules of the Wnt signaling pathways (the Wnt proteins) was discovered almost four decades ago by Nüsslein-Volhard and Wieschaus. They identified and originally named the gene "wingless" (wg) after a phenotype discovered during their landmark genetic screen in Drosophila for body pattern defects. At around the same time, another researcher named Harold Varmus found that a murine tumor virus activates the mammalian wg homolog, Int-1, which...
8.7K
Somatic to iPS Cell Reprogramming01:29

Somatic to iPS Cell Reprogramming

Reprogramming alters the gene expression in somatic cells, transforming them into induced pluripotent stem (iPS) cells over several generations. Scientists can reprogram cells by introducing genes for four transcription factors—Oct4, Sox2, Klf4, and c-Myc (OSKM) by viral or non-viral methods. These factors are also known as Yamanaka factors after Shinya Yamanaka, who first generated iPS cells using mouse skin cells. Yamanaka was awarded the Nobel Prize in Physiology or Medicine in 2012...
2.2K
Pleiotropy01:33

Pleiotropy

Pleiotropy is the phenomenon in which a single gene impacts multiple, seemingly unrelated phenotypic traits. For example, defects in the SOX10 gene cause Waardenburg Syndrome Type 4, or WS4, which can cause defects in pigmentation, hearing impairments, and an absence of intestinal contractions necessary for elimination. This diversity of phenotypes results from the expression pattern of SOX10 in early embryonic and fetal development. SOX10 is found in neural crest cells that form melanocytes,...
39.5K
Methods of Nuclear Reprogramming01:24

Methods of Nuclear Reprogramming

Nuclear reprogramming is a process of transforming one cell type into an unrelated cell type by epigenetic changes that alter the cell’s original gene expression pattern. Such epigenetic changes force cells to express a different set of genes, which play a significant role in inducing transformation into other cell types. Nuclear reprogramming offers applications in reproductive cloning for livestock propagation and regenerative medicine — developing patient-specific cells for...
1.8K
Non-Canonical Wnt Signaling Pathways01:41

Non-Canonical Wnt Signaling Pathways

Wnt is a zygotic effect gene that is expressed during very early embryonic development. It regulates various processes in animals starting from early development through the adult stage, such as organogenesis in the embryo and maintenance of neuronal and blood stem cells. Wnt proteins can induce a wide variety of intracellular pathways depending upon the specific abilities of different Wnt ligands to form a complex with shared and cognate receptors in the presence of different co-receptors. The...
7.2K
Role of Ephrin-Eph Signalling in Intestinal Stem Cell Renewal01:22

Role of Ephrin-Eph Signalling in Intestinal Stem Cell Renewal

Erythropoietin-producing hepatocellular carcinoma receptor (Eph) and its ligand, Eph receptor-interacting protein (Ephrin) were first discovered in the human carcinoma cell line, hence the name. Ephrin-Eph interaction guides cells to reach their appropriate location in adult tissues. They also play an essential role in the immune system by helping in immune cell migration, adhesion, and activation. Based on their structure and function, Eph is divided into two classes — EphA and EphB.
2.2K