Patient‐Derived Organoids as Therapy Screening Platforms in Cancer Patients

Khorsandi, Danial; Yang, Jia‐Wei; Foster, Samuel; Khosravi, Safoora; Hosseinzadeh Kouchehbaghi, Negar; Zarei, Fahimeh; Lee, Yun Bin; Runa, Farhana; Gangrade, Ankit; Voskanian, Leon; Adnan, Darbaz; Zhu, Yangzhi; Wang, Zhaohui; Jucaud, Vadim; Dokmeci, Mehmet Remzi; Shen, Xiling; Bishehsari, Faraz; Kelber, Jonathan A.; Khademhosseini, Ali; de Barros, Natan Roberto

doi:10.1002/adhm.202302331

Cited by 3 publications

(1 citation statement)

References 112 publications

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“…Indeed, PDOs can accurately represent the genomic landscape of their source in terms of mutation rates, DNA methylation patterns, gene expression signatures, and copy number variations [13]. This makes PDOs clinically relevant tools for disease modelling towards predictive drug screening [14,15]. Cocultures of PDOs with components of the tumour microenvironment (TME) (i.e., cancer-associated fibroblasts, CAFs) can provide important information, as CAFs represent a large cell subpopulation of the TME that is actively involved in tumour progression/tumour resistance [16].…”

Section: Introductionmentioning

confidence: 99%

Mesothelioma-Associated Fibroblasts Modulate the Response of Mesothelioma Patient-Derived Organoids to Chemotherapy via Interleukin-6

Cioce,

Gatti,

Napolitano

et al. 2024

IJMS

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Malignant pleural mesothelioma (MPM) remains an incurable disease. This is partly due to the lack of experimental models that fully recapitulate the complexity and heterogeneity of MPM, a major challenge for therapeutic management of the disease. In addition, the contribution of the MPM microenvironment is relevant for the adaptive response to therapy. We established mesothelioma patient-derived organoid (mPDO) cultures from MPM pleural effusions and tested their response to pemetrexed and cisplatin. We aimed to evaluate the contribution of mesothelioma-associated fibroblasts (MAFs) to the response to pemetrexed and cisplatin (P+C). Organoid cultures were obtained from eight MPM patients using specific growth media and conditions to expand pleural effusion-derived cells. Flow cytometry was used to verify the similarity of the organoid cultures to the original samples. MAFs were isolated and co-cultured with mPDOs, and the addition of MAFs reduced the sensitivity of mPDOs to P+C. Organoid formation and expression of cancer stem cell markers such as ABCG2, NANOG, and CD44 were altered by conditioned media from treated MAFs. We identified IL-6 as the major contributor to the attenuated response to chemotherapy. IL-6 secretion by MAFs is correlated with increased resistance of mPDOs to pemetrexed and cisplatin.

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Section: Introductionmentioning

confidence: 99%

Mesothelioma-Associated Fibroblasts Modulate the Response of Mesothelioma Patient-Derived Organoids to Chemotherapy via Interleukin-6

Cioce,

Gatti,

Napolitano

et al. 2024

IJMS

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Advancing diagnostics and disease modeling: current concepts in biofabrication of soft microfluidic systems

Casanova,

Reis

et al. 2024

In vitro models

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Soft microfluidic systems play a pivotal role in personalized medicine, particularly in in vitro diagnostics tools and disease modeling. These systems offer unprecedented precision and versatility, enabling the creation of intricate three-dimensional (3D) tissue models that can closely emulate both physiological and pathophysiological conditions. By leveraging innovative biomaterials and bioinks, soft microfluidic systems can circumvent the current limitations involving the use of polydimethylsiloxane (PDMS), thus facilitating the development of customizable systems capable of sustaining the functions of encapsulated cells and mimicking complex biological microenvironments. The integration of lab-on-a-chip technologies with soft nanodevices further enhances disease models, paving the way for tailored therapeutic strategies. The current research concepts underscore the transformative potential of soft microfluidic systems, exemplified by recent breakthroughs in soft lithography and 3D (bio)printing. Novel applications, such as multi-layered tissues-on-chips and skin-on-a-chip devices, demonstrate significant advancements in disease modeling and personalized medicine. However, further exploration is warranted to address challenges in replicating intricate tissue structures while ensuring scalability and reproducibility. This exploration promises to drive innovation in biomedical research and healthcare, thus offering new insights and solutions to complex medical challenges and unmet needs.

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Microphysiological system modeling pericyte-induced temozolomide resistance in glioblastoma

Maity,

Jewell,

Yilgor

et al. 2024

Preprint

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Glioblastoma (GBM) is a malignancy with poor survival and high rates of chemoresistance. Temozolomide (TMZ), the standard-of-care chemotherapy for GBM patients, but GBM cells can be resistant to TMZ, resulting in limited clinical efficacy. Elucidating the complex mechanisms of TMZ chemoresistance in GBM requires novel in vitro models replicating the complex tumor microenvironment (TME). We present an multicellular 3D GBM model recapitulating the biomechanical characteristics of brain tissues and pericyte-mediated TMZ resistance. The composite hydrogel used to encapsulate GBM spheroids (U87, LN229, and PDM140), pericytes, or GBM spheroids with pericytes, mimics the rheological properties of brain tissues. When untreated, the GBM models remain viable and proliferative for 14 days. PDM140 spheroids were most sensitive to TMZ (IC50=73μM), followed by LN229 (IC50=278μM) and U87 (IC50=446μM). With pericytes, the viability of TMZ-treated GBM spheroids significantly increases by 22.7% for PDM140, 32.5% for LN229, and 22.1% for U87, confirming pericyte-induced GBM chemoresistance responses. The upregulation (380-fold) of C-C motif chemokine ligand 5 (CCL5) in pericytes upon TMZ treatment could explain the chemoresistance responses. This innovative brain-mimicking 3D GBM model represents a novel in vitro platform for testing the efficacy of TMZ and novel drugs targeting CCL5-mediated chemoresistance pathways in GBM.

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Patient‐Derived Organoids as Therapy Screening Platforms in Cancer Patients

Cited by 3 publications

References 112 publications

Mesothelioma-Associated Fibroblasts Modulate the Response of Mesothelioma Patient-Derived Organoids to Chemotherapy via Interleukin-6

Mesothelioma-Associated Fibroblasts Modulate the Response of Mesothelioma Patient-Derived Organoids to Chemotherapy via Interleukin-6

Advancing diagnostics and disease modeling: current concepts in biofabrication of soft microfluidic systems

Microphysiological system modeling pericyte-induced temozolomide resistance in glioblastoma

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