Dual Inhibition of Myc Transcription and PI3K Activity Effectively Targets Colorectal Cancer Stem Cells
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Isolation and Maintenance of CR-CSphCs and CAFs
2.2. CR-CSphCs In Vitro Treatment
2.3. Clonogenic, Sphere-Forming and Colony-Formation Assays
2.4. Cell Viability
2.5. Lentiviral Production and Transduction
2.6. Flow Cytometry and Cell Sorting
2.7. Western Blot
2.8. RNA Extraction and Gene Expression Analysis
2.9. Immunofluorescence/Immunohistochemistry
2.10. In Vivo Experiments
2.11. Statistical Analysis
3. Results
3.1. CD44v6-Positive CR-CSphCs Are Refractory toward BRAF Inhibition
3.2. CR-CSCs Emerge after Inhibition of HER2, BRAF and PI3K
3.3. Resistance to BRAF-Based Combination Therapy Is Sustained by Myc Expression
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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CD44v6 expression | ||||||||||||||||||||||||||||||||||||||
MYC GCN | ||||||||||||||||||||||||||||||||||||||
MSI status | NA | |||||||||||||||||||||||||||||||||||||
Site | S | L | R | R | R | R | R | R | S | L | R | R | R | R | L | R | L | S | R | R | M | M | R | NA | L | R | R | R | R | S | S | R | S | R | S | L | L | M |
BRAF | ||||||||||||||||||||||||||||||||||||||
KRAS | ||||||||||||||||||||||||||||||||||||||
CSphC # | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 19 | 20 | 21 | 22 | 23 | 24 | 25 | 27 | 29 | 30 | 33 | 37 | 44 | 49 | 52 | 53 | 55 | 56 | 57 | 58 | 59 |
CD44v6 expression levels (%) | MYC/EIF2C1 ratio | MSI status | Mutation Type | |||||||||||||||||||||||||||||||||||
high | >70% | MYC GCN < 4 | stable | wt | ||||||||||||||||||||||||||||||||||
medium | 30–70% | MYC GCN ≥ 4 | low | Missense | ||||||||||||||||||||||||||||||||||
low | <30% | high | ||||||||||||||||||||||||||||||||||||
NA |
Name | Type | Target |
---|---|---|
Vemurafenib | Small molecule | BRAFV600E |
Cetuximab | Recombinant human/mouse chimeric IgG(1) monoclonal antibody | EGFR |
Trastuzumab | Recombinant humanized monoclonal antibody | HER2 |
BKM120 | dimorpholino pyrimidine derivative | class I PI3K |
Dinaciclib | small molecule | CDK1/2/5/9 |
Taselisib | small molecule | PIK3CA |
Gene Name | Assay ID | Gene Name | Assay ID | Gene Name | Assay ID |
---|---|---|---|---|---|
AXIN1 | qHsaCID0010131 | ILKAP | qHsaCID0011777 | SERPINE1 | qHsaCID0006432 |
AXIN2 | qHsaCID0017930 | ITGA5 | qHsaCID0021495 | SFRP1 | qHsaCID0015548 |
BMP1 | qHsaCID0010875 | ITGAV | qHsaCID0006233 | SFRP4 | qHsaCED0043151 |
BMP2 | qHsaCID0015400 | ITGB1 | qHsaCED0005248 | SMAD2 | qHsaCID0022031 |
BMP7 | qHsaCID0011038 | JAG1 | qHsaCID0006831 | SMAD4 | qHsaCID0015670 |
CCND1 | qHsaCID0013833 | KISS1 | qHsaCED0004976 | SNAI1 | qHsaCED0002998 |
CD44 | qHsaCID0013679 | KISS1R | qHsaCID0011504 | SNAI2 | qHsaCID0011342 |
CDH1 | qHsaCID0015365 | KREMEN1 | qHsaCED0047626 | SNAI3 | qHsaCED0047761 |
CDH2 | qHsaCID0015189 | KRT14 | qHsaCED0047868 | SOX17 | qHsaCED0001884 |
CDKN2A | qHsaCED0023006 | LRP5 | qHsaCED0045974 | SRC | qHsaCED0004489 |
COL1A1 | qHsaCED0002181 | LRP6 | qHsaCID0010231 | STAT3 | qHsaCID0010912 |
CTNNB1 | qHsaCID0010363 | MDM2 | qHsaCID0011000 | TGFB1 | qHsaCID0017026 |
CXCL12 | qHsaCID0012398 | MET | qHsaCED0002004 | TGFB2 | qHsaCID0018360 |
CXCR4 | qHsaCED0002020 | MMP2 | qHsaCID0015623 | TGFB3 | qHsaCID0022239 |
DKK1 | qHsaCED0002060 | MMP3 | qHsaCID0006170 | TIMP1 | qHsaCID0007434 |
DKK3 | qHsaCED0001115 | MMP7 | qHsaCID0011537 | TIMP2 | qHsaCID0022953 |
EGFR | qHsaCID0007564 | MMP9 | qHsaCID0011597 | TIMP3 | qHsaCID0015238 |
EPHB2 | qHsaCID0009881 | MMP10 | qHsaCED0046399 | TIMP4 | qHsaCID0016129 |
ERBB2 | qHsaCID0012766 | MMP11 | qHsaCID0022136 | TP53 | qHsaCID0013658 |
ERBB3 | qHsaCID0018397 | MMP13 | qHsaCID0008487 | TSHR | qHsaCID0009606 |
ERBB4 | qHsaCID0017862 | MYC | qHsaCID0012921 | TWIST1 | qHsaCED0003856 |
ESR1 | qHsaCED0033920 | NODAL | qHsaCID0006123 | VIM | qHsaCID0012604 |
FGFBP1 | qHsaCID0015948 | NOTCH1 | qHsaCID0011825 | WNT3A | qHsaCED0045634 |
FGFR4 | qHsaCED0045915 | OCLN | qHsaCED0038290 | WNT5A | qHsaCID0012240 |
FN1 | qHsaCID0012349 | PDGFRB | qHsaCID0013272 | WNT5B | qHsaCID0038673 |
FZD7 | qHsaCED0019290 | PTEN | qHsaCED0036796 | WNT7A | qHsaCID0018523 |
GAPDH | qHsaCED0038674 | RAC1 | qHsaCED0001330 | WNT7B | qHsaCED0003528 |
GSK3B | qHsaCID0010097 | RB1 | qHsaCID0007095 | WNT11 | qHsaCID0011927 |
HGF | qHsaCID0011441 | RGS2 | qHsaCED0001744 | ZEB1 | qHsaCID0009210 |
HPRT1 | qHsaCID0016375 | RHOA | qHsaCID0008947 |
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Gaggianesi, M.; Mangiapane, L.R.; Modica, C.; Pantina, V.D.; Porcelli, G.; Di Franco, S.; Lo Iacono, M.; D’Accardo, C.; Verona, F.; Pillitteri, I.; et al. Dual Inhibition of Myc Transcription and PI3K Activity Effectively Targets Colorectal Cancer Stem Cells. Cancers 2022, 14, 673. https://doi.org/10.3390/cancers14030673
Gaggianesi M, Mangiapane LR, Modica C, Pantina VD, Porcelli G, Di Franco S, Lo Iacono M, D’Accardo C, Verona F, Pillitteri I, et al. Dual Inhibition of Myc Transcription and PI3K Activity Effectively Targets Colorectal Cancer Stem Cells. Cancers. 2022; 14(3):673. https://doi.org/10.3390/cancers14030673
Chicago/Turabian StyleGaggianesi, Miriam, Laura Rosa Mangiapane, Chiara Modica, Vincenzo Davide Pantina, Gaetana Porcelli, Simone Di Franco, Melania Lo Iacono, Caterina D’Accardo, Francesco Verona, Irene Pillitteri, and et al. 2022. "Dual Inhibition of Myc Transcription and PI3K Activity Effectively Targets Colorectal Cancer Stem Cells" Cancers 14, no. 3: 673. https://doi.org/10.3390/cancers14030673