Stromal contribution to the colorectal cancer transcriptome

Isella, Claudio; Terrasi, Andrea; Bellomo, Sara E.; Petti, Consalvo; Galatola, G.; Muratore, Andrea; Mellano, Alfredo; Senetta, Rebecca; Cassenti, Adele; Sonetto, Cristina; Inghirami, Giorgio; Trusolino, Livio; Fekete, Zsolt; Ridder, Mark De; Cassoni, Paola; Storme, Guy; Bertotti, Andrea; Medico, Enzo

doi:10.1038/ng.3224

Cited by 554 publications

(655 citation statements)

References 57 publications

(76 reference statements)

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“…As a consequence of this substitution, species-specific RNA sequencing-based expression profiling of PDXs offers a unique opportunity to distinguish mouse stroma-derived transcripts from human cancer cell-derived transcripts without the need to physically separate the two components before RNA extraction. Such analyses led to the identification of stromal-associated transcriptional signatures in colorectal cancer associated with poor prognosis and treatment resistance 156 . The negative prognostic significance of tumour stromal transcriptional signatures and their value for therapeutic decision-making and patient follow-up have also been described in other reports 157,158 .…”

Section: Modelling Metastatic Disease Subcutaneous Transplantation Umentioning

confidence: 99%

“…Athough both stromal and immune components are replaced over time by murine analogues, the haematopoietic elements show important differences in their spatial distribution 167 or may be missing overall 156,168 . This affects the signal received from molecular profiling, and could require application of specific algorithms for signal correction to avoid or reduce artefacts and biases 156,169 . …”

Section: Main Objectivesmentioning

confidence: 99%

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Interrogating open issues in cancer precision medicine with patient-derived xenografts

et al. 2017

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Patient-derived xenografts (PDXs) have emerged as an important platform to elucidate new treatments and biomarkers in oncology. PDX models are used to address clinically relevant questions, including the contribution of tumour heterogeneity to therapeutic responsiveness, the patterns of cancer evolutionary dynamics during tumour progression and under drug pressure, and the mechanisms of resistance to treatment. The ability of PDX models to predict clinical outcomes is being improved through mouse humanization strategies and implementation of co-clinical trials, within which patients and PDXs reciprocally inform therapeutic decisions. This Opinion article discusses aspects of PDX modelling that are relevant to these questions and highlights the merits of shared PDX resources to advance cancer medicine from the 6 perspective of EurOPDX, an international initiative devoted to PDX-based research.Response to anticancer therapies varies owing to the substantial molecular heterogeneity of human tumours and to poorly defined mechanisms of drug efficacy and resistance 1 . Immortalized cancer cell lines, either cultured in vitro or grown as xenografts, cannot interrogate the complexity of human tumours, and only provide determinate insights into human disease, as they are limited in number and diversity, and have been cultured on plastic over decades 2 .This disconnection in scale and biological accuracy contributes considerably to attrition in drug development [3][4][5] .Surgically derived clinical tumour samples that are implanted in mice (known as patient-derived xenografts (PDXs)) are expected to better inform therapeutic development strategies. As intact tissue -in which the tumour architecture and the relative proportion of cancer cells and stromal cells are both maintained -is directly implanted into recipient animals, the alignment with human disease is enhanced. More importantly, PDXs retain the idiosyncratic characteristics of different tumours from different patients; hence, they can effectively recapitulate the intra-tumour and inter-tumour heterogeneity that typifies human cancer 6-9 . 7 Exhaustive information on the key characteristics and the practical applications of PDXs can be found in recent reviews [10][11][12][13] . In this Opinion article, we discuss basic methodological concepts, as well as challenges and opportunities in developing "next-generation" models to improve the reach of PDXs as preclinical tools for in vivo studies (TABLE 1). We also elaborate on the merits of PDXs for exploring the intrinsic heterogeneity and subclonal genetic evolution of individual tumours, and discuss how this may influence therapeutic resistance. Finally, we examine the utility of PDXs in navigating complex variables in clinical decision-making, such as the discovery of predictive and prognostic biomarkers, and the categorization of genotype-drug response correlations in high-throughput formats. Being primarily co-authored by leading members of the EurOPDX Consortium (see Further information), we provide...

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Section: Modelling Metastatic Disease Subcutaneous Transplantation Umentioning

confidence: 99%

Section: Main Objectivesmentioning

confidence: 99%

Interrogating open issues in cancer precision medicine with patient-derived xenografts

et al. 2017

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“…Stroma-derived factors have long been known to influence cancer progression (1), and the importance of the microenvironment for molecular classification of colorectal cancer tumors has been confirmed (2,3). These studies highlight the influence of the nonneoplastic component of the tumor on patient prognosis.…”

Section: Introductionmentioning

confidence: 96%

Immune-Derived PD-L1 Gene Expression Defines a Subgroup of Stage II/III Colorectal Cancer Patients with Favorable Prognosis Who May Be Harmed by Adjuvant Chemotherapy

Dunne

McArt

O’Reilly

et al. 2016

Cancer Immunology Research

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A recent phase II study of patients with metastatic colorectal carcinoma showed that mismatch repair gene status was predictive of clinical response to PD-1-targeting immune checkpoint blockade. Further examination revealed strong correlation between PD-L1 protein expression and microsatellite instability (MSI) in stage IV colorectal carcinoma, suggesting that the amount of PD-L1 protein expression could identify late-stage patients who might benefit from immunotherapy. To assess whether the clinical associations between PD-L1 gene expression and MSI identified in metastatic colorectal carcinoma are also present in stage II/III colorectal carcinoma, we used in silico analysis to elucidate the cell types expressing the PD-L1 gene. We found a statistically significant association of PD-L1 gene expression with MSI in early-stage colorectal carcinoma (P < 0.001) and show that, unlike in non-colorectal carcinoma tumors, PD-L1 is derived predominantly from the immune infiltrate. We demonstrate that PD-L1 gene expression has positive prognostic value in the adjuvant disease setting (PD-L1 low vs. PD-L1 high HR ¼ 9.09; CI, 2.11-39.10). PD-L1 gene expression had predictive value, as patients with high PD-L1 expression appear to be harmed by standard-of-care treatment (HR ¼ 4.95; CI, 1.10-22.35). Building on the promising results from the metastatic colorectal carcinoma PD-1-targeting trial, we provide compelling evidence that patients with PD-L1 high /MSI/ immune high stage II/III colorectal carcinoma should not receive standard chemotherapy. This conclusion supports the rationale to clinically evaluate this patient subgroup for PD-1 blockade treatment.

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“…Two very recent publications demonstrate the important contribution of the cancer stroma to the variable molecular signature seen in different CRC subtypes. Both studies independently show that each of the stromal tissue elements (cancer‐associated fibroblasts, infiltrating immunocytes, and endothelial cells) contributes more towards poor prognosis molecular signatures than the cancer epithelium itself 48, 49. In these poor prognosis tumours, stromal molecular signatures were also associated with a poor response to radiotherapy in rectal cancer, indicating the important influence of the tumour microenvironment on cancer epithelial cell behaviour and response to treatment.…”

Section: Genetic and Environmental Interaction And Crc Heterogeneitymentioning

confidence: 98%

Microenvironmental control of stem cell fate in intestinal homeostasis and disease

Biswas

Belnoue-Davis

Irshad

et al. 2015

The Journal of Pathology

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The conventional model of intestinal epithelial architecture describes a unidirectional tissue organizational hierarchy with stem cells situated at the crypt base and daughter cells proliferating and terminally differentiating as they progress along the vertical (crypt–luminal) axis. In this model, the fate of a cell that has left the niche is determined and its lifespan limited. Evidence is accumulating to suggest that stem cell control and daughter cell fate determination is not solely an intrinsic, cell autonomous property but is heavily influenced by the microenvironment including paracrine, mesenchymal, and endogenous epithelial morphogen gradients. Recent research suggests that in intestinal homeostasis, stem cells transit reversibly between states of variable competence in the niche. Furthermore, selective pressures that disrupt the homeostatic balance, such as intestinal inflammation or morphogen dysregulation, can cause committed progenitor cells and even some differentiated cells to regain stem cell properties. Importantly, it has been recently shown that this disruption of cell fate determination can lead to somatic mutation and neoplastic transformation of cells situated outside the crypt base stem cell niche. This paper reviews the exciting developments in the study of stem cell dynamics in homeostasis, intestinal regeneration, and carcinogenesis, and explores the implications for human disease and cancer therapies. © 2015 Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Stromal contribution to the colorectal cancer transcriptome

Cited by 554 publications

References 57 publications

Interrogating open issues in cancer precision medicine with patient-derived xenografts

Interrogating open issues in cancer precision medicine with patient-derived xenografts

Immune-Derived PD-L1 Gene Expression Defines a Subgroup of Stage II/III Colorectal Cancer Patients with Favorable Prognosis Who May Be Harmed by Adjuvant Chemotherapy

Microenvironmental control of stem cell fate in intestinal homeostasis and disease

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