Some Recent Developments On Gastric Organoid Research And Gastric Epithelial Organoid Culture Recipe

by Dolly the Sheep | Jan 7, 2022 | Cancer, CRISPR, Organoids, Stem Cell

The Gastric Organoids

Challenges in research on human stomach and gastric cancer
Opportunities on organoid technology in scientific research
Application of gastric organoids in research
Example on limitation of current organoid research
Some future trends on organoid-related cancer research
Selected compositions for gastric epithelial organoid culture recipe by Lab-A-Porter

Challenges in research on human stomach and gastric cancer

The traditional in vitro cancer model used to screen novel therapies is the monolayer 2D cancer cell line culture [3].

- - These models establish unnatural geometric and mechanical constraints by adhering cells to an artificial substrate (either plastic or glass). [3]
  - Such as culture affects cell polarity and therefore, potentially, tumour phenotypes. [3]

Transgenic animal models of gastric cancer tumorigenesis have been advanced. [3]

- - However, these models have all shown limitations connected to genetic background irrelevance, animal resistance and the inability to allow examination of the mechanisms that characterize the aggressive metastasis tumours [3]

Opportunities on organoid technology in scientific research

In the last 10 years, researchers have employed gastric organoids in a wide range of research areas, such as basic stomach biology research, the study of pathogens like Helicobacter pylori and gastric cancer research. Particularly, patient-derived organoids biobanks of gastric cancer act as a useful tool in studying gastric cancer biology:

- - Gastric cancer ranking as the fifth most common malignancy, the third leading cause of cancer-related deaths. [2]
  - Gastric cancer is a heterogenous disease displaying many different histological and molecular subtypes [1,3]
  - The prognosis of gastric cancer is poor and most advanced forms of the disease remain incurable. [3]
    - - Although treatment effectiveness has improved during the past decade, gastric cancer survival rates remain poor. [3]
      - This suggests an urgent need to advance innovative therapies available to gastric cancer patients. [3]

Patient-derived organoids biobanks provide a great advantage over classical 2D cell lines in gastric tumour research [1]

- - Nanki and colleagues have generated 37 PDO lines. [1]
    - - They obtained patient-derived organoids of all gastric tumour subtypes except for the Epstein-Barr virus-associated one. [1]
      - Established patient-derived organoids recapitulated the same histopathological features as the original tumour. [1]
  - Yan and colleagues have established 46 PDOs. [1]
    - - They classified them into 4 gastric subtypes with comparable mutational spectra. [1]
      - They observed sub-clonal tumour evolution by comparing multiple biopsies obtained from the primary tumour or even metastasis of the same patient. [1]

Application of gastric organoids in research

Use organoids as a preclinical model

Organoids are 3D cultures that can retain the morphologies and gene expression profiles of their organs of origin [3].

Use human and mouse organoids for disease modelling

For example, the use of gastric organoids has facilitated many important discoveries regarding H. pylori pathogenesis [5], pediatric gastric homeostasis and pediatric mucosal diseases [6]

Use patient-derived organoids to personalize medicine for gastric cancer patients

Patient-derived organoids can be derived from endoscopic tumour biopsies, which maintain heterogeneity in culture. [1]

- They can be rapidly established and expanded in a relatively short time for in vitro drug screening experiments, for therapy prediction and guidance. [1]

Example on limitation of current organoid research

- Organoids only contain epithelial layers without tissue microenvironments, such as the immune system and nervous system. [5]
- Fully maturation to adult organs or tissues is a bottleneck needed to be addressed. [5]
- Dependence on the extracellular matrix or basement membrane extract of current organoids. [5]
- The culture medium needs to be further refined for the long-term expansion of some organoids. [5]
- Growth factors or molecular inhibitors in culture medium might have some effects on drug responses of organoids. [5]

Some future trends on organoid-related cancer research

- Current data suggest a good predictive value of patient-derived organoids in drug and radiation assays, even if the overall mutational landscape is unknown.[1]
- The evolution of translational research, through its applications with patient-derived tumour organoid models, makes it emerge as a crucial strategy in personalized medicine programs. [3]
- New clinical trials are required to further validate the benefits of gastric cancer patient-derived tumour organoids in personalized medicine.[3]
  - - To assess the correlation between the in vivo primary tumour response and the ex vivo drug-mediated cytotoxicity. [3]

Selected compositions for gastric epithelial organoid culture recipe by Lab-A-Porter

EGF

EGF is a potent growth factor that stimulates the proliferation of various epidermal and epithelial cells. It has been shown to inhibit gastric secretion and be involved in wound healing.

FGF-10

FGF-10 is a heparin-binding growth factor that belongs to the FGF family. Proteins of this family play a central role during prenatal development, postnatal growth and regeneration of a variety of tissues.

Noggin

Noggin belongs to a group of diffusible proteins that bind to ligands of the TGF-β family and regulate their activity by inhibiting their access to signalling receptors.

R-Spondin-1

R-Spondin-1 is expressed in certain areas of the developing central nervous system, as well as in the adrenal glands, ovary, testis, thyroid, and trachea.

Wnt-3a

Wnt-3a signalling is essential for various morphogenetic events, including embryonic patterning, cell determination, cell proliferation, CNS development, and cytoskeletal formation.

Gastrin

Gastrin is a peptide hormone that is a major physiological regulator of the gastric acid section and a promoter of gastric mucosal growth.

Y 27632

Y-27632 is a selective inhibitor of Rho-associated coiled-coil forming protein serine/threonine kinase (ROCK) family of protein kinases that selectively competes with ATP for binding to the catalytic site.

A 83-01

A 83-01 is a potent activating receptor-like kinase inhibitor (ALK4 IC50 45nM, ALK5 IC50 12nM, ALK7 IC50 7.5nM). It is a more potent inhibitor of ALK5 than SB 431542 and is reported to inhibit Smad signalling and epithelial-to-mesenchymal transition by transforming growth factor-beta.

Nicotinamide

Nicotinamide is an amide of nicotinic acid, a vitamin of the B complex. In cells, it is incorporated into NADP+ and NAD+, coenzymes for a wide variety of enzymatic oxidation-reduction reactions.

SB 202190

SB 202190 is a selective and potent p38 MAP kinases inhibitor, binding to its ATP pocket. It has negligible inhibiting properties on other MAP kinases such as ERKs and JNKs.

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References:

Busslinger, Georg A et al. “The potential and challenges of patient-derived organoids in guiding the multimodality treatment of upper gastrointestinal malignancies.” Open biologyvol. 10,4 (2020): 190274. doi:10.1098/rsob.190274
Seidlitz, Therese et al. “Gastric organoids-an in vitro model system for the study of gastric development and road to personalized medicine.” Cell death and differentiation vol. 28,1 (2021): 68-83. doi:10.1038/s41418-020-00662-2
Alzeeb, George et al. “Three-Dimensional Culture Systems in Gastric Cancer Research.” Cancersvol. 12,10 2800. 29 Sep. 2020, doi:10.3390/cancers12102800
Lo, Yuan-Hung et al. “A CRISPR/Cas9-Engineered ARID1A-Deficient Human Gastric Cancer Organoid Model Reveals Essential and Nonessential Modes of Oncogenic Transformation.” Cancer discovery vol. 11,6 (2021): 1562-1581. doi:10.1158/2159-8290.CD-20-1109
Xu, Hanxiao et al. “Organoid technology in disease modelling, drug development, personalized treatment and regeneration medicine.” Experimental hematology & oncology vol. 7 30. 5 Dec. 2018, doi:10.1186/s40164-018-0122-9

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