Transcriptomic Analysis Reveals Early Alterations Associated with Intrinsic Resistance to Targeted Therapy in Lung Adenocarcinoma Cell Lines.

Lung adenocarcinoma is the most prevalent form of lung cancer, and drug resistance poses a significant obstacle in its treatment. This study aimed to investigate the overexpression of long non-coding RNAs (lncRNAs) as a mechanism that promotes intrinsic resistance in tumor cells from the onset of treatment. Drug-tolerant persister (DTP) cells are a subset of cancer cells that survive and proliferate after exposure to therapeutic drugs, making them an essential object of study in cancer treatment. The molecular mechanisms underlying DTP cell survival are not fully understood; however, long non-coding RNAs (lncRNAs) have been proposed to play a crucial role. DTP cells from lung adenocarcinoma cell lines were obtained after single exposure to tyrosine kinase inhibitors (TKIs; erlotinib or osimertinib). After establishing DTP cells, RNA sequencing was performed to investigate the differential expression of the lncRNAs. Some lncRNAs and one mRNA were overexpressed in DTP cells. The clinical relevance of lncRNAs was evaluated in a cohort of patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA). RT-qPCR validated the overexpression of lncRNAs and mRNA in the residual DTP cells and LUAD biopsies. Knockdown of these lncRNAs increases the sensitivity of DTP cells to therapeutic drugs. This study provides an opportunity to investigate the involvement of lncRNAs in the genetic and epigenetic mechanisms that underlie intrinsic resistance. The identified lncRNAs and CD74 mRNA may serve as potential prognostic markers or therapeutic targets to improve the overall survival (OS) of patients with lung cancer.

Transcriptional signature of early cisplatin drug-tolerant persister cells in lung adenocarcinoma.

Resistance to cisplatin is the main cause of treatment failure in lung adenocarcinoma. Drug-tolerant-persister (DTP) cells are responsible for intrinsic resistance, since they survive the initial cycles of treatment, representing a reservoir for the emergence of clones that display acquired resistance. Although the molecular mechanisms of DTP cells have been described, few studies have investigated the earliest molecular alterations of DTP cells in intrinsic resistance to cisplatin. In this work, we report a gene expression signature associated with the emergence of cisplatin-DTP cells in lung adenocarcinoma cell lines. After a single exposure to cisplatin, we sequenced the transcriptome of cisplatin-DTPs to identify differentially expressed genes. Bioinformatic analysis revealed that early cisplatin-DTP cells deregulate metabolic and proliferative pathways to survive the drug insult. Interaction network analysis identified three highly connected submodules in which SOCS1 had a significant participation in controlling the proliferation of cisplatin-DTP cells. Expression of the candidate genes and their corresponding protein was validated in lung adenocarcinoma cell lines. Importantly, the expression level of SOCS1 was different between CDDP-susceptible and CDDP-resistant lung adenocarcinoma cell lines. Moreover, knockdown of SOCS1 in the CDDP-resistant cell line partially promoted its susceptibility to CDDP. Finally, the clinical relevance of the candidate genes was analyzed in silico, according to the overall survival of cisplatin-treated patients from The Cancer Genome Atlas. Survival analysis showed that downregulation or upregulation of the selected genes was associated with overall survival. The results obtained indicate that these genes could be employed as predictive biomarkers or potential targets to improve the effectiveness of CDDP treatment in lung cancer patients.

The systemic-level repercussions of cancer-associated inflammation mediators produced in the tumor microenvironment.

The tumor microenvironment is a dynamic, complex, and redundant network of interactions between tumor, immune, and stromal cells. In this intricate environment, cells communicate through membrane-membrane, ligand-receptor, exosome, soluble factors, and transporter interactions that govern cell fate. These interactions activate the diverse and superfluous signaling pathways involved in tumor promotion and progression and induce subtle changes in the functional activity of infiltrating immune cells. The immune response participates as a selective pressure in tumor development. In the early stages of tumor development, the immune response exerts anti-tumor activity, whereas during the advanced stages, the tumor establishes mechanisms to evade the immune response, eliciting a chronic inflammation process that shows a pro-tumor effect. The deregulated inflammatory state, in addition to acting locally, also triggers systemic inflammation that has repercussions in various organs and tissues that are distant from the tumor site, causing the emergence of various symptoms designated as paraneoplastic syndromes, which compromise the response to treatment, quality of life, and survival of cancer patients. Considering the tumor-host relationship as an integral and dynamic biological system, the chronic inflammation generated by the tumor is a communication mechanism among tissues and organs that is primarily orchestrated through different signals, such as cytokines, chemokines, growth factors, and exosomes, to provide the tumor with energetic components that allow it to continue proliferating. In this review, we aim to provide a succinct overview of the involvement of cancer-related inflammation at the local and systemic level throughout tumor development and the emergence of some paraneoplastic syndromes and their main clinical manifestations. In addition, the involvement of these signals throughout tumor development will be discussed based on the physiological/biological activities of innate and adaptive immune cells. These cellular interactions require a metabolic reprogramming program for the full activation of the various cells; thus, these requirements and the by-products released into the microenvironment will be considered. In addition, the systemic impact of cancer-related proinflammatory cytokines on the liver-as a critical organ that produces the leading inflammatory markers described to date-will be summarized. Finally, the contribution of cancer-related inflammation to the development of two paraneoplastic syndromes, myelopoiesis and cachexia, will be discussed.

Partners in crime: The feedback loop between metabolic reprogramming and immune checkpoints in the tumor microenvironment.

The tumor microenvironment (TME) is a complex and constantly changing cellular system composed of heterogeneous populations of tumor cells and non-transformed stromal cells, such as stem cells, fibroblasts, endothelial cells, pericytes, adipocytes, and innate and adaptive immune cells. Tumor, stromal, and immune cells consume available nutrients to sustain their proliferation and effector functions and, as a result of their metabolism, produce a wide array of by-products that gradually alter the composition of the milieu. The resulting depletion of essential nutrients and enrichment of by-products work together with other features of the hostile TME to inhibit the antitumor functions of immune cells and skew their phenotype to promote tumor progression. This review briefly describes the participation of the innate and adaptive immune cells in recognizing and eliminating tumor cells and how the gradual metabolic changes in the TME alter their antitumor functions. In addition, we discuss the overexpression of the immune checkpoints and their ligands as a result of nutrient deprivation and by-products accumulation, as well as the amplification of the metabolic alterations induced by the immune checkpoints, which creates an immunosuppressive feedback loop in the TME. Finally, the combination of metabolic and immune checkpoint inhibitors as a potential strategy to treat cancer and enhance the outcome of patients is highlighted.