Speaker's Highlight

• Don Sin University of British Columbia, St. Paul Hospital (Canada)
  Kenneth R. Chapman Toronto General Hospital Research Institute (Canada)
• Parameswaran Nair McMaster University (Canada)
  Carolyn Calfee UCSF (U.S.A.)
• Gregory P. Downey University of Colorado School of Medicine (U.S.A.)
  David A. Schwartz University of Colorado School of Medicine (U.S.A.)
• Neil Schluger Tuberculosis Control Branch, California Department of Public Health (U.S.A.)
  Nick Kim Critical Care & Sleep Medicine, University of California San Diego (U.S.A.)
• Nicola Hananiah Baylor College of Medicine (U.S.A.)
  Jae-Joon Yim Seoul National University College of Medicine (Republic of Korea)
• Koichiro Asano Tokai University School of Medicine (Japan)
  Diahn-Warng Perng Taipei Veterans General Hospital (Taiwan)
• Konstantinos Kostikas University of Ioannina (Greece)
  Karin Klooster University Medical Center Groningen (Kingdom of the Netherlands)

• Long non-coding RNAs shaping lung cancer progression in Australia and beyond

  Lung cancer remains the leading cause of cancer-related mortality worldwide, accounting for roughly 1.8 million deaths annually. In Australia, the Australian Institute of Health and Welfare reports more than 8,000 deaths from the disease each year, and Indigenous Australians carry a disproportionately high burden. Long non-coding RNAs have emerged as pivotal regulators of tumour biology, and researchers from Perth to Brisbane are mapping how these molecules drive lung cancer progression. Their findings are reshaping early detection, prognosis, and treatment.

  Once dismissed as genomic noise, long non-coding RNAs are now recognised as essential players in gene regulation. These transcripts, longer than 200 nucleotides, do not encode proteins but interact with DNA, RNA, and proteins to influence cellular behaviour. In lung cancer, their dysregulation contributes to uncontrolled proliferation, invasion, and metastasis. The molecular pathways they govern overlap with those driving other serious pulmonary conditions, an area of active exploration within respiratory medicine.

  Molecular mechanisms driving tumour behaviour

  Long non-coding RNAs operate through several distinct mechanisms that converge on cancer hallmarks. One well-studied mode is chromatin remodelling, where lncRNAs recruit histone-modifying complexes to silence or activate target genes. The lncRNA ANRIL, for instance, interacts with polycomb repressive complex 1 to silence tumour suppressors in non-small cell lung cancer. Other transcripts act in the nucleus as scaffolds for transcription factors, or in the cytoplasm as competing endogenous RNAs that sponge microRNAs and relieve repression of oncogenic mRNAs.

  The competing endogenous RNA hypothesis has gained substantial traction in Australian laboratories. Studies at the Garvan Institute of Medical Research in Sydney have mapped ceRNA networks that amplify EGFR signalling in lung adenocarcinoma. These networks create a layered regulatory system where a single lncRNA can alter the expression of hundreds of downstream genes, giving tumours a remarkable capacity to adapt to cellular stress.

  Key lncRNAs with context-dependent roles

  MALAT1 is one of the most extensively characterised lncRNAs in lung cancer, where it promotes tumour cell survival and metastatic spread. HOTAIR, encoded within the HOXC cluster, drives invasion by recruiting the PRC2 complex to silence developmental genes. Australian researchers at the Peter MacCallum Cancer Centre have contributed key data on how these transcripts remodel the tumour microenvironment.

  Equally important are lncRNAs with tumour-suppressive roles. GAS5 is frequently downregulated in lung cancer tissues, and its loss correlates with accelerated disease progression. H19, while oncogenic in many contexts, shows tissue-specific behaviour that complicates therapeutic targeting. These examples illustrate that lncRNA function is highly context-dependent, a recurring theme that Australian pathologists discuss at meetings of the Thoracic Society of Australia and New Zealand.

  Metastasis and the epithelial-to-mesenchymal transition

  Metastatic spread accounts for the vast majority of lung cancer deaths, and lncRNAs sit at the heart of this process. The epithelial-to-mesenchymal transition enables tumour cells to detach, migrate, and colonise distant sites. MALAT1 regulates splicing factors that control EMT-related transcripts, while HOTAIR alters chromatin accessibility at mesenchymal gene loci. Together, they orchestrate the cellular plasticity that makes metastasis so lethal.

  Targeting these pathways remains technically demanding. RNA-based therapeutics must reach tumour cells without triggering innate immune responses, and Australian delivery platforms are being refined to meet that challenge. Lipid nanoparticle technology, familiar to anyone who queued for a booster at their local GP, is being adapted for inhaled administration. Early work suggests that direct airway delivery could achieve high local concentrations while limiting systemic exposure.

  Diagnostic and prognostic biomarker potential

  Circulating lncRNAs offer a tantalising prospect for non-invasive cancer detection. Several transcripts, including MALAT1 and H19, are detectable in plasma and sputum, and their levels correlate with tumour burden. Researchers at the University of Melbourne are validating panels of these molecules as screening tools for high-risk populations, including long-term smokers and people with asbestos exposure histories related to sites such as Wittenoom. Early results suggest that lncRNA signatures could complement low-dose computed tomography.

  Prognostic applications are equally promising. High HOTAIR expression associates with reduced overall survival in multiple cohorts, while low GAS5 predicts resistance to platinum-based chemotherapy. Integrating lncRNA panels into routine pathology reporting could refine risk stratification and guide adjuvant therapy decisions. The Pharmaceutical Benefits Scheme already reimburses several targeted agents for lung cancer, and biomarker-driven prescribing aligns with Australia's push towards value-based healthcare.

  Therapeutic targeting and clinical translation

  Therapeutic strategies against lncRNAs include antisense oligonucleotides, small interfering RNAs, and small molecule inhibitors that disrupt RNA-protein interactions. Preclinical work has shown that MALAT1 knockdown reduces metastasis in murine models, though delivery to the lung remains a hurdle. Parallel advances in interventional pulmonology are reshaping clinical practice, and recent work summarised in the role of pulmonary artery denervation in pulmonary hypertension highlights how procedural approaches can complement pharmacological ones.

  Combination regimens are likely to yield the greatest benefit. Pairing lncRNA-targeted therapy with immune checkpoint blockade could overcome resistance mechanisms that currently limit response rates. Clinical trial infrastructure in Australia, coordinated through the Australian Clinical Trials Network, places the country in a strong position to contribute to international studies. Patients in Melbourne and Sydney already access next-generation agents through hospital-based early-phase programmes, and expanding that access remains a national priority.

  Australian research landscape and future directions

  The next wave of lncRNA research will integrate single-cell sequencing, spatial transcriptomics, and machine learning to map cell-to-cell variation within tumours. Australian teams are well represented in these consortia, and NHMRC funding supports ambitious multi-centre programmes. Public engagement will be equally critical, because lung cancer carries a stigma that can delay diagnosis. Community initiatives that pair health messaging with popular events help normalise conversations about symptoms and screening.

  Sporting occasions sometimes carry that message further than clinical pamphlets. Charity days at professional golf tournaments have raised funds for respiratory research, and similar partnerships could be replicated locally. Bringing molecular discoveries into everyday conversation requires creative platforms, from fundraising at Adelaide Hills football clubs to national awareness campaigns timed around the Aussie summer. Continued investment in basic science, combined with equitable access to emerging therapies, will determine whether lncRNA research translates into meaningful survival gains.

  A concrete next step for clinicians is to review current lncRNA biomarker literature over the next quarter and identify which panels could realistically be incorporated into multidisciplinary team discussions within twelve months.

  Richard Russell Nuffield Department of Clinical Medicine, University of Oxford (United Kingdom)
• Mona Bafadhel King’s College London (United Kingdom)
  David Jackson Guy’s and St Thomas’ Hospital, King’s College London (United Kingdom)
• James Chalmers University of Dundee (United Kingdom)
  David Price University of Aberdeen (United Kingdom)