Integration of lipidomics with targeted, single cell, and spatial transcriptomics defines an unresolved pro-inflammatory state in colon cancer.

Background: Over a century ago, Virchow proposed that cancer represents a chronically inflamed, poorly healing wound. Normal wound healing is represented by a transitory phase of inflammation, followed by a pro-resolution phase, with prostaglandin (PGE2/PGD2)-induced 'lipid class switching' producing inflammation-quenching lipoxins (LXA4, LXB4).

Objective: We explored if lipid dysregulation in colorectal cancers (CRCs) is driven by a failure to resolve inflammation.

The deubiquitylase USP7 is a novel cyclin F-interacting protein and regulates cyclin F protein stability.

Cyclin F, unlike canonical and transcriptional cyclins, does not bind or activate any cyclin-dependent kinases. Instead, it harbors an F-box motif and primarily functions as the substrate recognition subunit of the Skp1-Cul1-F-box E3 ubiquitin ligase complex, SCF . By targeting specific proteins for ubiquitin-mediated proteasomal degradation, cyclin F plays a critical role in the regulation of centrosomal duplication, DNA replication and repair, and maintenance of genomic stability.

Ras Pathway Activation and MEKi Resistance Scores Predict the Efficiency of MEKi and SRCi Combination to Induce Apoptosis in Colorectal Cancer.

Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. The RAS pathway is activated in more than 55% of CRC and has been targeted for therapeutic intervention with MEK inhibitors. Unfortunately, many patients have de novo resistance, or can develop resistance to this new class of drugs.

An integrative gene expression signature analysis identifies CMS4 KRAS-mutated colorectal cancers sensitive to combined MEK and SRC targeted therapy.

Background: Over half of colorectal cancers (CRCs) are hard-wired to RAS/RAF/MEK/ERK pathway oncogenic signaling. However, the promise of targeted therapeutic inhibitors, has been tempered by disappointing clinical activity, likely due to complex resistance mechanisms that are not well understood. This study aims to investigate MEK inhibitor-associated resistance signaling and identify subpopulation(s) of CRC patients who may be sensitive to biomarker-driven drug combination(s).

and Mutations Predict Cetuximab Sensitivity across Consensus Molecular Subtypes.

Recently, it was suggested that consensus molecular subtyping (CMS) may aide in predicting response to EGFR inhibitor (cetuximab) therapies. We recently identified that and as two tumor suppressor genes, when mutated, may enhance cetuximab sensitivity and may represent easily measured biomarkers in tumors or blood. Our study aimed to use and mutations (AP) to refine the CMS classification to better predict responses to cetuximab.

PTPRS drives adaptive resistance to MEK/ERK inhibitors through SRC.

PTPRS is the most commonly mutated receptor tyrosine phosphatase in colorectal cancer (CRC). PTPRS has been shown to directly affect ERK and regulate its activation and nuclear localization. Here we identify that PTPRS may play a significant role in developing adaptive resistance to MEK/ERK inhibitors (MEKi/ERKi) through SRC activation.

Repurposing EGFR Inhibitor Utility in Colorectal Cancer in Mutant and Subpopulations.

Background: EGFR is a major therapeutic target for colorectal cancer. Currently, extended testing identifies only nonresponders to EGFR inhibitors (EGFRi). We aimed to develop a mutation signature that further refines drug-sensitive subpopulations to improve EGFRi outcomes.

PTPRS Regulates Colorectal Cancer RAS Pathway Activity by Inactivating Erk and Preventing Its Nuclear Translocation.

Colorectal cancer (CRC) growth and progression is frequently driven by RAS pathway activation through upstream growth factor receptor activation or through mutational activation of KRAS or BRAF. Here we describe an additional mechanism by which the RAS pathway may be modulated in CRC. PTPRS, a receptor-type protein tyrosine phosphatase, appears to regulate RAS pathway activation through ERK.

The non-canonical functions of p27(Kip1) in normal and tumor biology.

p27(Kip1) was first discovered as a key regulator of cell proliferation. The canonical function of p27(Kip1) is inhibition of cyclin-dependent kinase (CDK) activity. In addition to its initial identification as a CDK inhibitor, p27(Kip1) has also emerged as an intrinsically unstructured, multifunctional protein with numerous non-canonical, CDK-independent functions that exert influence on key processes such as cell cycle regulation, cytoskeletal dynamics and cellular plasticity, cell migration, and stem-cell proliferation and differentiation.

p27Kip1 inhibits the cell cycle through non-canonical G1/S phase-specific gatekeeper mechanism.

The cyclin-dependent kinase (CDK) inhibitor p27Kip1 has been shown to regulate cellular proliferation via inhibition of CDK activities. It is now recognized that p27Kip1 can regulate cellular processes through non-canonical, CDK-independent mechanisms. We have developed an inducible p27Kip1 model in cultured cells to explore CDK-independent p27Kip1 regulation of biological processes.

Assessing needs and assets for building a regional network infrastructure to reduce cancer related health disparities.

Significant cancer health disparities exist in the United States and Puerto Rico. While numerous initiatives have been implemented to reduce cancer disparities, regional coordination of these efforts between institutions is often limited. To address cancer health disparities nation-wide, a series of regional transdisciplinary networks through the Geographic Management Program (GMaP) and the Minority Biospecimen/Biobanking Geographic Management Program (BMaP) were established in six regions across the country.

Proliferative status regulates HDAC11 mRNA abundance in nontransformed fibroblasts.

Histone deacetylases (HDACs) are important determinants of gene transcription and other biological processes. HDAC11 is one of the least characterized HDACs and is the only member of the class IV HDAC family. Our studies examined the events that control the expression of the HDAC11 transcript.

Apoptosis of osteosarcoma cultures by the combination of the cyclin-dependent kinase inhibitor SCH727965 and a heat shock protein 90 inhibitor.

Osteosarcoma (OS) is an aggressive bone cancer typically observed in adolescents and young adults. Metastatic relapse accounts primarily for treatment failure, and obstacles to improving cure rates include a lack of efficacious agents. Our studies show apoptosis of OS cells prepared from localized and metastatic tumors by a novel drug combination: SCH727965 (SCH), a cyclin-dependent kinase inhibitor, and NVP-AUY922 (AUY) or other heat shock protein 90 inhibitor.

Vitamin E δ-tocotrienol induces p27(Kip1)-dependent cell-cycle arrest in pancreatic cancer cells via an E2F-1-dependent mechanism.

Vitamin E δ-tocotrienol has been shown to have antitumor activity, but the precise molecular mechanism by which it inhibits the proliferation of cancer cells remains unclear. Here, we demonstrated that δ-tocotrienol exerted significant cell growth inhibition pancreatic ductal cancer (PDCA) cells without affecting normal human pancreatic ductal epithelial cell growth. We also showed that δ-tocotrienol-induced growth inhibition occurred concomitantly with G(1) cell-cycle arrest and increased p27(Kip1) nuclear accumulation.

p53 promotes repair of heterochromatin DNA by regulating JMJD2b and SUV39H1 expression.

Constitutive heterochromatin (HC) is important for maintaining chromosome stability, but also delays the repair of DNA double-strand breaks (DSBs). DSB repair in complex mammalian genomes involves a fast phase (2-6 h) in which most of the breaks are rapidly repaired, and a slow phase (up to 24 h) in which the remaining damages in HC are repaired. We found that p53 deficiency delays the slow-phase DNA repair after ionizing irradiation.

A p27Kip1 mutant that does not inhibit CDK activity promotes centrosome amplification and micronucleation.

Mitotic catastrophe occurs when cells enter mitosis with damaged DNA or excess centrosomes. Cells overexpressing the centrosome protein CP110 or depleted of cyclin F, which targets CP110 for destruction, have more than two centrosomes and undergo mitotic catastrophe. Our studies show centrosome reduplication and mitotic catastrophe in osteosarcoma cells inducibly expressing a p27Kip1 mutant (termed p27K) that binds cyclins but not cyclin-dependent kinases (CDKs).

The Establishment of the First Cancer Tissue Biobank at a Hispanic-Serving Institution: A National Cancer Institute-Funded Initiative between Moffitt Cancer Center in Florida and the Ponce School of Medicine and Health Sciences in Puerto Rico.

Population-based studies are important to address emerging issues in health disparities among populations. The Partnership between the Moffitt Cancer Center (MCC) in Florida and the Ponce School of Medicine and Health Sciences (PSMHS) in Puerto Rico (the PSMHS-MCC Partnership) was developed to facilitate high-quality research, training, and community outreach focusing on the Puerto Rican population in the island and in the mainland, with funding from the National Cancer Institute. We report here the establishment of a Tissue Biobank at PSMHS, modeled after the MCC tissue biorepository, to support translational research projects on this minority population.

The cyclin-dependent kinase inhibitor SCH 727965 (dinacliclib) induces the apoptosis of osteosarcoma cells.

Although rare, osteosarcoma is an aggressive cancer that often metastasizes to the lungs. Toward the goal of developing new treatment options for osteosarcoma, we show that the cyclin-dependent kinase (CDK) inhibitor SCH 727965 (SCH) induces the apoptosis of several osteosarcoma cell lines including those resistant to doxorubicin and dasatinib. Cell lines prepared in our laboratory from patients who had received adjuvant chemotherapy and explants derived from a human osteosarcoma xenograft in mice were also responsive to SCH.

Blockade of protein geranylgeranylation inhibits Cdk2-dependent p27Kip1 phosphorylation on Thr187 and accumulates p27Kip1 in the nucleus: implications for breast cancer therapy.

We describe the design of a potent and selective peptidomimetic inhibitor of geranylgeranyltransferase I (GGTI), GGTI-2418, and its methyl ester GGTI-2417, which increases the levels of the cyclin-dependent kinase (Cdk) inhibitor p27(Kip1) and induces breast tumor regression in vivo. Experiments with p27(Kip1) small interfering RNA in breast cancer cells and p27(Kip1) null murine embryonic fibroblasts demonstrate that the ability of GGTI-2417 to induce cell death requires p27(Kip1). GGTI-2417 inhibits the Cdk2-mediated phosphorylation of p27(Kip1) at Thr187 and accumulates p27(Kip1) in the nucleus.

Inhibition of p27Kip1 gene transcription by mitogens.

How mitogens reduce the abundance of the cell cycle inhibitor p27(Kip1) is an important question, and regulation of p27(Kip1) translation and turnover has been described. Here we show that platelet-derived growth factor (PDGF) reduces the activity of the p27(Kip1) promoter and the abundance of the p27(Kip1) transcript in density-arrested mouse fibroblasts. Inhibition of p27(Kip1) gene expression by PDGF required protein synthesis and histone deacetylase activity but not Akt or ERK activity.

Identification of Aurora-A as a direct target of E2F3 during G2/M cell cycle progression.

Aurora-A is a centrosome kinase and plays a pivotal role in G(2)/M cell cycle progression. Expression of Aurora-A is cell cycle-dependent. Levels of Aurora-A mRNA and protein are low in G(1)/S, accumulate during G(2)/M, and decrease rapidly after mitosis.

Apoptosis of metastatic prostate cancer cells by a combination of cyclin-dependent kinase and AKT inhibitors.

Effective treatments for advanced prostate cancer are much needed. Toward this goal, we show apoptosis and impaired long-term survival of androgen-independent prostate cancer cells (PC3 and PC3 derivatives) co-treated with the cyclin-dependent kinase (CDK) inhibitor roscovitine and an AKT inhibitor (LY294002 or API-2). Apoptosis of PC3 cells by the drug combination required caspase-9 but not caspase-8 activity and thus is mitochondria-dependent.

Increased cyclin D3 expression significantly correlates with p27 nuclear positivity in gastrointestinal stromal tumors.

Gastrointestinal stromal tumors, the most common mesenchymal tumors of the gastrointestinal tract, are characterized by strong expression of c-Kit protein. Recently, it has been shown that gastrointestinal stromal tumors may also contain alterations of genes involved in the regulation of cell cycle. In this study, we evaluate the prevalence and clinical significance of cyclin D1 and D3, Ki-67, p27, and retinoblastoma protein expression in a group of 50 human gastrointestinal stromal tumors selected from the files of the Moffitt Cancer Center.