Whole-organ analysis of TGF-b-mediated remodelling of the tumour microenvironment
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE153468 | GEO | 2021/03/10
REPOSITORIES: GEO
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Project description:Inter- and intra-tumour heterogeneity of breast cancer might be one of the reasons that develops endocrine therapy resistance. Here, we conduct an integrated scRNA-seq and scATAC-seq analysis of ~80K breast tissue cells from two normal (NTs), three primary (PTs) and three tamoxifen-treated recurrent tumour tissues (RTs). We identify distinct cell types among breast tumour tissues and observe a striking level of cell-to-cell heterogeneity among six tumuor tissues and delineates the primary to recurrent tumour progression, underscoring the significance of these single-cell level tumour cell clusters classified from scRNA-seq data. We then define nine cancer cell states (CSs), including five PT-specific, three RT-specific and one PT-RT-shared CSs and identify a heterogeneity-guided core signature. We further identify distinct open chromatin regions and specific transcription factors (TFs) associated with cancer cell states as well as novel biological pathways that mediate their communications with the tumour microenvironment. We finally in silico characterize the core signature and in vitro functionally examine the role of one of core signature, BMP7 suggesting that it plays an oncogenic role in tamoxifen-resistant breast cancer cells, and could be a promising therapeutic target in treating endocrine resistant breast cancer. We envision this integrated single-cell epigenomic and transcriptomic measure will become a powerful approach to unravel how epigenetic factors and tumour microenvironment govern the development of tumour heterogeneity and to uncover potential therapeutic targets that circumvent heterogeneity-related failures.
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Project description:Mouse tumour organoids (MTOs) derived from a compound mutant (LAKTP) intestinal cancer model were orthoptopically transplanted into syngeneic C57BL/6J mice. Tumour-bearing mice were treated with TGF-beta inhibitor Galunisertib or vehicle control. Whole tumour mRNA was extracted from primary tumours and expression profiling was performed with the objective to characterize the tumour microenvironment (TME). As a TGF-beta-activated TME has been associated to a poor prognosis and the CRC consensum molecular subtype CMS4, and the mouse model was found to have such an activated TME, we used the array data to classify these tumours in this mouse model system as CMS4-like. Furthermore, treatment with TGF-beta inhibitor reduced the fibroblast- and T cell-specific TGF-beta response signatures, also associated to poor prognosis in human CRC. This treatment was associated to a strong reduction/prevention of liver metastasis, as well as a reduction of primary tumour (and local carcinomatosis) size.
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Project description:3D collagen-based scaffolds for biophysical tumour microenvironment studies
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Project description:Tumor microenvironment coevolves with and simultaneously sustains cancer progression. Reactive fibroblasts found in prostate cancer (PCa), known as cancer associated fibroblasts (CAF), have been indeed shown to fuel tumor development and metastasis by mutually interacting with PCa cells. Little is known about the molecular mechanisms that lead to activation of CAFs from tissue-resident fibroblasts, circulating marrow-derived fibroblast progenitors or mesenchymal stem cells. Through integrated gene and microRNA expression profiling, here we showed that transcriptome of CAFs isolated from prostate tumors strictly resembles that of normal fibroblasts stimulated in vitro with interleukin-6 (IL6), thus confirming the capability of the cytokine to promote acquisition of an activated and cancer-promoting phenotype, and, for the first time, proving that IL6 is able per se to induce all the complex transcriptional changes characteristic of patient-derived CAFs. Comparison with publicly available datasets, however, suggested that prostate CAFs may be alternatively characterized by IL6 and TGF?-related signatures, indicating that either signal, depending on the context, tumor stage and etiology, may concur to fibroblast activation. Our analyses also highlighted pathways relevant for induction of reactive stroma, including genes the role of which in fibroblast activation is still to be explored. In addition, we revealed a role for muscle-specific miR-133b as a soluble factor secreted by activated fibroblasts to support paracrine activation of non-activated fibroblasts or promote tumor progression. Overall, in this study we provided insights on the molecular mechanisms driving fibroblast activation in prostate cancer, thus contributing to identify novel hits for the development of therapeutic strategies targeting the crucial interplay between tumor cells and their microenvironment. Tumor microenvironment coevolves with and simultaneously sustains cancer progression. Reactive fibroblasts found in prostate cancer (PCa), known as cancer associated fibroblasts (CAF), have been indeed shown to fuel tumor development and metastasis by mutually interacting with PCa cells. Little is known about the molecular mechanisms that lead to activation of CAFs from tissue-resident fibroblasts, circulating marrow-derived fibroblast progenitors or mesenchymal stem cells. Through integrated gene and microRNA expression profiling, here we showed that transcriptome of CAFs isolated from prostate tumors strictly resembles that of normal fibroblasts stimulated in vitro with interleukin-6 (IL6), thus confirming the capability of the cytokine to promote acquisition of an activated and cancer-promoting phenotype, and, for the first time, proving that IL6 is able per se to induce all the complex transcriptional changes characteristic of patient-derived CAFs. Comparison with publicly available datasets, however, suggested that prostate CAFs may be alternatively characterized by IL6 and TGF?-related signatures, indicating that either signal, depending on the context, tumor stage and etiology, may concur to fibroblast activation. Our analyses also highlighted pathways relevant for induction of reactive stroma, including genes the role of which in fibroblast activation is still to be explored. In addition, we revealed a role for muscle-specific miR-133b as a soluble factor secreted by activated fibroblasts to support paracrine activation of non-activated fibroblasts or promote tumor progression. Overall, in this study we provided insights on the molecular mechanisms driving fibroblast activation in prostate cancer, thus contributing to identify novel hits for the development of therapeutic strategies targeting the crucial interplay between tumor cells and their microenvironment. Tumor microenvironment coevolves with and simultaneously sustains cancer progression. Reactive fibroblasts found in prostate cancer (PCa), known as cancer associated fibroblasts (CAF), have been indeed shown to fuel tumor development and metastasis by mutually interacting with PCa cells. Little is known about the molecular mechanisms that lead to activation of CAFs from tissue-resident fibroblasts, circulating marrow-derived fibroblast progenitors or mesenchymal stem cells. Through integrated gene and microRNA expression profiling, here we showed that transcriptome of CAFs isolated from prostate tumors strictly resembles that of normal fibroblasts stimulated in vitro with interleukin-6 (IL6), thus confirming the capability of the cytokine to promote acquisition of an activated and cancer-promoting phenotype, and, for the first time, proving that IL6 is able per se to induce all the complex transcriptional changes characteristic of patient-derived CAFs. Comparison with publicly available datasets, however, suggested that prostate CAFs may be alternatively characterized by IL6 and TGF?-related signatures, indicating that either signal, depending on the context, tumor stage and etiology, may concur to fibroblast activation. Our analyses also highlighted pathways relevant for induction of reactive stroma, including genes the role of which in fibroblast activation is still to be explored. In addition, we revealed a role for muscle-specific miR-133b as a soluble factor secreted by activated fibroblasts to support paracrine activation of non-activated fibroblasts or promote tumor progression. Overall, in this study we provided insights on the molecular mechanisms driving fibroblast activation in prostate cancer, thus contributing to identify novel hits for the development of therapeutic strategies targeting the crucial interplay between tumor cells and their microenvironment. In the present study, patient derived-CAFs and HPFs activated in vitro with either TGF? or IL6 were comparatively analyzed for gene and microRNA (miRNA) expression profiles, with the aim to define transcriptional pathways responsible for fibroblast activation and establish whether different subpopulations of CAFs may exist in PCa.
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