Targeting genome integrity dysfunctions impedes metastatic potency in non–small cell lung cancer circulating tumor cell–derived explants

Tayoun, Tala; Faugeroux, Vincent; Oulhen, Marianne; Déas, Olivier; Michels, Judith; Brullé-Soumaré, Laura; Cairo, Stefano; Scoazec, Jean‐Yves; Marty, Virginie; Aberlenc, Agathe; Planchard, David; Remón, Jordi; Ponce, Santiago; Besse, Benjamin; Kannouche, Patricia; Judde, Jean-Gabriel; Pawlikowska, Patrycja; Farace, Françoise

doi:10.1172/jci.insight.155804

Cited by 7 publications

(5 citation statements)

References 52 publications

(63 reference statements)

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“…An important criterion for successfully establishing CDX models from liquid biopsies has usually been a high initial extracted CTC count (≥400 CTCs) [ 11 , 18 , 33 , 34 , 35 ] with one recent exception wherein recently, a CDX model from a non-small lung cancer was established using only 35 EpCAM + CD45 − cells [ 36 ]. Unfortunately, patients with a high CTC count in peripheral blood are extremely rare as usually <10 cells/mL are present in the patient’s blood.…”

Section: Resultsmentioning

confidence: 99%

Propagated Circulating Tumor Cells Uncover the Potential Role of NFκB, EMT, and TGFβ Signaling Pathways and COP1 in Metastasis

Jian-yun

Sharma

Arab

et al. 2023

Cancers

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Circulating tumor cells (CTCs), a population of cancer cells that represent the seeds of metastatic nodules, are a promising model system for studying metastasis. However, the expansion of patient-derived CTCs ex vivo is challenging and dependent on the collection of high numbers of CTCs, which are ultra-rare. Here we report the development of a combined CTC and cultured CTC-derived xenograft (CDX) platform for expanding and studying patient-derived CTCs from metastatic colon, lung, and pancreatic cancers. The propagated CTCs yielded a highly aggressive population of cells that could be used to routinely and robustly establish primary tumors and metastatic lesions in CDXs. Differential gene analysis of the resultant CTC models emphasized a role for NF-κB, EMT, and TGFβ signaling as pan-cancer signaling pathways involved in metastasis. Furthermore, metastatic CTCs were identified through a prospective five-gene signature (BCAR1, COL1A1, IGSF3, RRAD, and TFPI2). Whole-exome sequencing of CDX models and metastases further identified mutations in constitutive photomorphogenesis protein 1 (COP1) as a potential driver of metastasis. These findings illustrate the utility of the combined patient-derived CTC model and provide a glimpse of the promise of CTCs in identifying drivers of cancer metastasis.

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Section: Resultsmentioning

confidence: 99%

Propagated Circulating Tumor Cells Uncover the Potential Role of NFκB, EMT, and TGFβ Signaling Pathways and COP1 in Metastasis

Jian-yun

Sharma

Arab

et al. 2023

Cancers

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“…The CDX and the derived cell line retained 16% of the primary tumour mutations, 56% of CTC mutations and 83% of primary tumour copy‐number aberrations 99 . In another study, researchers cultured three CDX models and one CDX‐derived cell line using CTCs from non‐small cell lung cancer patients, outlining patient tumour histology and response to platinum‐based chemotherapy, which mirrored the patient's clinical progression and reflected the patient's response 100 …”

Section: Pdtos and Assembloidsmentioning

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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“…Tala et al focused on DNA damage response (DDR) and genome integrity-related genes characterized in NSCLC CDXs. Key DDR-related mutations emerge from whole-exome sequencing analysis, including TP53 , BRCA2 , CHEK2 , and ARID1B , which might associate with CTC-mediated metastatic progression [ 52 ]. NGS of the SCLC CTC samples and CDX models observed more frequent copy number aberration (CNA) gains in chemorefractory CDXs and CTCs [ 38 ].…”

Section: Studying Ctcs and Ctc Clusters In Pdx And Pdomentioning

confidence: 99%

The functional and clinical roles of liquid biopsy in patient-derived models

Zhu

Shen

et al. 2023

J Hematol Oncol

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The liquid biopsy includes the detection of circulating tumor cells (CTCs) and CTC clusters in blood, as well as the detection of, cell-free DNA (cfDNA)/circulating tumor DNA (ctDNA) and extracellular vesicles (EVs) in the patient's body fluid. Liquid biopsy has important roles in translational research. But its clinical utility is still under investigation. Newly emerged patient-derived xenograft (PDX) and CTC-derived xenograft (CDX) faithfully recapitulate the genetic and morphological features of the donor patients’ tumor and patient-derived organoid (PDO) can mostly mimic tumor growth, tumor microenvironment and its response to drugs. In this review, we describe how the development of these patient-derived models has assisted the studies of CTCs and CTC clusters in terms of tumor biological behavior exploration, genomic analysis, and drug testing, with the help of the latest technology. We then summarize the studies of EVs and cfDNA/ctDNA in PDX and PDO models in early cancer diagnosis, tumor burden monitoring, drug test and response monitoring, and molecular profiling. The challenges faced and future perspectives of research related to liquid biopsy using patient-derived models are also discussed.

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Targeting genome integrity dysfunctions impedes metastatic potency in non–small cell lung cancer circulating tumor cell–derived explants

Cited by 7 publications

References 52 publications

Propagated Circulating Tumor Cells Uncover the Potential Role of NFκB, EMT, and TGFβ Signaling Pathways and COP1 in Metastasis

Propagated Circulating Tumor Cells Uncover the Potential Role of NFκB, EMT, and TGFβ Signaling Pathways and COP1 in Metastasis

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

The functional and clinical roles of liquid biopsy in patient-derived models

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