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Project description:Preclinical and clinical data have highlighted the challenges in targeting KRAS mutant tumors, revealing that cancer cells initially sensitive to treatment circumvent KRAS dependence and become tolerant. However, the exact mechanisms governing the transition from a drug-sensitive to a drug-tolerant state remain unclear. Herein, we used 3D culture models of mutant KRAS colorectal cancer cells with distinct KRAS dependencies to show that sensitive and resistant cells undergo distinct chromatin and transcriptional adaptations upon acute KRAS loss. KRAS-silenced sensitive cells presented G0/G1 cell cycle arrest and exhibited a transcriptional signature characteristic of quiescent cells. Moreover, proteomic profiling underscored common biological processes up-regulated in sensitive cells, including nucleosome assembly, gene expression regulation, and mRNA splicing. A detailed analysis of chromatin features revealed that sensitive cells altered eu/heterochromatin states and gained TADs after KRAS silencing whereas the eu/heterochromatin states of resistant cells remained unchanged, and the number of TADs decreased. Strikingly, only KRAS-silenced sensitive cells displayed alterations in how chromatin organizes into packing domains, displaying a lower domain packing scaling. Chromatin packing scaling regulates the interaction between macromolecular complexes and DNA, thus controlling transcriptional malleability and plasticity. Accordingly, although KRAS-silenced sensitive and resistant cells displayed a transcriptomic profile distinct from their controls, only sensitive cells presented higher variability over time, thus suggesting higher transcriptional plasticity. Overall, our findings provide compelling evidence supporting chromatin 3D reorganization and transcriptional variability in KRAS-silenced sensitive cells. This epigenetic mechanism is likely to underlie the remarkable ability of cancer cells to adapt, persist, and sustain malignancy without oncogenic KRAS.
| S-EPMC10896403 | biostudies-literature
Project description:Preclinical and clinical data revealed that targeting KRAS mutant tumors is more challenging than expected. While initially sensitive to the treatment, cancer cells have the capability to rapidly bypass dependence on this oncogene to acquire a drug-tolerant phenotype. Gaining a comprehensive understanding of the mechanisms underlying the transition from a drug-sensitive to a drug-tolerant state holds the key to invaluable insights. Such insights will inform the development of therapeutic strategies aimed at disrupting intrinsic or adaptive resilience, ultimately enhancing therapeutic outcomes. Building upon this rationale, we established three-dimensional culture models of mutant KRAS CRC cell lines with distinct KRAS dependencies to investigate the cellular response to KRAS silencing. Our approach revealed a unique response in KRAS-dependent cells, characterized by G0/G1 cell cycle arrest and entry into a quiescent-like state. Proteomics analysis identified nucleosome assembly, regulation of gene expression, mRNA splicing, and mRNA processing as the top biologic processes specifically up-regulated in KRAS-dependent CRC cell lines upon KRAS silencing. Additionally, alterations in histone 3 post-translational modifications and chromatin compaction were also observed, along with enhanced transcriptional performance revealed by longitudinal RNA-Seq analysis. Our discoveries substantiate the existence of an epigenetic mechanism responsible for inducing tolerance to KRAS loss. This mechanism relies on both chromatin reorganization and transcriptional upregulation, illuminating the cancer cells' remarkable capacity to swiftly adapt, survive, and sustain malignancy even in the absence of oncogenic KRAS.
2023-12-15 | GSE250118 | GEO
Project description:Preclinical and clinical data revealed that targeting KRAS mutant tumors is more challenging than expected. While initially sensitive to the treatment, cancer cells have the capability to rapidly bypass dependence on this oncogene to acquire a drug-tolerant phenotype. Gaining a comprehensive understanding of the mechanisms underlying the transition from a drug-sensitive to a drug-tolerant state holds the key to invaluable insights. Such insights will inform the development of therapeutic strategies aimed at disrupting intrinsic or adaptive resilience, ultimately enhancing therapeutic outcomes. Building upon this rationale, we established three-dimensional culture models of mutant KRAS CRC cell lines with distinct KRAS dependencies to investigate the cellular response to KRAS silencing. Our approach revealed a unique response in KRAS-dependent cells, characterized by G0/G1 cell cycle arrest and entry into a quiescent-like state. Proteomics analysis identified nucleosome assembly, regulation of gene expression, mRNA splicing, and mRNA processing as the top biologic processes specifically up-regulated in KRAS-dependent CRC cell lines upon KRAS silencing. Additionally, alterations in histone 3 post-translational modifications and chromatin compaction were also observed, along with enhanced transcriptional performance revealed by longitudinal RNA-Seq analysis. Our discoveries substantiate the existence of an epigenetic mechanism responsible for inducing tolerance to KRAS loss. This mechanism relies on both chromatin reorganization and transcriptional upregulation, illuminating the cancer cells' remarkable capacity to swiftly adapt, survive, and sustain malignancy even in the absence of oncogenic KRAS.
2023-12-15 | GSE250117 | GEO
Project description:Preclinical and clinical data revealed that targeting KRAS mutant tumors is more challenging than expected. While initially sensitive to the treatment, cancer cells have the capability to rapidly bypass dependence on this oncogene to acquire a drug-tolerant phenotype. Gaining a comprehensive understanding of the mechanisms underlying the transition from a drug-sensitive to a drug-tolerant state holds the key to invaluable insights. Such insights will inform the development of therapeutic strategies aimed at disrupting intrinsic or adaptive resilience, ultimately enhancing therapeutic outcomes. Building upon this rationale, we established three-dimensional culture models of mutant KRAS CRC cell lines with distinct KRAS dependencies to investigate the cellular response to KRAS silencing. Our approach revealed a unique response in KRAS-dependent cells, characterized by G0/G1 cell cycle arrest and entry into a quiescent-like state. Proteomics analysis identified nucleosome assembly, regulation of gene expression, mRNA splicing, and mRNA processing as the top biologic processes specifically up-regulated in KRAS-dependent CRC cell lines upon KRAS silencing. Additionally, alterations in histone 3 post-translational modifications and chromatin compaction were also observed, along with enhanced transcriptional performance revealed by longitudinal RNA-Seq analysis. Our discoveries substantiate the existence of an epigenetic mechanism responsible for inducing tolerance to KRAS loss. This mechanism relies on both chromatin reorganization and transcriptional upregulation, illuminating the cancer cells' remarkable capacity to swiftly adapt, survive, and sustain malignancy even in the absence of oncogenic KRAS.
2023-12-15 | GSE249954 | GEO
Project description:KRAS inhibition impacts chromatin organization and transcriptional performance in colorectal cancer cells
| PRJNA1052048 | ENA
Project description:KRAS inhibition impacts chromatin organization and transcriptional performance in colorectal cancer cells [HCT116 RNA-seq]
| PRJNA1051274 | ENA
Project description:KRAS inhibition impacts chromatin organization and transcriptional performance in colorectal cancer cells [LS174T RNA-seq]
| PRJNA1052057 | ENA
Project description:KRAS inhibition impacts chromatin organization and transcriptional performance in colorectal cancer cells [SW480 RNA-seq]
| PRJNA1052056 | ENA
Project description:About half of colorectal cancers harbor mutations in the KRAS gene. The presence of these mutations is associated with worse prognosis and, until now, the absence of matched targeted therapy options. In this review, we discuss clinical efforts to target KRAS in colorectal cancer from studies of downstream inhibitors to recent direct inhibitors of KRASG12C and other KRAS mutants. Early clinical trial data, however, suggest more limited activity for these novel inhibitors in colorectal cancer compared to other cancer types, and we discuss the role of receptor tyrosine kinase signaling and parallel signaling pathways in modulating response to these inhibitors. We also review the effect of KRAS mutations on the tumor-immune microenvironment and efforts to induce an immune response against these tumors.
| S-EPMC9908842 | biostudies-literature
Project description:ObjectiveTo identify primary care practice characteristics associated with colorectal cancer (CRC) screening performance, controlling for patient-level factors.Data sources/study settingPrimary care director survey (1999-2000) of 155 VA primary care clinics linked with 38,818 eligible patients' sociodemographics, utilization, and CRC screening experience using centralized administrative and chart-review data (2001).Study designPractices were characterized by degrees of centralization (e.g., authority over operations, staffing, outside-practice influence); resources (e.g., sufficiency of nonphysician staffing, space, clinical support arrangements); and complexity (e.g., facility size, academic status, managed care penetration), adjusting for patient-level covariates and contextual factors.Data collection/extraction methodsChart-based evidence of CRC screening through direct colonoscopy, sigmoidoscopy, or consecutive fecal occult blood tests, eliminating cases with documented histories of CRC, polyps, or inflammatory bowel disease.Principal findingsAfter adjusting for sociodemographic characteristics and health care utilization, patients were significantly more likely to be screened for CRC if their primary care practices had greater autonomy over the internal structure of care delivery (p<.04), more clinical support arrangements (p<.03), and smaller size (p<.001).ConclusionsDeficits in primary care clinical support arrangements and local autonomy over operational management and referral procedures are associated with significantly lower CRC screening performance. Competition with hospital resource demands may impinge on the degree of internal organization of their affiliated primary care practices.
| S-EPMC1955248 | biostudies-literature