CRIPTO promotes an aggressive tumour phenotype and resistance to treatment in hepatocellular carcinoma

Karkampouna, Sofia; Helm, Danny van der; Gray, Peter C.; Chen, Lanpeng; Klima, Irena; Grosjean, Joël; Burgmans, Mark C.; Fariña-Sarasqueta, Arantza; Snaar‐Jagalska, Ewa; Stroka, Deborah; Terracciano, Luigi; Hoek, Bart van; Schaapherder, Alexander F.; Osanto, S.; Thalmann, George N.; Verspaget, Hein W.; Coenraad, Minneke J.; Julio, Marianna Kruithof-de

doi:10.1002/path.5083

Cited by 29 publications

(43 citation statements)

References 54 publications

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“…In our assay, we reduced variability by performing organoid seeding, formation, drug treatment and readout, sequentially in the same culture vessel without transfer of organoids or medium exchange. In addition to the organoid systems, we also cross-validated drug responses using cultured ex vivo tissue slices derived from the established PDXs, based on our previously developed methodology [47]. [48,49].…”

Section: Discussionmentioning

confidence: 99%

Patient-derived xenografts and organoids model therapy response in prostate cancer

Karkampouna

Manna

Filippo

et al. 2020

Preprint

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Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe a novel androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa).RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbours BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modelled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX-and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds.This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds. Conflict of interest and Disclosure Statement:The authors declare no conflict of interest.

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Section: Discussionmentioning

confidence: 99%

Patient-derived xenografts and organoids model therapy response in prostate cancer

Karkampouna

Manna

Filippo

et al. 2020

Preprint

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“…Hepatocellular carcinoma (HCC) has been one of the cancers with the highest probability of mortality. 1,2 Recently, a lot of proteins have been reported as HCC biomarkers or therapeutic targets, including Forkhead box protein A1 (FOXA1) and Anterior gradient homolog 2 (AGR2). As a transcriptional activator for liverspecific transcripts, FOXA1 plays a key role in proliferation, apoptosis and cell cycle.…”

Section: Introductionmentioning

confidence: 99%

<p>FOXA1 Promotes Cell Proliferation and Suppresses Apoptosis in HCC by Directly Regulating miR-212-3p/FOXA1/AGR2 Signaling Pathway</p>

Yuan¹,

Ye²,

Qie³

et al. 2020

OTT

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Background: Forkhead box protein A1 (FOXA1), acting as a transcriptional activator for liver-specific transcripts, plays a vital part in proliferation, apoptosis and cell cycle. Methods: The mRNA expression of FOXA1 in 90 HCC tissues and matched adjacent nontumor tissues was determined by qRT-PCR. The downstream and upstream regulators of FOXA1 were identified by bioinformatics analysis and experimental confirmation. Results: We found out that the expression of FOXA1 was obviously higher in hepatocellular carcinoma (HCC) tissues than that in matched non-tumor tissues. Similarly, FOXA1 is also highly expressed in HCC cell lines as compared with normal human hepatic cell line L02. Clinical association analysis indicated that high expression of FOXA1 was prominently correlated with high HBV level, large tumor size, high venous infiltration, high Edmondson-Steiner grading, and advanced tumor-node-metastasis tumor stage. Furthermore, the in vitro tests showed that ectopic expression of FOXA1 promoted HepG2 cell proliferation and suppressed apoptosis. In contrast, the downregulation of FOXA1 inhibited cell proliferation, and induced apoptosis in Hep3B cells. To investigate the functional mechanism of FOXA1, anterior gradient 2 (AGR2), an executor in proliferation and apoptosis, was identified as the direct target gene of FOXA1. Meanwhile, we also found the expression of FOXA1 could be inhibited by miR-212-3p, which working as a tumor suppressor downregulated in HCC. Conclusion: We revealed that FOXA1 exerted its biological function by regulating AGR2 expression, and its ectopic expression may be blamed for low expression of miR-212-3p.

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“…Digestive system cancers Hepatocellular carcinoma. Hepatocellular carcinoma is the third most common type of cancer globally (25)(26)(27). Hepatitis B and C virus infections are considered to be the main causes of hepatocellular carcinoma, which can also be caused by non-alcoholic liver disease or alcohol abuse (28).…”

Section: Mir-33a and Its Role In Cancermentioning

confidence: 99%

Role of microRNA‑33a in malignant cells (Review)

et al. 2020

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Cancer causes most of the mortality and morbidity worldwide, with a significant increase in incidence during recent years. MicroRNAs (miRNAs/miRs) are non-coding small RNAs capable of regulating gene expression. They regulate crucial cellular processes, including proliferation, differentiation, metastasis and apoptosis. Therefore, abnormal miRNA expression is associated with multiple diseases, including cancer. There are two types of cancer-associated miRNAs, oncogenic and tumor suppressor miRNAs, depending on their roles and expression patterns in cancer. Accordingly, miRNAs are considered to be targets for cancer prevention and treatment. miR-33a controls cellular cholesterol uptake and synthesis, which are both closely associated with carcinogenesis. The present review thoroughly describes the roles of miR-33a in more than a dozen types of cancer and the underlying mechanisms. Accordingly, the present review may serve as a guide for researchers studying the involvement of miR-33a in diverse cancer settings. Contents 1. Introduction 2. miR-33a and its role in cancer 3. Discussion 4. Conclusions

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CRIPTO promotes an aggressive tumour phenotype and resistance to treatment in hepatocellular carcinoma

Cited by 29 publications

References 54 publications

Patient-derived xenografts and organoids model therapy response in prostate cancer

Patient-derived xenografts and organoids model therapy response in prostate cancer

<p>FOXA1 Promotes Cell Proliferation and Suppresses Apoptosis in HCC by Directly Regulating miR-212-3p/FOXA1/AGR2 Signaling Pathway</p>

Role of microRNA‑33a in malignant cells (Review)

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