Patient-Derived Colorectal Cancer Organoids Upregulate Revival Stem Cell Marker Genes following Chemotherapeutic Treatment

Engel, Rebekah; Chan, Wing Man; Nickless, David; Hlavca, Sara; Richards, Elizabeth; Kerr, Genevieve; Oliva, Karen; McMurrick, Paul; Jardé, Thierry; Abud, Helen E.

doi:10.3390/jcm9010128

Cited by 39 publications

(42 citation statements)

References 42 publications

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“…Tumoroids permit a faster culturing method, amenable to multiplexing a wider range of analysis tools in a pre-clinical setting. Several studies have shown promising results of tumoroid cultures mimicking histological morphology and drug responses across multiple cancer types [11][12][13][14][15]. However, a thorough analysis of the shifting stromal cell populations and the resulting effects on cancer cell behavior as a product of the culturing method have yet to be thoroughly investigated.…”

Section: Introductionmentioning

confidence: 99%

Comparative Molecular Analysis of Cancer Behavior Cultured In Vitro, In Vivo, and Ex Vivo

Hum

Sebastian

Gilmore

et al. 2020

Cancers

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Current pre-clinical models of cancer fail to recapitulate the cancer cell behavior in primary tumors primarily because of the lack of a deeper understanding of the effects that the microenvironment has on cancer cell phenotype. Transcriptomic profiling of 4T1 murine mammary carcinoma cells from 2D and 3D cultures, subcutaneous or orthotopic allografts (from immunocompetent or immunodeficient mice), as well as ex vivo tumoroids, revealed differences in molecular signatures including altered expression of genes involved in cell cycle progression, cell signaling and extracellular matrix remodeling. The 3D culture platforms had more in vivo-like transcriptional profiles than 2D cultures. In vivo tumors had more cells undergoing epithelial-to-mesenchymal transition (EMT) while in vitro cultures had cells residing primarily in an epithelial or mesenchymal state. Ex vivo tumoroids incorporated aspects of in vivo and in vitro culturing, retaining higher abundance of cells undergoing EMT while shifting cancer cell fate towards a more mesenchymal state. Cellular heterogeneity surveyed by scRNA-seq revealed that ex vivo tumoroids, while rapidly expanding cancer and fibroblast populations, lose a significant proportion of immune components. This study emphasizes the need to improve in vitro culture systems and preserve syngeneic-like tumor composition by maintaining similar EMT heterogeneity as well as inclusion of stromal subpopulations.

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Section: Introductionmentioning

confidence: 99%

Comparative Molecular Analysis of Cancer Behavior Cultured In Vitro, In Vivo, and Ex Vivo

Hum

Sebastian

Gilmore

et al. 2020

Cancers

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“…[44][45][46][47][48] Stem cell markers Prognosis 'Stem cell signature' on cancer cells is associated with more aggressive tumors and predicts disease relapse. [49][50][51][52][53][54][55][56][57][58] ctDNA and cfDNA Prognosis ctDNA in blood tests could be used to predict whether a patient would relapse following surgical resection. cfDNA in blood tests could predict shorter overall survival and inferior recurrence free survival.…”

Section: Cimp Prognosismentioning

confidence: 99%

“…The ability of differentiated cancer cells to form metastases and re-establish the cellular hierarchy highlights the need to target endogenous cellular plasticity in order to inactivate metastatic potential. More recently, following the identification of a novel stem cell population it was shown that a marker of the revival stem cell population, Clusterin, may predict resistance to 5-FU based chemotherapies; however, these preliminary observations require further validation [58]. Targeting the CSC population in mCRC represents a powerful strategy for future treatments, however, a robust biomarker that can be utilized in the clinic is yet to be developed.…”

Section: Stem Cell Markersmentioning

confidence: 99%

“…These features allow tumor organoids to recapitulate the cellular heterogeneity of patient tumors at a greater level than traditional models [212][213][214][215][216][217][218]. Tumor organoid technology is recognized for generating reproducible, high quality drug sensitivity data and can be highly effective in identifying and evaluating biomarkers that underpin drug sensitivity [58]. There is also significant potential for discovery of novel combinatorial drug treatments and repurposing of drugs with previously unknown therapeutic benefit with organoid technology amenable to high-throughput screening [213,219].…”

Section: Future Directionsmentioning

confidence: 99%

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Personalized Medicine—Current and Emerging Predictive and Prognostic Biomarkers in Colorectal Cancer

Koulis

Yap

Engel

et al. 2020

Cancers

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Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide and is heterogeneous both morphologically and molecularly. In an era of personalized medicine, the greatest challenge is to predict individual response to therapy and distinguish patients likely to be cured with surgical resection of tumors and systemic therapy from those resistant or non-responsive to treatment. Patients would avoid futile treatments, including clinical trial regimes and ultimately this would prevent under- and over-treatment and reduce unnecessary adverse side effects. In this review, the potential of specific biomarkers will be explored to address two key questions—1) Can the prognosis of patients that will fare well or poorly be determined beyond currently recognized prognostic indicators? and 2) Can an individual patient’s response to therapy be predicted and those who will most likely benefit from treatment/s be identified? Identifying and validating key prognostic and predictive biomarkers and an understanding of the underlying mechanisms of drug resistance and toxicity in CRC are important steps in order to personalize treatment. This review addresses recent data on biological prognostic and predictive biomarkers in CRC. In addition, patient cohorts most likely to benefit from currently available systemic treatments and/or targeted therapies are discussed in this review.

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“…These cells are present in proportions and a relative spatial arrangement that imitates what is observed in vivo. Since hiOs functionally mimic normal human gastrointestinal tract physiology and pathophysiology [151], they represent an effective platform to study human gastrointestinal functions and diseases [154] and are already being successfully employed to model epithelial barrier function [155,156], nutrient transport physiology during digestion [157], celiac disease [158], inflammatory bowel disease [159], and cancer [160][161][162][163]. hiOs provide unprecedented opportunities for the generation of in vitro systems with a sufficient level of complexity to model physiological and pathological diet-microbiome-host conditions [164,165] and pathogen-host interactions [72,155,[166][167][168][169][170][171][172][173][174][175].…”

Section: Human Intestinal Organoidsmentioning

confidence: 99%

Links between Nutrition, Infectious Diseases, and Microbiota: Emerging Technologies and Opportunities for Human-Focused Research

et al. 2020

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The interaction between nutrition and human infectious diseases has always been recognized. With the emergence of molecular tools and post-genomics, high-resolution sequencing technologies, the gut microbiota has been emerging as a key moderator in the complex interplay between nutrients, human body, and infections. Much of the host–microbial and nutrition research is currently based on animals or simplistic in vitro models. Although traditional in vivo and in vitro models have helped to develop mechanistic hypotheses and assess the causality of the host–microbiota interactions, they often fail to faithfully recapitulate the complexity of the human nutrient–microbiome axis in gastrointestinal homeostasis and infections. Over the last decade, remarkable progress in tissue engineering, stem cell biology, microfluidics, sequencing technologies, and computing power has taken place, which has produced a new generation of human-focused, relevant, and predictive tools. These tools, which include patient-derived organoids, organs-on-a-chip, computational analyses, and models, together with multi-omics readouts, represent novel and exciting equipment to advance the research into microbiota, infectious diseases, and nutrition from a human-biology-based perspective. After considering some limitations of the conventional in vivo and in vitro approaches, in this review, we present the main novel available and emerging tools that are suitable for designing human-oriented research.

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Patient-Derived Colorectal Cancer Organoids Upregulate Revival Stem Cell Marker Genes following Chemotherapeutic Treatment

Cited by 39 publications

References 42 publications

Comparative Molecular Analysis of Cancer Behavior Cultured In Vitro, In Vivo, and Ex Vivo

Comparative Molecular Analysis of Cancer Behavior Cultured In Vitro, In Vivo, and Ex Vivo

Personalized Medicine—Current and Emerging Predictive and Prognostic Biomarkers in Colorectal Cancer

Links between Nutrition, Infectious Diseases, and Microbiota: Emerging Technologies and Opportunities for Human-Focused Research

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