αSMA+ fibroblasts suppress differentiation of Lgr5+ cancer stem cells via BMP4 and restrain progression of colorectal cancer
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE164300 | GEO | 2021/01/06
REPOSITORIES: GEO
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Project description:Background and aims Cancer-associated fibroblasts (CAFs) play a critical role in colorectal cancer (CRC) progression. However, the precise cellular origins of the tumor stroma remain unknown, making it challenging to therapeutically target the tumor mesenchyme. Here, we aimed to identify key cellular contributors to and components of the CRC mesenchyme associated with poor prognosis. Methods We used a mouse model of inflammation-associated CRC in 5 different genetic fate-mapping transgenic mouse lines to characterize the origins of the CRC stroma. To identify a potential therapeutic target expressed by the CRC stroma, RNA-sequencing of fluorescence-activated cell sorting (FACS)-purified CRC stromal cells was performed. CRC patient RNA-sequencing data (n=621) and tissue microarray (n=101) were used to examine the prognostic significance of marker expression. Results We found that approximately half of the CRC CAFs marked by α-smooth muscle actin (αSMA) in a mouse model of CRC emerge through proliferation. Lineage tracing experiments revealed that intestinal leptin receptor (Lepr)-lineage stromal cells expanded and contributed to 75% of the αSMA+ proliferating CAFs. Notably, no αSMA+ CAFs arose from Krt19-lineage epithelial cells or bone marrow-derived cells. Moreover, RNA-sequencing of FACS-purified CRC mesenchymal cells identified MCAM as a CRC stroma-specific marker, which is expressed by Lepr-lineage cells. Analysis of human CRC samples showed that high MCAM expression driven, in part, by TGF-β was independently prognostic of poor overall survival. Conclusion Our data identify intestinal Lepr-lineage cells as a major source of the tumor stroma in CRC and suggest that targeting MCAM+ cells may serve as an attractive therapeutic approach to restrain CRC progression.
2022-11-01 | GSE162508 | GEO
Project description:Carcinoma-associated fibroblasts (CAFs) that express α-smooth-muscle-actin (αSMA+) contribute to cancer progression, but their precise origin and role in tumorigenesis is not established. Using mouse models of inflammation-induced gastric cancer, we show that at least 20% of CAFs originate from bone marrow and derive from mesenchymal stem cells (MSCs). Surprisingly, we find that αSMA+ myofibroblasts (MF) are niche cells normally present in bone marrow and increase markedly in the bone marrow and blood during progression to dysplasia. MSC-derived CAFs that are recruited to the dysplastic stomach express IL-6, Wnt5α and BMP4 and show DNA hypomethylation. Bone marrow (BM)-derived CAFs strongly promote tumor growth in organotypic and xenograft models. In addition, CAFs are generated from MSCs and are recruited to distant tumor sites in a TGF-β- and SDF-1α-dependent manner. Carcinogenesis therefore involves the expansion and relocation of normal bone marrow niche cells to the tumor site where they create a new niche to sustain cancer progression. Since resident (non-BM-derived) CAFs could not be cultured and directly compared to BM-derived CAFs, we additionally isolated total RFP(+) gastric CAFs from aSMA-RFP mice with Helicobacter felis-induced dysplasia, and compared them to GFP(+) BM-derived gastric CAFs from mice with H. felis-induced dysplasia mice that had been transplanted with UBC-EGFP bone marrow. The RFP+ CAFs (HF CAF) represent total CAFs (of which only 20% were BM-derived), while the latter represented only BM-derived CAFs (BM CAF). We compared their gene expression using the Illumina array (MouseWG-6v2) directly after FACS sorting. Interestingly, the GFP+ BM-derived CAFs expressed higher levels of inflammatory genes (IL-6, IL-1β, IL-33) and a number of tumor and stem cell associated factors (CCL5, SPP1, Notch3, MMP9, CD47, CXCR4, PARP10,) compared to the total (RFP+) population of gastric CAFs.
2010-10-01 | GSE23548 | GEO
Project description:Oncogenic KRAS (KRAS*) contributes to many cancer hallmarks. In colorectal cancer (CRC), KRAS* has been shown to suppress anti-tumor immunity which promotes tumor metastasis. Here, we show that the protumor actions of KRAS* extend to the adipogenic transformation of fibroblasts into lipid-laden cancer-associated fibroblasts (CAFs), which spur angiogenesis. Mechanistically, KRAS*-mediated activation of the transcription factor CP2 (TFCP2) resulted in TFCP2-mediated transcriptional upregulation of pro-adipogenic factors BMP4 and WNT5B to drive lipid-rich CAF transformation. Functionally, these lipid-rich CAFs promoted tumor growth via their production of vascular endothelial growth factor A (VEGFA). Correspondingly, genetic and pharmacological neutralization of TFCP2 decreased the abundance of lipid-rich CAFs, reduced tumor angiogenesis, and increased survival in an autochthonous KRAS*–driven CRC mouse model. These murine findings mirror translational profiles in human CRC. Thus, KRAS* transforms the stromal cell state to promote tumor angiogenesis and disease progression, providing an actionable therapeutic intervention for KRAS*–driven CRC.
2023-09-15 | GSE229559 | GEO
Project description:Cross-presentation of exogenous antigens in HLA-class I molecules by professional antigen presenting cells (APCs) is crucial for CD8+ T cell function. Recent murine studies show that several non-professional APCs, including cancer-associated fibroblasts (CAFs) also possess this capacity. It is currently unknown whether human CAFs are able to cross-present exogenous antigen, which molecular pathways are involved in this process and how this ultimately affects tumor-specific CD8+ T cell function. Here we show that human colorectal cancer (CRC)-derived CAFs display an enhanced capacity to cross-present neoantigen-derived synthetic long peptides (SLPs) when compared to normal colonic fibroblasts. Importantly, cross-presentation of antigens required the lysosomal protease Cathepsin S. Cathepsin S expression by CAFs was detected in situ in human CRC tissue, was upregulated in ex vivo cultured CRC-derived CAFs and showed increased expression in normal fibroblasts after exposure to CRC-conditioned medium. Cognate interaction between CD8+ T cells and cross-presenting CAFs suppressed T cell function, reflected by decreased cytotoxicity, reduced activation (CD25, CD137) and increased exhaustion (TIM3) marker expression. Our data indicate that CAFs may directly suppress tumor-specific T cell function in an antigen-dependent fashion in human CRC.
2022-03-03 | PXD029507 | Pride
Project description:Endoglin is a membrane glycoprotein primarily expressed by the vascular endothelium and involved in cardiovascular diseases. Upon the proteolytic processing of the membrane-bound protein, a circulating form of endoglin (soluble endoglin, sEng) can be released, and high levels of sEng have been observed in several endothelial-related pathological conditions, where it appears to contribute to endothelial dysfunction. Preeclampsia is a multisystem disorder of high prevalence in pregnant women characterized by the onset of high blood pressure and often associated with increased levels of sEng. Although a pathogenic role for sEng involving hypertension has been reported in several animal models of preeclampsia, the exact molecular mechanisms implicated remain to be identified. To search for sEng-induced mediators, we have analyzed the protein secretome of human endothelial cells in the presence of sEng. We find that sEng induces the expression of BMP4 in endothelial cells, as evidenced by their proteomic signature, gene transcript levels and BMP4 promoter activity. A mouse model of preeclampsia with high sEng plasma levels (sEng+) showed increased levels of BMP4 transcripts in lungs and increased circulating BMP4, compared to those of control animals. In addition, after crossing female wild type with male sEng+ mice, hypertension appears 18 days after mating, precisely coinciding with the appearance of high plasma levels of BMP4. Also, serum levels of sEng and BMP4 are positively correlated in pregnant women with and without preeclampsia. Interestingly, sEng-induced arterial pressure elevation in sEng+ mice was abolished in the presence of the BMP4 inhibitor noggin, suggesting that BMP4 is a downstream mediator of sEng. These results provide a better understanding on the role of sEng in the pathobiology of preeclampsia and other cardiovascular diseases, where sEng levels are increased.
2020-04-23 | PXD016228 | Pride
Project description:Carcinoma-associated fibroblasts (CAFs) that express ?-smooth-muscle-actin (?SMA+) contribute to cancer progression, but their precise origin and role in tumorigenesis is not established. Using mouse models of inflammation-induced gastric cancer, we show that at least 20% of CAFs originate from bone marrow and derive from mesenchymal stem cells (MSCs). Surprisingly, we find that ?SMA+ myofibroblasts (MF) are niche cells normally present in bone marrow and increase markedly in the bone marrow and blood during progression to dysplasia. MSC-derived CAFs that are recruited to the dysplastic stomach express IL-6, Wnt5? and BMP4 and show DNA hypomethylation. Bone marrow (BM)-derived CAFs strongly promote tumor growth in organotypic and xenograft models. In addition, CAFs are generated from MSCs and are recruited to distant tumor sites in a TGF-?- and SDF-1?-dependent manner. Carcinogenesis therefore involves the expansion and relocation of normal bone marrow niche cells to the tumor site where they create a new niche to sustain cancer progression. Since resident (non-BM-derived) CAFs could not be cultured and directly compared to BM-derived CAFs, we additionally isolated total RFP(+) gastric CAFs from aSMA-RFP mice with Helicobacter felis-induced dysplasia, and compared them to GFP(+) BM-derived gastric CAFs from mice with H. felis-induced dysplasia mice that had been transplanted with UBC-EGFP bone marrow. The RFP+ CAFs (HF CAF) represent total CAFs (of which only 20% were BM-derived), while the latter represented only BM-derived CAFs (BM CAF). We compared their gene expression using the Illumina array (MouseWG-6v2) directly after FACS sorting. Interestingly, the GFP+ BM-derived CAFs expressed higher levels of inflammatory genes (IL-6, IL-1?, IL-33) and a number of tumor and stem cell associated factors (CCL5, SPP1, Notch3, MMP9, CD47, CXCR4, PARP10,) compared to the total (RFP+) population of gastric CAFs. Comparison of bone marrow-derived GFP-labeled gastric CAFs versus all gastric CAFs.
2010-10-01 | E-GEOD-23548 | biostudies-arrayexpress
Project description:The pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β) are expressed simultaneously and have tumor-promoting roles in breast cancer. In parallel, mesenchymal stem cells (MSCs) undergo transition at the tumor site to cancer-associated fibroblasts (CAFs), which are generally connected to enhanced tumor progression. Here, we determined the impact of consistent inflammatory stimulation on stromal cell plasticity. MSCs that were persistently stimulated by TNFα+IL-1β (2-3 weeks) gained a CAF-like morphology, accompanied by prominent changes in gene expression, including in stroma/fibroblast-related genes. These CAF-like cells expressed elevated levels of vimentin and fibroblast activation protein (FAP) and demonstrated significantly increased ability to contract collagen gels. Moreover, they have gained the phenotype of inflammatory CAFs, as indicated by reduced expression of α smooth muscle actin (αSMA), increased proliferation and elevated expression of inflammatory genes and proteins, primarily inflammatory chemokines. These inflammatory CAFs released factors that enhanced tumor cell detachment, spreading and migration; the inflammatory CAF-derived factors elevated cancer cell migration by stimulating the chemokine receptors CCR2, CCR5 and CXCR1/2 and Ras-activating receptors, expressed by the cancer cells. Together, these novel findings demonstrate that chronic inflammation, per se, can induce MSC-to-CAF transition, leading to generation of tumor-promoting inflammatory CAFs.
2021-08-10 | PXD022635 | Pride
Project description:Aberrant activation of WNT signaling and loss of BMP signals represent the two main alterations leading to the initiation of colorectal cancer (CRC). Here we screen for genes required for maintaining the tumor stem cell phenotype and identify the zinc-finger transcription factor GATA6 as key regulator of the WNT and BMP pathways in CRC. GATA6 directly drives the expression of LGR5 in adenoma stem cells while it restricts BMP signaling to differentiated tumor cells. Genetic deletion of Gata6 in mouse colon adenomas increases the levels of BMP factors, which signal to block self-renewal of tumor stem cells. In human tumors, GATA6 represses BMP4 gene expression through binding to a regulatory region that has been previously linked to increased susceptibility to develop CRC. Thus, GATA6 creates a permissive environment for tumor stem cell expansion by controlling the major signaling pathways that influence CRC initiation. Total RNA from biological replicates of VillinCreERT2Gata6+/+Apcfl/fl and VillinCreERT2Gata6fl/flApcfl/fl colon adenoma tumor organoids grown for one week in control media (see growth protocol).Total RNA was extracted using the TRIzolM-BM-. Plus RNA Purification Kit (Life Technologies).
2014-06-19 | E-GEOD-49479 | biostudies-arrayexpress
Project description:Cancer-associated fibroblasts (CAFs) play a significant role in human breast cancer as a major stromal component. While their role in promoting cancer proliferation and malignancy through interaction with cancer cells in the tumor microenvironment is known, the exact mechanisms behind this interaction are not fully understood. Our study reveals that lymphoid enhancer-binding factor 1 (LEF1), a central transcription factor for Wnt/β-catenin signaling, is expressed in experimentally generated tumor-promoting CAFs (exp-CAFs) as well as in CAFs from breast cancer patients, particularly those with a poor prognosis. Notably, LEF1-expressing CAFs are prevalent in the stroma of squamous cell carcinoma (SCC), an aggressive metaplastic breast cancer subtype with a limited understanding of its development. To investigate the functional importance of LEF1 expression in CAFs, we depleted LEF1 in the exp-CAFs and subcutaneously implanted them along with breast ductal carcinoma MCF10DCIS.com cells into immunodeficient mice. Depleting LEF1 resulted in reduced xenograft tumor growth, accompanied by decreased cancer-cell proliferation and angiogenesis in the tumors. Additionally, we observed a significant reduction in the expression of SCC markers p40 (ΔNp63) and cytokeratin 5/6 in the xenograft tumors when LEF1 was depleted in the exp-CAFs. Furthermore, we identified 13 genes, none of which are established downstream genes of the Wnt/β-catenin pathway, that exhibit expression patterns similar to LFE1 in our cultured fibroblasts. In summary, our findings suggest that LEF1 expression contributes to the tumor-promoting abilities of breast CAFs and that LEF1-expressing CAFs may drive transdifferentiation toward SCC, possibly through a pathway independent of the canonical Wnt/β-catenin signaling.
2025-02-01 | GSE287907 | GEO
Project description:WNT2 is important for placenta vascularization and acts as a pro-angiogenic factor for liver and other endothelial cells (ECs). WNT2 induction has been shown in many carcinomas and is associated with tumor progression. In colorectal cancer (CRC) WNT2 is selectively elevated in cancer associated fibroblasts (CAFs), leading to increased invasion and metastasis. However, if there is a role for WNT2 in colon cancer angiogenesis has not been addressed so far. Here, we demonstrate that WNT2 enhances EC migration and invasion, while it induces ß catenin dependent signaling in only a small subset of HUVECs. We show that siRNA-mediated knockdown of WNT2 in CAFs reduced the growth of vessel-like structures significantly in a co-culture assay, while the overexpression of WNT2 in skin fibroblasts otherwise being devoid of WNT2 led to increased angiogenesis in vitro. In a xenograft model, overexpression of WNT2 in HCT116 led to enhanced tumor volume and vessel density. Moreover, WNT2 expression correlates with vessel markers in human CRC. Secretome profiling of CAFs revealed that proteins related to angiogenesis and extracellular matrix (ECM) remodeling are regulated by WNT2. Thus, stroma-derived WNT2 positively affects angiogenesis in CRC by shifting the balance towards pro-angiogenic signals.
2020-05-26 | PXD014019 | Pride