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. Design We performed liquid chromatography and tandem mass spectrometry (LC–MS/MS) untargeted analysis of 40 human CRC and normal paired samples and targeted, quantitative analysis of 81 human CRC and normal paired samples. We integrated analysis of lipidomics, quantitative reverse transcription-PCR, large scale gene expression, and spatial transcriptomics with public scRNASEQ data to characterize pattern, expression and cellular localisation of genes that produce and modify lipid mediators. Results Targeted, quantitative LC–MS/MS demonstrated a marked imbalance of pro-inflammatory mediators, with a dearth of resolving lipid mediators. In tumours, we observed prominent over-expression of arachidonic acid derivatives, the genes encoding their synthetic enzymes and receptors, but poor expression of genes producing pro-resolving synthetic enzymes and resultant lipoxins (LXA4, LXB4) and associated receptors. These results indicate that CRC is the product of defective lipid class switching likely related to inadequate or ineffective levels of PGE2/PGD2. Conclusion We show that the lipidomic profile of CRC tumours exhibits a distinct pro-inflammatory bias with a deficiency of endogenous resolving mediators secondary to defective lipid class switching. These observations pave the way for ‘resolution medicine’, a novel therapeutic approach for inducing or providing resolvins to mitigate the chronic inflammation driving cancer growth and progression.

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). Methods: We classified 2250 primary and metastatic human CRC tumors by consensus molecular subtypes (CMS). For each tumor, we generated multiple gene expression signature scores measuring MEK pathway activation, MEKi “bypass” resistance, SRC activation, dasatinib sensitivity, EMT, PC1, Hu-Lgr5-ISC, Hu-EphB2-ISC, Hu-Late TA, Hu-Proliferation, and WNT activity. We carried out correlation, survival and other bioinformatic analyses. Validation analyses were performed in two independent publicly available CRC tumor datasets (n = 585 and n = 677) and a CRC cell line dataset (n = 154). Results: Here we report a central role of SRC in mediating “bypass”-resistance to MEK inhibition (MEKi), primarily in cancer stem cells (CSCs). Our integrated and comprehensive gene expression signature analyses in 2250 CRC tumors reveal that MEKi-resistance is strikingly-correlated with SRC activation (Spearman P < 10^–320), which is similarly associated with EMT (epithelial to mesenchymal transition), regional metastasis and disease recurrence with poor prognosis. Deeper analysis shows that both MEKi-resistance and SRC activation are preferentially associated with a mesenchymal CSC phenotype. This association is validated in additional independent CRC tumor and cell lines datasets. The CMS classification analysis demonstrates the strikingly-distinct associations of CMS1-4 subtypes with the MEKi-resistance and SRC activation. Importantly, MEKi + SRCi sensitivities are predicted to occur predominantly in the KRAS mutant, mesenchymal CSC-like CMS4 CRCs. Conclusions: Large human tumor gene expression datasets representing CRC heterogeneity can provide deep biological insights heretofore not possible with cell line models, suggesting novel repurposed drug combinations. We identified SRC as a common targetable node–-an Achilles’ heel–-in MEKi-targeted therapy-associated resistance in mesenchymal stem-like CRCs, which may help development of a biomarker-driven drug combination (MEKi + SRCi) to treat problematic subpopulations of CRC.

Background. Psoriasis and cutaneous T‐cell lymphoma (CTCL) expose patients to chronic inflammation as well as physical and psychological disabilities, but the impact of such alterations on cognitive function is unknown. Objective. This study is aimed at determining if CTCL and psoriasis impact cognitive functioning in relation to psychological and health‐related quality of life (HR‐QOL) status. Methods. A cross‐sectional study was performed in an outpatient dermatology clinic of a university teaching hospital. Thirty‐nine subjects with CTCL (N = 20) or psoriasis (N = 19) who met eligibility criteria were included. The cognitive domains of memory, attention and processing speed, and executive function were assessed with standard neuropsychological tests. Subjects were assessed for depression, anxiety, and HR‐QOL (using the SKINDEX‐29 questionnaire). Results. Study participants were CTCL and psoriasis subjects; cognitive impairment was found in the domain of memory in 17.9% subjects with CTCL or psoriasis. Lower scores on executive function tests were predicted by higher (worse HR‐QOL) SKINDEX‐29 functioning scores (p = 0.01). A higher estimated baseline intellectual functioning predicted lower scores (better HR‐QOL) on the symptoms and functioning domains of SKINDEX‐29 (p = 0.01 and 0.02, respectively) and a statistical trend (p = 0.07) for the emotion domain. Memory and acute anxiety were adversely impacted by shorter disease duration (p = 0.01 for both). Conclusions. Memory impairment may be associated comorbidity in CTCL and psoriasis. Subjects with stronger cognitive resources appear to cope better with health‐related quality of life (HR‐QOL) challenges.

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. We have hypothesized that much of this resistance may pass through SRC as a common signal transduction node, and that inhibition of SRC may suppress MEK inhibition resistance mechanisms. CRC tumors of the Consensus Molecular Subtype (CMS) 4, enriched in stem cells, are difficult to successfully treat and have been suggested to evade traditional chemotherapy agents through resistance mechanisms. Here, we evaluate targeting two pathways simultaneously to produce an effective treatment by overcoming resistance. We show that combining Trametinib (MEKi) with Dasatinib (SRCi) provides enhanced cell death in 8 of the 16 tested CRC cell lines compared to treatment with either agent alone. To be able to select sensitive cells, we simultaneously evaluated a validated 18-gene RAS pathway activation signature score along with a 13-gene MEKi resistance signature score, which we hypothesize predict tumor sensitivity to this dual targeted therapy. We found the cell lines that were sensitive to the dual treatment were predominantly CMS4 and had both a high 18-gene and a high 13-gene score, suggesting these cell lines had potential for de novo MEKi sensitivity but were subject to the rapid development of MEKi resistance. The 13-gene score is highly correlated to a score for SRC activation, suggesting resistance is dependent on SRC. Our data show that gene expression signature scores for RAS pathway activation and for MEKi resistance may be useful in determining which CRC tumors will respond to the novel drug combination of MEKi and SRCi.

Background: Thirty years ago, the “sphingosine rheostat” model proposed a pro-survival/pro-apoptotic role for sphingosine-1-phosphate/ceramide in tumor cells. In cancer, ceramide-derived sphingosine-1-phosphate increases, raising the sphingosine-1-phosphate/ceramide ratio, whereas in normal tissue ceramide synthesis predominates. We hypothesize that the rheostat presents more relevance in the context of immune and stromal components rather than tumor epithelial cells and may govern both inflammation and immunosuppression. Methods: Quantitative liquid chromatography–tandem mass spectrometry analysis of the sphingosine-1-phosphate/ceramide pathway was performed in resected primary ( n = 480) and in metastatic colorectal cancer tumors ( n = 94). An integrative multi-omics approach combined high-throughput quantitative real time PCR, targeted lipidomics, a large gene-expression dataset ( n = 2,373), clinical data, standard as well as high-definition spatial transcriptomics, and public single cell RNA-sequencing. Results: Metastatic colorectal cancer specimens showed enrichment in sphingosine-1-phosphate and sphinganine-1-phosphate, whereas ceramide (24:1) was decreased. Gene-expression analysis and quantitative real time PCR confirmed increased sphingosine-1-phosphate and sphinganine-1-phosphate synthesizing enzymes (SPHK1) and receptors S1PR3-5 in metastatic colorectal cancer vs. primary colorectal cancer. Cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) and public single cell RNAseq data analysis showed SPHK1/S1PR3 expression was predominant in stromal, and immune tumor microenvironment cells, whereas SPHK2 predominated in epithelial cells. A three-gene sphingosine-1-phosphate signature was associated with stromal enrichment, myeloid derived suppressor cells, M2 macrophages, advanced stage, poor survival, nodal infiltration and weak to negative correlations with validated checkpoint inhibitor response scores. Conclusions: Metastatic colorectal cancer lesions display a sphingosine-1-phosphate /ceramide imbalance with negative associations to patient prognosis and checkpoint inhibitor response gene-signatures. These findings reposition the rheostat as primarily active in the immunosuppressive tumor microenvironment rather than in tumor cells. Our findings warrant the exploration of new therapeutic strategies potentially rebalancing the sphingosine-1-phosphate/ceramide ratio, reprograming the immunosuppressive tumor microenvironment and enhancing immunotherapy responses, thereby addressing an unmet need in colorectal cancer treatment.