Related Experiment Video
Updated: Aug 14, 2025
Author Spotlight: Transmitochondrial Cybrid Generation Using Cancer Cell Lines
Published on: March 17, 2023
Localized heterochrony integrates overgrowth potential of oncogenic clones
Nicola Blum1,2, Matthew P Harris1,2
1Department of Orthopaedics, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
Abstract:
Somatic mutations occur frequently and can arise during embryogenesis, resulting in the formation of a patchwork of mutant clones. Such mosaicism has been implicated in a broad range of developmental anomalies; however, their etiology is poorly understood. Patients carrying a common somatic oncogenic mutation in either PIK3CA or AKT1 can present with disproportionally large digits or limbs. How mutant clones, carrying an oncogenic mutation that often drives unchecked proliferation, can lead to controlled and coordinated overgrowth is unknown. We use zebrafish to explore the growth dynamics of oncogenic clones during development. Here, in a subset of clones, we observed a local increase in proportion of the fin skeleton closely resembling overgrowth phenotypes in patients. We unravel the cellular and developmental mechanisms of these overgrowths, and pinpoint the cell type and timing of clonal expansion. Coordinated overgrowth is associated with rapid clone expansion during early pre-chondrogenic phase of bone development, inducing a heterochronic shift that drives the change in bone size. Our study details how development integrates and translates growth potential of oncogenic clones, thereby shaping the phenotypic consequences of somatic mutations.
Insights
Somatic mutations causing mosaicism can lead to overgrowth. In zebrafish, rapid expansion of oncogenic clones during early bone development drives coordinated overgrowth, explaining patient phenotypes.
Area of Science:
- Developmental Biology
- Genetics
- Cell Biology
Background:
- Somatic mutations during embryogenesis cause mosaicism, leading to developmental anomalies.
- Oncogenic mutations in PIK3CA or AKT1 are linked to disproportionate limb overgrowth in patients.
- The mechanisms behind controlled overgrowth from oncogenic clones are poorly understood.
Purpose of the Study:
- To explore the growth dynamics of oncogenic clones during development using zebrafish.
- To unravel the cellular and developmental mechanisms underlying overgrowth phenotypes.
- To identify the cell type and timing of clonal expansion responsible for overgrowth.
Main Methods:
- Utilized zebrafish as a model organism to study oncogenic clone dynamics.
- Observed and analyzed clonal expansion and its impact on skeletal development.
- Investigated the cellular and temporal aspects of clone expansion during pre-chondrogenesis.
Main Results:
- Identified rapid clone expansion during early bone development in a subset of clones.
- Observed local increases in fin skeleton proportion, mimicking patient overgrowth phenotypes.
- Demonstrated that coordinated overgrowth is linked to a heterochronic shift in bone development.
Conclusions:
- Rapid expansion of oncogenic clones during the pre-chondrogenic phase drives coordinated overgrowth.
- Developmental timing and cell type are critical in translating oncogenic potential into phenotypic overgrowth.
- This study elucidates how developmental processes integrate oncogenic clone growth to shape somatic mutation consequences.
More Related Videos
12:04Engineering Oncogenic Heterozygous Gain-of-Function Mutations in Human Hematopoietic Stem and Progenitor Cells
Published on: March 10, 2023
10:24Generation of Heterogeneous Drug Gradients Across Cancer Populations on a Microfluidic Evolution Accelerator for Real-Time Observation
Published on: September 19, 2019
Related Concept Videos
02:21Cancers Originate from Somatic Mutations in a Single Cell
02:07Tumor Progression
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...
01:33Cancer-Critical Genes I: Proto-oncogenes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
02:53Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
02:23Abnormal Proliferation
01:20Mismatch Repair
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...