Phenotypic Plasticity and Cancer: A System Biology Perspective.

Epithelial-to-mesenchymal transition (EMT) is a major axis of phenotypic plasticity not only in diseased conditions such as cancer metastasis and fibrosis but also during normal development and wound healing. Yet-another important axis of plasticity with metastatic implications includes the cancer stem cell (CSCs) and non-CSC transitions. However, in both processes, epithelial (E) and mesenchymal (M) phenotypes are not merely binary states. Cancer cells acquire a spectrum of phenotypes with traits, properties, and markers of both E and M phenotypes, giving rise to intermediary hybrid (E/M) phenotypes. E/M cells play an important role in tumor initiation, metastasis, and disease progression in multiple cancers. Furthermore, the hybrid phenotypes also play a major role in causing therapeutic resistance in cancer. Here, we discuss how a systems biology perspective on the problem, which is implicit in the 'Team Medicine' approach outlined in the theme of this Special Issue of The Journal of Clinical Medicine and includes an interdisciplinary team of experts, is more likely to shed new light on EMT in cancer and help us to identify novel therapeutics and strategies to target phenotypic plasticity in cancer.

A Nexus between Genetic and Non-Genetic Mechanisms Guides KRAS Inhibitor Resistance in Lung Cancer.

Several studies in the last few years have determined that, in contrast to the prevailing dogma that drug resistance is simply due to Darwinian evolution-the selection of mutant clones in response to drug treatment-non-genetic changes can also lead to drug resistance whereby tolerant, reversible phenotypes are eventually relinquished by resistant, irreversible phenotypes. Here, using KRAS as a paradigm, we illustrate how this nexus between genetic and non-genetic mechanisms enables cancer cells to evade the harmful effects of drug treatment. We discuss how the conformational dynamics of the KRAS molecule, that includes intrinsically disordered regions, is influenced by the binding of the targeted therapies contributing to conformational noise and how this noise impacts the interaction of KRAS with partner proteins to rewire the protein interaction network. Thus, in response to drug treatment, reversible drug-tolerant phenotypes emerge via non-genetic mechanisms that eventually enable the emergence of irreversible resistant clones via genetic mutations. Furthermore, we also discuss the recent data demonstrating how combination therapy can help alleviate KRAS drug resistance in lung cancer, and how new treatment strategies based on evolutionary principles may help minimize or even preclude the emergence of drug resistance.

Awareness, perspectives and satisfaction levels among patients with psoriatic arthritis: a multicentric cross-sectional survey.

Perception of the disease and its management impacts patients with Psoriatic arthritis (PsA) to a great degree. Studies examining patients' viewpoints and perception of their disease and its management are scarce. This multicentric cross-sectional survey was undertaken to understand the perspectives of patients with PsA. A survey questionnaire with items on demographics, awareness about their disease, treatment, physical therapy, quality of life and satisfaction with the care received was designed. After internal and external validation, a pilot survey was conducted, and the questionnaire was finalized. The final survey (with translations in local languages) was carried out at 17 centres across India. There were 262 respondents (56% males) with mean age of 45.14 ± 12.89 years. In 40%, the time lag between onset of symptoms and medical assessment for it was more than a year. In most of the patients, the diagnosis of PsA was made by a rheumatologist. Over 83% of patients were consulting their rheumatologist periodically as advised and fully compliant with the treatment. Lack of time and cost of therapy were the most common reasons for non-adherence to therapy. Eighty-eight patients (34%) were not fully satisfied with their current treatment. Over two-third of patients had never seen a physiotherapist due to barriers including a lack of time, pain, and fatigue. The daily activities and employment status were affected in nearly 50% of patients with PsA. The current survey has identified a gap in patients' awareness levels and helps healthcare providers in understanding the varied perceptions of patients with PsA. Addressing these issues in a systematic manner would potentially improve the treatment approaches, outcomes, and patient satisfaction levels.