A PIK3CA-mutant breast cancer metastatic patient-derived organoid approach to evaluate alpelisib treatment for multiple secondary lesions

Donzelli, Sara; Cioce, Mario; Sacconi, Andrea; Zanconato, Francesca; Daralioti, Theodora; Goeman, Frauke; Orlandi, Giulia; Martino, Simona Di; Fazio, Vito Michele; Alessandrini, Gabriele; Telera, Stefano; Carosi, Mariantonia; Ciliberto, Gennaro; Botti, Claudio; Strano, Sabrina; Piccolo, Stefano; Blandino, Giovanni

doi:10.1186/s12943-022-01617-6

Cited by 15 publications

(11 citation statements)

References 17 publications

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“…This is reminiscent of the “molecular mimicry with the host tissue”, a property evoked in the past for the metastatic cells. 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 ].…”

Section: Discussionmentioning

confidence: 70%

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: 70%

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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“…We demonstrate that by undirected targeting of MYC-SPAG5 axis, we sensitize TNBC-PDTO to cisplatin treatment, eliciting reliable inhibition of cell viability. Nowadays, effective therapeutic model for drugs testing is one of the major challenges in the oncologic elds (35,46,47). Our TNBC-PDTO model, displays similar drugs response to TNBC cell lines, corroborating the relevance of our results and the potential of their clinical application.…”

Section: Discussionmentioning

confidence: 99%

“…To translate our ndings on three-dimensional (3D) system that simulate clinical behavior of tumoral cells, we used TNBC patients derived tumor organoids (TNBC-PDTOs) (33)(34)(35). RNA-seq analysis reveals similar expression levels of SPAG5, MYC, TP53, YAP1, G3BP1, XRCC6, CCT3, NME1 genes between parental tumoral tissues and TNBC-PDTO (Fig.…”

Section: Targeting Of Spag5 Expression Reduces Viability Of Patients ...mentioning

confidence: 99%

Targeting of Mutant-p53 and MYC as a novel strategy to inhibit oncogenic SPAG5 activity in triple negative breast cancer

Blandino,

Canu,

Vaccarella

et al. 2024

Preprint

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Triple negative breast cancer (TNBC) is an aggressive disease which currently has no effective therapeutic targets and prominent biomarkers. The Sperm Associated antigen 5 (SPAG5) is a mitotic spindle associated protein with oncogenic function in several human cancers. In TNBC, increased SPAG5 expression has been associated with tumor progression, chemoresistance, relapse, and poor clinical outcome. Here we show that high SPAG5 expression in TNBC is regulated by coordinated activity of YAP, mutant p53 and MYC. Depletion of YAP or mutant p53 proteins reduced SPAG5 expression and the recruitment of MYC onto SPAG5 promoter. Targeting of MYC also reduced SPAG5 expression and concomitantly tumorigenicity of TNBC cells. These effects of MYC targeting were synergized with cytotoxic chemotherapy and markedly reduced TNBC oncogenicity in SPAG5-expression dependent manner. These results suggest that mutant p53-MYC-SPAG5 expression can be considered as bona fide predictors of patient’s outcome, and reliable biomarkers for effective anticancer therapies.

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“…Thanks to organoid technology, the first cancer organoid or patient‐derived tumour organoids (PDTOs) was reported from colorectal cancer in 2011 29 . To date, various cancer organoids, including breast cancer, 30 bladder cancer, 31 gastric cancer, 32 oesophageal adenocarcinoma, 33 lung cancer 34 and renal cell carcinoma, 35 have been generated in the laboratory for fundamental researches. More importantly, cancer organoids using primary cancer cells have been reported to have higher similarity to the original tumours than the immortalized cancer cell lines and PDX models 36 .…”

Section: Organoid and Assembloid Technologymentioning

confidence: 99%

Tumour organoids and assembloids: Patient‐derived cancer avatars for immunotherapy

Mei,

Liu,

Tian

et al. 2024

Clinical & Translational Med

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BackgroundOrganoid technology is an emerging and rapidly growing field that shows promise in studying organ development and screening therapeutic regimens. Although organoids have been proposed for a decade, concerns exist, including batch‐to‐batch variations, lack of the native microenvironment and clinical applicability.Main bodyThe concept of organoids has derived patient‐derived tumour organoids (PDTOs) for personalized drug screening and new drug discovery, mitigating the risks of medication misuse. The greater the similarity between the PDTOs and the primary tumours, the more influential the model will be. Recently, ‘tumour assembloids’ inspired by cell‐coculture technology have attracted attention to complement the current PDTO technology. High‐quality PDTOs must reassemble critical components, including multiple cell types, tumour matrix, paracrine factors, angiogenesis and microorganisms. This review begins with a brief overview of the history of organoids and PDTOs, followed by the current approaches for generating PDTOs and tumour assembloids. Personalized drug screening has been practised; however, it remains unclear whether PDTOs can predict immunotherapies, including immune drugs (e.g. immune checkpoint inhibitors) and immune cells (e.g. tumour‐infiltrating lymphocyte, T cell receptor‐engineered T cell and chimeric antigen receptor‐T cell). PDTOs, as cancer avatars of the patients, can be expanded and stored to form a biobank.ConclusionFundamental research and clinical trials are ongoing, and the intention is to use these models to replace animals. Pre‐clinical immunotherapy screening using PDTOs will be beneficial to cancer patients.Key Points The current PDTO models have not yet constructed key cellular and non‐cellular components. PDTOs should be expandable and editable. PDTOs are promising preclinical models for immunotherapy unless mature PDTOs can be established. PDTO biobanks with consensual standards are urgently needed.

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A PIK3CA-mutant breast cancer metastatic patient-derived organoid approach to evaluate alpelisib treatment for multiple secondary lesions

Cited by 15 publications

References 17 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

Targeting of Mutant-p53 and MYC as a novel strategy to inhibit oncogenic SPAG5 activity in triple negative breast cancer

Tumour organoids and assembloids: Patient‐derived cancer avatars for immunotherapy

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