New advances in Cancer Cell's oncology resistance research! "Genetic mutations" may not be necessary.

Clinically, cancer patients who pass chemotherapy usually have a period of remission, unfortunately, after the remission period, the disease tends to progress, and relapsed tumor cells will also appear resistant to the original chemotherapy drugs.
the reasons for the emergence of drug resistance has been a constant area of exploration by scientists.
A recent study published in the journal Science found that when clinically using chemotherapy drugs to fight cancer progression, tumor cells in the body tend to develop drug-resistant cell strains through stress-induced mutations (stress-induced mutates , SIM) that cause tumors to return... However, many scientists also believe that genetic mutations do not fully explain the phenomenon of drug resistance in tumor cells, and more and more research has focused on non-genetic changes in cells1.
that one of the mechanisms by which tumor cells develop resistance is to change their esopolype characteristics.
prostate cancer cells, which are sensitive to hormone therapy, can be transformed into cell types that do not rely on hormone growth to avoid drug damage! On July 27, 2020, scientists from the Sloan Kettering Cancer Center, Harvard University, and the Massachusetts Institute of Technology jointly published an article on CancerCell called "Spectreof a High-PlasticIty Cell State In The Cancer Evolution."
paper studies the key role of a particular state of tumor cells, high-plasticity cell state (high-plasticitycell state, HPCS) in tumor development.
This study used genetically engineered mouse models from pre-tumor hyperplision to adenocarcinoma to study changes in single-cell transcription groups of lung adenocarcinoma (LUAD), and found that HPCS was present in tumor cells isolated in both mouse tumors and patients with heterogeneous transplantation, with high differentiation and proliferation capabilities.
further experiments, HPCS was found to be highly tumor-resistant and resistant and associated with poor prognosis in patients.
note that the emergence and maintenance of tumor cell heterogeneity is also driven by HPCS.
this study provides guidance and reference for the study of tumor heterogeneity and future HPCS-targeted treatment2. The heterogeneity of
tumor is one of the characteristics of malignant tumor, which means that the tumor in the growth process, after many division and proliferation, its subcells show molecular biology or genetic changes, so that the tumor growth rate, invasive ability, drug sensitivity, prognostic and other aspects of the difference.
1: In tumors, the esogram or state of each cancer cell is influenced by a variety of inward and extracellular factors, and changes in tumor cell state diversity are also one of the challenges of cancer treatment.
over the past 30 years, gene expression scores common to some common cancers have been described in detail, and expressions of some advanced tumors in mice and humans have been established.
, however, at the molecular level, changes in the diversity of tumor cell development processes, and in a certain genetic context, why can this diversity change be repeated? Is there an association, support, or competition between different cell states of the same tumor? And what role does the change in the state of the cell play in driving the progress of the tumor? These questions are not yet clear.
significant increase in esophageal diversity and reproducible characteristics of LUAD progression, pulmonary adenocarcinoma (LUAD) originated mainly in type 2 analgesic (AT2) cells.
researchers first genetically engineered a LUAD model (Geneticallyengered mouse models, GEMM) of mice, recreating eight different states from precanceum status to malignant changes in pulmonary adenocarcinoma.
3,891 high-quality, full-length single-cell transcription groups evolved by collecting LUAD from 39 mice, and studied the diversity of tumor molecular levels through RNA-seq.
results show that with the development of tumors, the heterogeneity of cell esolyses increases, the late diversity increases, develops into a large number of different clusters, and the expression patterns become more diverse.
same time, these changes were significantly repeatable between tumors in mice and between mice, and were consistent with the pathological progression of each tumor.
adenocarcinoma contains clusters 10, 11, and 12, and includes early cell states found in normal AT2 cells and early tumors, in addition to all cell states detected at the beginning of the tumor.
addition, most cancer cell ideopses appear at 30 weeks in each individual KP tumor (carcinogenic gene KRAS-G12D active type).
note that in mice and individual tumors, there were clusters of 5 and 9 cells in each sample analyzed from the adenoma stage.
therefore, in this animal model, the tumor underwent a relatively orderly and replicable diversity of transcriptional states.
Figure 2: Mouse LUAD model - RNA-seq tumor cell esotypic diversity or gene mutation independent of previous studies have shown that LUAD tumor mutations are mainly caused by changes in chromosomal copy numbers, while tumors do not have relapse point mutations.
, the study of the human body in the experiment, using the scRNA-seq spectrum of each cell inferred chromosomal copy number changes (CNVs).
KPT cells have more CNVs at the corresponding point in time than KT (p53 gene mutant) tumors.
in a sub-group of 30-week-old KPT tumors, the researchers estimated the number of copies of DNA using the whole genome sequencing (scDNA-seq) of individual tumor cells.
, which are significantly shared in mouse tumors, come from the same clone group.
time, cells with highly similar CNV patterns belong to several different transcription clusters, while cells with different cloned CNVs belong to the same transcription cluster.
results suggest that a large number of esoteric heterogenesity in KP tumors is repetitive, but this is not just the result of changes in gene CNV.
figure 3: Tumor cell esoteric diversity is not related to CNV changes LUAD progression process appeared a "highly mixed state" researchers immediately analyzed luad cell esoteric change characteristics, found that during the progression process, tumor albaccus cell esotype loss, the appearance of pulmonary progenitocytes, embryonic endosperm and endotysurfest-charged transformation (EMT)-related characteristics.
suggests that cells are dynamic in tumor evolutionary continuums, so the researchers then used non-negative matrix decomposition (NMF) to explore continuous changes in transcription procedures and cell state transitions.
11 transcription procedures were discovered through experiments, five of which highlighted continuous esolyped changes during tumor progression.
three of these five procedures related to AT2 cell characteristics appeared at the beginning of LUAD development, embryo sample procedures and EMT procedures later in the process.
at the same time, two previously unknown cell programs were found in the experiment, an early procedure (mixed AT1/AT2 state) that mixed AT1 and AT2 cell characteristics, and another program that did not match the explicit cell recognition program (highly mixed state).
by performing immuno-staining markers, the cells were detected to jointly express a mixture of markers, suggesting that the cells may be transitioning from one state to another.
Figure 4: When tumor cell esoplasms change, cells in a "mixed state" and a "highly mixed state" can mark a highly malleable unit (i.e. HPCS), thus forming a transition point Where researchers first found that the timing of the emergence of transcript cluster 5, its expression in a highly mixed program, and its particular persistence in the tumor suggest a possible correlation between cluster 5 and HPCS.
single-cell analysis of cluster 5-positive cells was carried out by trans-seatase and chromatin sequencing.
results showed an increase in the proximity of tumor cells to genes characterized by cluster 5.
further studies have found that RUNX2 is the driver of the primary tumor metastasis ideotype, and CD109 signal activity through the Jak/Stat pathway has been shown to be associated with this ideotype.
same time, CD109 was found to mark cluster 11 as EMT-related.
, the above study suggests that HPCS may be a prelude to EMT status that obtains the ability to metastat the primary tumor.
Figure 5: The identification of HPCS in highly malleable cell states with obvious chromatin accessability characteristics is not a stem cell characteristic, and last in human tumor cells, immuno-staining of different human LUAD tissues was also found in cell transition states observed in mouse models.
addition, an analysis of the malignant cell scRNA-seq spectrum in LUAD tumors showed that the HPCS state of the cells was present in each tumor cell.
RNA-seqRNA analysis of the cancer genome map (TCGA) found that LUAD tumor expression HPCS was associated with EMT and poor survival.
Through analysis of the characteristics of the integrator alpha2Hi human LUAD cells, it was found that the integrator alpha2Hi tumor cells formed significantly more tumor balls isolated from the heterogeneic transplant tumor models of three independent patient sources than the integrator alpha2Hi tumor cells.
and droplet-based scRNA-seq analysis showed that the transcriptional diversity of the integrated a2Hi human LUAD cells was higher than that of the integrated alpha2Lo large tumors.
, these results show that HPCS-like states are also present in human LUAD and may be important in clinically as drivers of tumor progression and resistance and biomarkers.
Figure 6: In luad mouse models and human tumors, the increase of transcription heterogeneity and genetic uncertainty and plasticity are important characteristics of tumor development.
HPCS, in addition to procedures that reflect the state of the lungs and other endosthal cells, is associated with chemotherapy resistance, high growth potential and low survival rates in patients, is a key driver of tumor development and heterogeneity within tumors, and may provide an important target for future tumor therapy.
authors report that the application of HPCS - changing drug resistance Although many previous studies have looked for "drug-resistant mutations" in tumors, the genetic changes that cause tumors to act as anti-cancer drugs.
, however, how to resist the mechanism of the drug after the mutation is still unknown.
Chan, the author of the study, believes the new findings provide a possible answer to the puzzle.
Chan said: "Our model can explain why some cancer cells are resistant to treatment, and HPCS is a form of tumor cell state that is more malleable and malleable.
, Dr. Chan believes that combining chemotherapy drugs with new drugs for these highly malleable cells may avoid the emergence of drug resistance and provide a longer period of sustained remission.
: 1 Lawson, D. A., Kessenbrock, K., Davis, R. T., Pervolarakis, N. and Werb, Z.Tumour heterogeneity and metastasis at single-cell resolution. NatureCell Biology 20, 1349-1360, doi:10.1038/s41556-018-0236-7 (2018).2 Marjanovic, N. D. et al. Edgy of a High-Plasticity Cell State inLung Cancer Evolution. Cancer Cell, doi: YT. Lin Source: BioImmunology !-- end of content presentation -- !-- determine if login ends.