Comparative transcriptome of normal and cancer-associated fibroblasts.

BACKGROUND: The characteristics of a tumor are largely determined by its interaction with the surrounding micro-environment (TME). TME consists of both cellular and non-cellular components. Cancer-associated fibroblasts (CAFs) are a major component of the TME. They are a source of many secreted factors that influence the survival and progression of tumors as well as their response to drugs. Identification of markers either overexpressed in CAFs or unique to CAFs would pave the way for novel therapeutic strategies that in combination with conventional chemotherapy are likely to have better patient outcome. METHODS: Fibroblasts have been derived from Benign Prostatic Hyperplasia (BPH) and prostate cancer. RNA from these has been used to perform a transcriptome analysis in order to get a comparative profile of normal and cancer-associated fibroblasts. RESULTS: The study has identified 818 differentially expressed mRNAs and 17 lincRNAs between normal and cancer-associated fibroblasts. Also, 15 potential lincRNA-miRNA-mRNA combinations have been identified which may be potential biomarkers. CONCLUSIONS: This study identified differentially expressed markers between normal and cancer-associated fibroblasts that would help in targeted therapy against CAFs/derived factors, in combination with conventional therapy. However, this would in future need more experimental validation.

Linoleoyl-lysophosphatidylcholine suppresses immune-related adverse events due to immune checkpoint blockade.

Immune related adverse events (irAEs) after immune checkpoint blockade (ICB) therapy occur in a significant proportion of cancer patients. To date, the circulating mediators of ICB-irAEs remain poorly understood. Using non-targeted mass spectrometry, here we identify the circulating bio-active lipid linoleoyl-lysophosphatidylcholine (LPC 18:2) as a modulator of ICB-irAEs. In three independent human studies of ICB treatment for solid tumor, loss of circulating LPC 18:2 preceded the development of severe irAEs across multiple organ systems. In both healthy humans and severe ICB-irAE patients, low LPC 18:2 was found to correlate with high blood neutrophilia. Reduced LPC 18:2 biosynthesis was confirmed in preclinical ICB-irAE models, and LPC 18:2 supplementation in vivo suppressed neutrophilia and tissue inflammation without impacting ICB anti-tumor response. Results indicate that circulating LPC 18:2 suppresses human ICB-irAEs, and LPC 18:2 supplementation may improve ICB outcomes by preventing severe inflammation while maintaining anti-tumor immunity.

Gene expression signature of castrate resistant prostate cancer.

Prostate gland is a highly androgen dependent gland and hence the first line of treatment for metastatic prostate cancer happens to be androgen ablation. This is achieved by multiple non-surgical methods. However, most of these cancers although respond well initially, become resistant to androgen ablation sooner or later. These cancers then become extremely aggressive and difficult to treat, thereby drastically affect the patient prognosis. Identification of a gene expression signature for castrate resistant prostate cancer may aid in identification of mechanisms responsible for castrate resistance, which in turn would help in better management of the disease. METHODS: Patient samples belonging to a. Control group; b. Castrate Sensitive group and c. Castrate Resistant group were collected. Gene expression profiling was performed on these samples using RNA-seq. Differentially expressed genes between control and castrate sensitive as well as control and castrate resistant groups were identified. This data was compared with data from The Cancer Genome Atlas (TCGA) in order to get relevance in prognosis. RESULTS: We have identified 481 differentially expressed genes between control and castrate sensitive groups; and 446 genes differentially expressed between control and castrate resistant groups. We have also identified 364 genes which are expressed in the castrate resistant group alone, which is of interest since these may have an implication in evolution of castrate resistance and also prognosis. When compared to prostate cancer data from TCGA, 763 genes were found in common to our dataset. With this, a CaS and CaR signature was defined. Using criteria such as overall survival, disease-free survival, progression-free survival and biochemical recurrence, we have identified genes that may have relevance in progression to castrate resistance and in prognosis. Functional annotation of these genes may give an insight into the mechanism of development of castrate resistance.

Non-canonical Estrogen Signaling in Endocrine Resistance.

Breast cancer is one of the leading causes of cancer related deaths in women worldwide. The disease is extremely heterogenous. A large percentage of the breast cancers are dependent on estrogen signaling and hence respond to endocrine therapies which essentially block the estrogen signaling. However, many of these tumors emerge as endocrine resistant tumors. Many mechanisms have been proposed to explain the emergence of endocrine resistance, which include mutations in the estrogen receptors, cross-talk with other signaling pathways, cancer stem cells etc. This review is focused on the role of non-canonical estrogen receptor signaling in endocrine resistance. Most of the therapeutics which are used currently are targeting the major receptor of estrogen namely ER-α. Last two decades has witnessed the discovery of alternate forms of ER-α, as well as other receptors for estrogen such as ERRgamma, GPER-1 as well as ER-ß, which are activated not only by estrogen, but also by the therapeutic agents such as tamoxifen that are routinely used in treatment of breast cancer. However, when the alternate receptors are activated, they result in activation of membrane signaling which subsequently activates pathways such as MAPK and GPCR leading to cell-proliferation. This renders the anticipated anti-estrogenic effects of tamoxifen less effective or ineffective. Future research in this area has to focus on the alternate mechanisms and develop a combinatorial strategy, which can complement the existing therapeutics to get better outcome of endocrine therapies.