Top Journals and National Nature's Preference: How Can Organoids Publish Top Journals of Oncology with 3 Pictures? Smooth application country natural?

Organoids are a research hotspot in recent years, but also the recent focus of the Ministry of Science and Technology, the article on organoids in the past two years is also more and more, so how to develop this year's organoid research?

We are learning today how to harness clinical advantage and how to combine clinical samples to publish organoid research in top oncology journal through an article published in 2022 in clinical cancer research, "Organoid Sensitivity Correlates with Therapeutic Response in Patients with Pancreatic Cancer.

First, the background

Pancreatic ductal adenocarcinoma (PDAC) is an important health problem with a poor prognosis of less than 5% in 5 years, and is known as the king
of cancers.

Second, research ideas

As shown in the figure, the flow of the entire experiment is as follows: Patients are included - tissue acquisition and biopsy - standard treatment is performed on patients - organoids are cultured and drug susceptibility testing is performed - results are obtained and followed up (flowchart):

Figure 1.

Third, the content of the study

Figure 1-2: Construct organoids and characterize and identify their features

To determine whether the constructed organoids can represent molecular subtypes of different pancreatic cancers, the authors performed immunohistochemical identification of 4 biopsy tissues and 6 organoids, transcriptomics detected in 9 organoids, and compared the molecular subtypes of RNA-seq data from PDOs using two algorithms (Figure2A).

Figure 2: Identification of tissues and organoids

In order to further identify whether the organoids summarize the histopathological characteristics of the tumor from the tissue level, the authors stained the tumor tissue and organoids separately, and found that the organoids can highly summarize the pathological characteristics of the primary tumor (Figure3A), in addition, the author compared the genetic information of the organoid and the primary tumor tissue to further detect whether the organoid retained the genetic information of the primary tumor from the gene expression and mutation level.

Figure 3: Morphological and genomic changes in tissues and organoids

Step 1: Characterization and identification of organoids:

(1) Histological identification: HE staining compares the morphological changes of organoids and tissue samples;

(2) Antigen expression identification: whether the expression level of IHC/IF staining corresponds to tumor landmark protein is consistent;

(3) Genetic information expression identification: the relationship between
the expression of the corresponding transcription gene and the gene mutation is detected by genome full-length sequencing or transcriptomics sequencing.

Figure3: Comparison of PDO drug sensitivity and clinical relevance

PDO sensitivity to gemcitabine, 5-FU, oxaliplatin, SN-38 (active metabolite of irinotecan), paclitaxel and other drugs (Figure4A) was tested in 12 PDOs; Calculate an independent AUC assessment for each drug tested on each PDO line and then compare to develop a personalized ranking (Figure4B) for each patient and perform the correlation of AUC values to disease control (Figure4C), for each patient with a known clinical response to treatment, the drug combination received, the AUC estimate of the PDO diagnostic drug response, and the clinical response classified as disease control (Figure4D), It was shown that PDO can effectively predict the effectiveness
of patients with therapeutic drugs.

Figure4: Backtrack clinical data to seek clinical relevance

Step 2: Calculate the AUC value for predicting clinical drug response

Organoid testing effectiveness – Clinical follow-up to see if the patient is effective for the same therapeutic agent – Calculate the AUC value
of organoid predicted clinical therapy.

IV.

In summary, for organoid research, the characterization and identification of organoids is carried out first, and then the prediction of individualized treatment can reach the level
of clinical cancer research.

Improvement: If you add more accurate sequencing data to this and make it clear which drug is more sensitive under that molecular subtype, combining genetic testing and organoid models could greatly improve the innovation and practicality
of this paper.

5.

Organoids are one of the six key projects in the national 14th Five-Year National Key Research and Development Plan, as shown in the figure below, organoid-related projects have heated up rapidly in the past 10 years, and the number of annual quantities accounts for about 700 items, so organoid-related topics naturally have unique advantages
in the applicant country.

Figure 5.

The first step: to determine the disease species, it is best to choose a certain subtype, more refined
.

Step 2: Determine the research direction: mainly organoids, preferably tumor drug susceptibility or drug research and development; Collect clinical samples of corresponding diseases, and construct organoids one-on-one at the same time to do a good job in clinical follow-up
.

Step 3: Histological identification of the constructed organoids and staining pictures (preliminary data 1
).

Step 4: Detect organoid drug sensitivity and do a good job of grouping (sensitivity vs.
insensitivity) (previous data 2).

Step 5: Review the clinical data, do a good job of short-term follow-up results, and verify whether the organoid test results are consistent with the clinical results (preliminary data 3
).

Step 6: Omics Sequencing - Sequencing Requires Combination with Hot Issues (Focus on Epigenetics, Aging, and Dry Regulation) (Previous Data 4); Specific targets are screened according to omics results and simple phenotypic validation is done in organoids (previous data 4).

Step 7: Systematic phenotypic verification of specific targets (in vivo/in vitro experiments);

Step 8: Find the mechanism by which the target functions through multi-omics or by looking for direct proteins;

Step 9: Systematic humanized verification of the mechanism (organoid level);

Step 10 (application): Predict the therapeutic effect of the target / Design inhibitors to target the target to solve the problem
.

References: Grossman JE, Muthuswamy L, Huang L, et.
al.
Organoid Sensitivity Correlates with Therapeutic Response in Patients with Pancreatic Cancer.
Clin Cancer Res.
2022 Feb 15; 28(4):708-718.
doi: 10.
1158/1078-0432.
CCR-20-4116.