A Positive Feedback Loop Between TGFβ and Androgen Receptors Supports Triple-Negative Breast Cancer Anoikis Resistance
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ABSTRACT:
PROVIDER: PRJNA662997 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12626837.fastq.gz | Fastqsanger.gz | |||
| SRR12626838.fastq.gz | Fastqsanger.gz | |||
| SRR12626839.fastq.gz | Fastqsanger.gz | |||
| SRR12626840.fastq.gz | Fastqsanger.gz | |||
| SRR12626841.fastq.gz | Fastqsanger.gz |
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Project description:Triple-negative breast cancer (TNBC) is an aggressive subtype with few treatment options for chemo-resistant disease. In both preclinical models and patient circulating tumor cells, androgen receptor (AR) expression is increased in anchorage independent TNBC. The AR inhibitor enzalutamide (Enza) leads to reduced TNBC growth in soft agar, invasion, mammosphere formation in vitro, and reduced tumorigenicity and recurrence when combined with chemotherapy in vivo pre-clinical models. Transforming growth factor β (TGFβ) pathway gene signatures are also increased during TNBC anchorage independent survival both in vitro and in vivo in pre-clinical models and CTC from patients during relapse while on chemotherapy. We hypothesized that a positive loop between AR and TGFβ signaling facilitates TNBC anchorage independent survival (anoikis resistance). We previously published that AR protein levels and transcriptional activity increased during anchorage independent conditions and we now find that that multiple components of the TGFβ pathway, including TGFβ1 and 3, as well as pathway activity, as measured by nuclear localization and transcriptional activity of pSmad3, are enhanced in anchorage independent conditions. Indeed, exogenous TGFβ increased AR protein and TGFβ inhibition decreased AR and TNBC viability, particularly under anchorage independent culture conditions. ChIP-Seq experiments revealed AR binding to genomic regions near the TGFB1 and SMAD3. TGFB3 and AR expression were positively correlated in clinical datasets and high levels of co-expression correspond to significantly worse recurrence-free and overall survival in both ER- and basal-like breast cancer. Finally, combining Enza with a TGFβ inhibitor decreased cell survival more than either drug alone, particularly under anchorage independent conditions, where the effect was more than additive. These findings warrant further investigations into whether combined inhibition of AR and TGFβ pathways might decrease metastatic recurrence rates and mortality from TNBC.
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Project description:Triple-negative breast cancer (TNBC) is an aggressive subtype with peak recurrence as metastatic disease within the first few years of diagnosis. Androgen receptor (AR) expression is increased in anchorage-independent cells in TNBC preclinical models. Both AR knockdown and inhibition lead to reduced TNBC invasion in vitro, reduced tumorigenicity, and less recurrence in vivo in preclinical models. Transforming growth factor β (TGFβ) pathway gene signatures also increased during anchorage-independent survival both in vitro and in vivo in preclinical models and in circulating tumor cells (CTCs) from patients during emergence of chemo resistant disease. We hypothesized that a positive loop between AR and TGFβ signaling facilitates TNBC anchorage-independent survival. We find that multiple components of the TGFβ pathway, including TGFβ1 and 3, as well as pathway activity measured by nuclear localization and transcriptional activity of phosphorylated Smad3, are enhanced in anchorage-independent conditions. Further, exogenous TGFβ increased AR protein while TGFβ inhibition decreased AR and TNBC viability, particularly under anchorage-independent culture conditions. ChIP-seq experiments revealed AR binding to TGFB1 and SMAD3 regulatory regions in MDA-MB-453 cells. In clinical datasets, TGFB3 and AR positively correlate and high expression of both genes together corresponded to significantly worse recurrence-free and overall survival in both ER-negative and basal-like breast cancer. Finally, inhibiting both AR and TGFβ decreased cell survival, particularly under anchorage-independent conditions. These findings warrant further investigations into whether combined inhibition of AR and TGFβ pathways might decrease metastatic recurrence rates and mortality from TNBC.
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Project description:Anoikis resistance or evasion of cell death triggered by cell detachment is a hallmark of cancer that is concurrent with cell survival and metastasis. Phenotypes of anoikis resistant cancer cells have been extensively investigated, however, how exposure to suspension stress may lead to acquisition of a anoikis resistance phenotype has not been previously described in detail. Here we show using a spectrum of ovarian cancer cells, that cycles of suspension stress followed by attached growth, leads to adaptation and acquisition of resistance to cell death in suspension . Comparing the stepwise transcriptomic changes as cells acquire resistance, we find strong transcriptional reprogramming in the population with a majority of differentially expressed genes being downregulated during progressive acquisition of anoikis resistance. Adapted anoikis resistant cells display an enhanced dependency on oxidative phosphorylation and are capable of evasion from T cell-mediated immune surveillance. We find that such acquired anoikis resistance is not genetic. However, transcriptional reprogramming is essential to this process as acquisition of such adaptive anoikis resistance invitro and invivo are both exquisitely sensitive to specific inhibition of transcriptional reprogramming. Our data demonstrate that recovery from the verge of anoikis leads to adaptation that promotes metastasis in ovarian cancer, but can be therapeutically prevented by specific inhibitors to transcriptional reprogramming.
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Project description:Background Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks hormone receptors and HER2 amplification, making it unresponsive to standard hormone or HER2-targeted therapies. Although immune checkpoint inhibitors (ICIs) have shown promise in tumors with high lymphocyte infiltration, their efficacy remains limited in tumors with minimal lymphocyte infiltration. To overcome this challenge, we developed a novel approach to reprogram tumor-associated macrophages (TAMs) from an immunosuppressive to an inflammatory phenotype within the tumor microenvironment (TME), aiming to enhance therapeutic outcomes in TNBC. Methods We designed a chimeric cytokine receptor (ChCR) that triggers STAT1 signaling upon stimulation with IL-10 or TGFβ, cytokines prevalent in the TME that typically drive immunosuppression. Human primary macrophages were transduced with a lentiviral vector expressing the ChCR, and changes in their phenotype, secretome, and transcriptome were analyzed following stimulation. The anti-tumoral activity of these reprogrammed macrophages was assessed using co-culture assays with 3D TNBC spheroids. Results ChCR-expressing macrophages showed robust STAT1 activation in response to IL-10 or TGFβ stimulation, resulting in an inflammatory phenotype similar to IFNγ activation, as confirmed by phenotypic markers, and transcriptomic profiling. These ChCR-stimulated macrophages demonstrated significant anti-tumoral effects in 3D TNBC spheroids. Moreover, ChCR stimulation led to the upregulation of CXCL9 and CXCL10, chemokines essential for lymphocyte recruitment, and genes associated with good response to ICIs. Conclusion We successfully engineered a ChCR that reprograms TAMs within an IL-10- and TGFβ-rich environment, inducing an inflammatory phenotype and anti-tumoral activity. The expression of CXCL9 and CXCL10 further supports lymphocyte recruitment, potentially facilitating greater lymphocyte infiltration and disrupting the immunosuppressive TME. This approach offers a promising strategy to improve immunotherapy outcomes in TNBC patients, particularly those with low immune cell infiltration, thereby addressing a critical unmet clinical need.
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Project description:To investigate potential molecular targets that regulate metastasis and metabolism in anoikis-resistance of prostate cancer cells, we have establised anoikis-resistant prostate PC-3 cells with ultra-low attachment 6-well plates (Corning) and employed whole genome microarray expression profiling as a discovery platform to identify differentially expressed genes between anoikis-resistant PC-3 cells and corresponding parental cells.
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Project description:Treatment of muscle-invasive bladder cancer remains a major clinical challenge. Aberrant HGF/c-MET upregulation and activation is frequently observed in bladder cancer correlating with cancer progression and invasion. However, the precise mechanisms underlying HGF/c-MET mediated invasion in bladder cancer remains unknown. As part of a negative feedback loop SMAD7 binds to the E3 ligase SMURF2 targeting the TGFβ receptor for degradation. Under these conditions SMAD7 acts as an agonist disrupting the intermolecular interactions within SMURF2, permitting SMURF2 activation. We demonstrate that HGF stimulates TGFβ signaling by inducing c-SRC mediated phosphorylation of SMURF2 at two tyrosine residues impeding SMAD7 binding and enhancing SMURF2 C2-HECT domain interaction, resulting in SMURF2 inhibition and TGFβ receptor stabilization. This upregulation of the TGFβ pathway by HGF leads to TGFβ-mediated EMT and invasion. Using biologically relevant orthotopic mouse models we show that inhibition of TGFβ signaling completely prevents HGF induced bladder cancer invasion. Furthermore, we make a rationale for the use of TGFβ receptor and MEK inhibitors in the treatment of high grade non-muscle-invasive bladder cancers or early stage muscle invasive bladder cancers.
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Project description:Increasing evidence points to an active stromal involvement in cancer initiation and progression. Cytokines derived from tumor cells are believed to modulate stromal cells to produce growth and angiogenic factors which in turn provide the tumor with the necessary microenvironment for expansion and invasion. Transforming growth factor beta (TGFβ) has been implicated as a candidate cytokine to mediate this communication. However, how its signaling in stromal cells regulates tumorigenesis and tumor progression remains unresolved. We show that normal, pre-senescent fibroblasts or prostate stromal cells cotransplanted with prostate carcinoma cells subcutaneously into nude mice reduced tumor latency and accelerated tumor growth. When their TGFβ signaling was blocked, the fibroblasts and stromal cells still stimulated tumor initiation, but no longer supported tumor growth as control cells did. The loss of the tumor growth-promoting activity of the stromal cells with attenuated TGFβ signaling was not associated with altered cellular senescence or tumor angiogenicity. TGFβ and the medium conditioned by the prostate carcinoma cells stimulated myofibroblast differentiation of the intact stromal cells, but not the stromal cells with attenuated TGFβ signaling. Gene microarray and quantitative RTPCR analyses showed that TGFβ upregulated a host of genes in stromal cells that are involved in tissue remodeling and wound healing. Thus, our study provides evidence for TGFβ as a supporting agent in tumor progression through the induction of a perpetual wound healing process in the tumor microenvironment. Keywords: Human prostate stromal cells (PrSC)
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