Breast cancer metastasis: Is it a matter of OMICS and proper ex-vivo models?

Cioce, Mario; Sacconi, Andrea; Donzelli, Sara; Bonomo, C.; Perracchio, Letizia; Carosi, Mariantonia; Telera, Stefano; Fazio, Vito Michele; Botti, Claudio; Strano, Sabrina; Blandino, Giovanni

doi:10.1016/j.csbj.2022.07.044

Cited by 4 publications

(3 citation statements)

References 60 publications

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“…Still in line with this, we recently found that, adding host tissue- specific factors, greatly facilitated the propagation of metastatic breast cancer PDOs [ 55 ]. We also observed, when comparing frank metastatic lesions with matched primary CRCs, that the genomic difference between the primary tumor and metastatic material could be inadequate to explain the heterogeneity in disease progression [ 56 ]. Both of those latter experimental observations suggest a high dependency of the metastatic cells from signaling of the host, unaffected tissue, which goes beyond the genomic similarity with the primary tumor and may rely on host tissue factors.…”

Section: Discussionmentioning

confidence: 99%

Interrogating colorectal cancer metastasis to liver: a search for clinically viable compounds and mechanistic insights in colorectal cancer Patient Derived Organoids

Cioce

Fumagalli

Donzelli

et al. 2023

J Exp Clin Cancer Res

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Background Approximately 20–50% of patients presenting with localized colorectal cancer progress to stage IV metastatic disease (mCRC) following initial treatment and this is a major prognostic determinant. Here, we have interrogated a heterogeneous set of primary colorectal cancer (CRC), liver CRC metastases and adjacent liver tissue to identify molecular determinants of the colon to liver spreading. Screening Food and Drug Administration (FDA) approved drugs for their ability to interfere with an identified colon to liver metastasis signature may help filling an unmet therapeutic need. Methods RNA sequencing of primary colorectal cancer specimens vs adjacent liver tissue vs synchronous and asynchronous liver metastases. Pathways enrichment analyses. The Library of Integrated Network-based Cellular Signatures (LINCS)-based and Connectivity Map (CMAP)-mediated identification of FDA-approved compounds capable to interfere with a 22 gene signature from primary CRC and liver metastases. Testing the identified compounds on CRC-Patient Derived Organoid (PDO) cultures. Microscopy and Fluorescence Activated Cell Sorting (FACS) based analysis of the treated PDOs. Results We have found that liver metastases acquire features of the adjacent liver tissue while partially losing those of the primary tumors they derived from. We have identified a 22-gene signature differentially expressed among primary tumors and metastases and validated in public databases. A pharmacogenomic screening for FDA-approved compounds capable of interfering with this signature has been performed. We have validated some of the identified representative compounds in CRC-Patient Derived Organoid cultures (PDOs) and found that pentoxyfilline and, to a minor extent, dexketoprofen and desloratadine, can variably interfere with number, size and viability of the CRC –PDOs in a patient-specific way. We explored the pentoxifylline mechanism of action and found that pentoxifylline treatment attenuated the 5-FU elicited increase of ALDHhigh cells by attenuating the IL-6 mediated STAT3 (tyr705) phosphorylation. Conclusions Pentoxifylline synergizes with 5-Fluorouracil (5-FU) in attenuating organoid formation. It does so by interfering with an IL-6-STAT3 axis leading to the emergence of chemoresistant ALDHhigh cell subpopulations in 5-FU treated PDOs. A larger cohort of CRC-PDOs will be required to validate and expand on the findings of this proof-of-concept study.

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Section: Discussionmentioning

confidence: 99%

Interrogating colorectal cancer metastasis to liver: a search for clinically viable compounds and mechanistic insights in colorectal cancer Patient Derived Organoids

Cioce

Fumagalli

Donzelli

et al. 2023

J Exp Clin Cancer Res

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“…The accumulated knowledge on the genomics of breast cancer over the last decade has significantly increased the understanding of intratumoural heterogeneity, which is now considered to be a driving force for cancer progression. In this context, the knowledge and understanding of metastatic breast cancer is somewhat behind that of primary cancer [105].…”

Section: Discussionmentioning

confidence: 99%

Organ-Specificity of Breast Cancer Metastasis

Ibragimova,

Tsyganov,

Kravtsova

et al. 2023

IJMS

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Breast cancer (BC) remains one of the most common malignancies among women worldwide. Breast cancer shows metastatic heterogeneity with priority to different organs, which leads to differences in prognosis and response to therapy among patients. The main targets for metastasis in BC are the bone, lung, liver and brain. The molecular mechanism of BC organ-specificity is still under investigation. In recent years, the appearance of new genomic approaches has led to unprecedented changes in the understanding of breast cancer metastasis organ-specificity and has provided a new platform for the development of more effective therapeutic agents. This review summarises recent data on molecular organ-specific markers of metastasis as the basis of a possible therapeutic approach in order to improve the diagnosis and prognosis of patients with metastatically heterogeneous breast cancer.

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“…1 ). We have recently shown that organoids derived from breast cancer metastatic lesions carrying PIK3CA mutations can be efficaciously treated with PI3K-a inhibitor, Alpelisib irrespective of the metastatic site [ 1 , 2 ]. This unique 3D-preclinical platform has proven to mostly recapitulate the genomic alterations and gene expression patterns of the originating metastatic tissue; thereby providing a robust cancer surrogate to test the impact of miRNA/mRNA networks in the metastatization process and unveil new metastatic targets to be tacklen therapeutically.…”

Section: Exploring Mirnas/mrnas Network In Breast Cancer Progressionmentioning

confidence: 99%

The new world of RNA diagnostics and therapeutics

Blandino

Dinami

Marcia

et al. 2023

J Exp Clin Cancer Res

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The 5th Workshop IRE on Translational Oncology was held in Rome (Italy) on 27–28 March at the IRCCS Regina Elena National Cancer Institute. This meeting entitled “The New World of RNA diagnostics and therapeutics” highlightes the significant progress in the RNA field made over the last years. Research moved from pure discovery towards the development of diagnostic biomarkers or RNA-base targeted therapies seeking validation in several clinical trials. Non-coding RNAs in particular have been the focus of this workshop due to their unique properties that make them attractive tools for the diagnosis and therapy of cancer.This report collected the presentations of many scientists from different institutions that discussed recent oncology research providing an excellent overview and representative examples for each possible application of RNA as biomarker, for therapy or to increase the number of patients that can benefit from precision oncology treatment.In particular, the meeting specifically emphasized two key features of RNA applications: RNA diagnostic (Blandino, Palcau, Sestito, Díaz Méndez, Cappelletto, Pulito, Monteonofrio, Calin, Sozzi, Cheong) and RNA therapeutics (Dinami, Marcia, Anastasiadou, Ryan, Fattore, Regazzo, Loria, Aharonov).

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Breast cancer metastasis: Is it a matter of OMICS and proper ex-vivo models?

Cited by 4 publications

References 60 publications

Interrogating colorectal cancer metastasis to liver: a search for clinically viable compounds and mechanistic insights in colorectal cancer Patient Derived Organoids

Interrogating colorectal cancer metastasis to liver: a search for clinically viable compounds and mechanistic insights in colorectal cancer Patient Derived Organoids

Organ-Specificity of Breast Cancer Metastasis

The new world of RNA diagnostics and therapeutics

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