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Therapy-induced senescence contributes to the efficacy of abemaciclib in patients with dedifferentiated liposarcoma

ABSTRACT: Therapy-induced senescence contributes to the efficacy of abemaciclib in patients with dedifferentiated liposarcoma

PROVIDER: PRJNA1006073 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25658745_1.fastq.gz	Fastqsanger.gz
	SRR25658745_2.fastq.gz	Fastqsanger.gz
	SRR25658746_1.fastq.gz	Fastqsanger.gz
	SRR25658746_2.fastq.gz	Fastqsanger.gz
	SRR25658747_1.fastq.gz	Fastqsanger.gz

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Therapy-induced senescence contributes to the efficacy of abemaciclib in patients with dedifferentiated liposarcoma

Project description:Current research on CDK4/6 inhibitors (CDK4/6i) in the pre-clinical and clinical spaces are largely concerned with gaining a deeper understanding of how these drugs delay tumor growth, and how to prevent cancer cell resistance. By coordinating a first-in-kind phase II clinical trial of the CDK4/6i abemaciclib for patients with progressive dedifferentiated liposarcoma (DDLS) with cellular studies to identify the molecular basis of geroconversion, we have defined how therapy induced senescence contributes to disease management. Thirty patients with progressing DDLS enrolled in the clinical trial and were treated with 200mg abemaciclib twice daily. The median progression free survival was 33 weeks at the time of the data lock, with 23 of 30 progression-free at 12 weeks (76.7%, two-sided 95% CI 57.7% - 90.1%). ANGPTL4 is a necessary late regulator of geroconversion, the pathway from reversible cell cycle exit to a stably arrested inflammation-provoking senescent cell, in liposarcoma cell lines treated with CDK4/6i. Using ANGPTL4 and CDKN2A expression, we were able to identify patients in which abemaciclib induced tumor cell senescence. We were then able to correlate this with outcomes. Senesence correlated with increased leukocyte infiltration, primarily CD4-positive cells, within a month of therapy, and possibly with an improved initial response to abemaciclib. However, those individuals with both senescence and increased TILs were also more likely to acquire resistance after six months of therapy. This suggests that combining senolytics with abemaciclib in a subset of patients may improve the durability of patient responses to this class of compounds.

2023-08-21 | GSE241031 | GEO

Therapy-Induced Senescence Contributes to the Efficacy of Abemaciclib in Patients with Dedifferentiated Liposarcoma.

Project description:PurposeWe conducted research on CDK4/6 inhibitors (CDK4/6i) simultaneously in the preclinical and clinical spaces to gain a deeper understanding of how senescence influences tumor growth in humans.Patients and methodsWe coordinated a first-in-kind phase II clinical trial of the CDK4/6i abemaciclib for patients with progressive dedifferentiated liposarcoma (DDLS) with cellular studies interrogating the molecular basis of geroconversion.ResultsThirty patients with progressing DDLS enrolled and were treated with 200 mg of abemaciclib twice daily. The median progression-free survival was 33 weeks at the time of the data lock, with 23 of 30 progression-free at 12 weeks (76.7%, two-sided 95% CI, 57.7%-90.1%). No new safety signals were identified. Concurrent preclinical work in liposarcoma cell lines identified ANGPTL4 as a necessary late regulator of geroconversion, the pathway from reversible cell-cycle exit to a stably arrested inflammation-provoking senescent cell. Using this insight, we were able to identify patients in which abemaciclib induced tumor cell senescence. Senescence correlated with increased leukocyte infiltration, primarily CD4-positive cells, within a month of therapy. However, those individuals with both senescence and increased TILs were also more likely to acquire resistance later in therapy. These suggest that combining senolytics with abemaciclib in a subset of patients may improve the duration of response.ConclusionsAbemaciclib was well tolerated and showed promising activity in DDLS. The discovery of ANGPTL4 as a late regulator of geroconversion helped to define how CDK4/6i-induced cellular senescence modulates the immune tumor microenvironment and contributes to both positive and negative clinical outcomes. See related commentary by Weiss et al., p. 649.

| S-EPMC10870201 | biostudies-literature

Genomic characterization of well differentiated/dedifferentiated retroperitoneal liposarcoma

Project description:An integrated profiling approach was performed to define molecular alterations associated to the aggressive behavior of retroperitoneal dedifferentiated liposarcoma. In particular, matched well and dedifferentiated components as well as normal adipose tissues, obtained from the same tumor sites, were comparatively investigated to higlight differences in gene expression.

2021-03-10 | GSE159659 | GEO

RNA-seq of four tissue samples of dedifferentiated liposarcoma and corresponding matched well-differentiated liposarcoma

Project description:Dedifferentiated liposarcoma (DDL) has the same cellular and molecular genetics features as well-differentiated liposarcoma (WDL), and there is still no ideal biomarker for the prediction of DDL patient prognosis in clinical practice. In order to explore the genes that cause WDL to obtain local invasion and distant metastasis capacities and transform it into DDL, The four DDL tissue specimens in this study were matched with four WDL tissue specimens according to baseline characteristics, such as gender, age, and recurrence, before high-throughput sequencing was conducted. Then total RNAs were subjected to RNA isolation and RNA-seq analyses were generated by deep sequencing using Illumina Hiseq.

2021-09-17 | GSE184199 | GEO

Genomic characterization of well differentiated/dedifferentiated retroperitoneal liposarcoma

Project description:Genomic characterization of well differentiated/dedifferentiated retroperitoneal liposarcoma

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Epigenetic profiling of well differentiated and dedifferentiated liposarcoma identifies H3K9me3 and Kruppel-like factor 6 (KLF6) as determinants of aggressiveness in sarcoma (expression)

Project description:Little is known about the epigenomics of liposarcoma (LPS). Here, we profiled the global expression of 9 epigenetic marks in well differentiated (WD) and dedifferentiated (DD) LPS from 151 patients and found increased H3K9me3 among DDLPS tumors. We performed ChIP-seq and gene expression profiling of patient derived cell lines to discover functionally significant regions of differential H3K9me3 enrichment between WDLPS and DDLPS associated with concomitant gene expression changes. We performed genome-wide transcriptional profiling of dedifferentiated liposarcoma (DDLPS) and well differentiated liposarcoma (WDLPS) cell lines using the Affymetrix U133A GeneChip array

2015-08-04 | E-GEOD-57750 | biostudies-arrayexpress

Epigenetic profiling of well differentiated and dedifferentiated liposarcoma identifies H3K9me3 and Kruppel-like factor 6 (KLF6) as determinants of aggressiveness in sarcoma (ChIP-seq)

Project description:Little is known about the epigenomics of liposarcoma (LPS). Here, we profiled the global expression of 9 epigenetic marks in well differentiated (WD) and dedifferentiated (DD) LPS from 151 patients and found increased H3K9me3 among DDLPS tumors. We performed ChIP-seq and gene expression profiling of patient derived cell lines to discover functionally significant regions of differential H3K9me3 enrichment between WDLPS and DDLPS associated with concomitant gene expression changes. We performed genome-wide transcriptional profiling of H3K9me3 in dedifferentiated liposarcoma DDLPS and well differentiated liposarcoma WDLPS cell lines.

2015-08-04 | E-GEOD-57749 | biostudies-arrayexpress

Novel dedifferentiated liposarcoma xenograft models reveal PTEN down regulation as a malignant signature and response to PI3K pathway inhibition

Project description:Liposarcoma is a type of soft tissue sarcoma, exhibiting poor survival and a high recurrence rate. Treatment is generally limited to surgery and radiation, emphasizing the need to understand this disease. Because very few in vivo and in vitro models can reproducibly recapitulate the human disease, we generated several xenograft models from surgically resected human dedifferentiated liposarcoma. Our study demonstrates that all xenografts recapitulate morphologic and gene expression characteristics of the patient tumors after continuous in vivo passages. Importantly, xenograftability is directly correlated with disease specific survival of liposarcoma patients. When treated with the PI3K/AKT/mTOR pathway inhibitor rapamycin alone or in combination with the multi-kinase inhibitor sorafenib, all xenografts responded with increased lipid content and a more differentiated gene expression profile. One-color arrays: Vehicle vs combination (rapamycin & sorafenib) treatment for 2 separate dedifferentiated liposarcoma xenografts. Two-color arrays: Comparison of patient tumor, several passages of xenograft generated from that tumor, and cells cultured from xenografted tumors.

2012-12-19 | E-GEOD-42975 | biostudies-arrayexpress

Cellular origin and clonal evolution of human dedifferentiated liposarcoma

Project description:Dedifferentiated liposarcoma (DDLPS) is the most frequent high-grade soft tissue sarcoma subtype. It is characterized by a component of undifferentiated tumor cells coexisting with a component of well-differentiated adipocytic tumor cells. Both dedifferentiated (DD) and well-differentiated (WD) components exhibit MDM2 amplification, however their cellular origin remains elusive. Using single-cell RNA sequencing and functional assays in paired WD and DD components from primary DDLPS tumors, we characterized the cellular heterogeneity of DDLPS tumor and micro-environment. We identified a population of tumor adipocyte stem cells (ASC) showing striking similarities with adipocyte stromal progenitors found in white adipose tissue. We show that tumor ASC harbor the ancestral genomic alterations of WD and DD components, suggesting that both derive from these progenitors following clonal evolution. Last, we show that DD tumor cells keep important biological properties of ASC including pluripotency and that their adipogenic properties are inhibited by a TGF-β high immunosuppressive tumor micro-environment.

2024-07-22 | GSE221493 | GEO

Cellular origin and clonal evolution of human dedifferentiated liposarcoma

2024-07-22 | GSE221492 | GEO