M3L7 Clinical implications of the tumour niche

  • Metastatic tumours have high genomic instability, low intratumour heterogeneity and strong accumulation of SVs

  • Magnitude of differences between primary and metastatic tumours is cancer type specific and influenced by exposure to treatments

  • Halsted & Cady-Fisher theories of cancer progression

    • Halsted theory (1890s): Cancer spreads in a predictable, orderly manner—first locally, then to regional lymph nodes, and finally to distant sites.

      Cady-Fisher theory (1970s): Cancer is a systemic disease from the outset, with early potential for distant spread; tumor biology, not just local invasion, determines progression.

    • Both patterns can be seen

  • Pancreatic cancer - originally studied for the important role of the TME

    • PDAC stem cells have high Hh signalling —> desmoplastic signalling (fibroblast proliferation, ECM deposition/fibrosis)

    • Hypothesis - Hh inhibitor (vesmodegib) + gemcitabine (chemo) will reduce fibrotic stroma and enhance delivery of chemotherapy agents

      • Works well in KPC mice but not in humans, causes the tumour to become more invasive without stroma

      • KPC mouse model (KRAS, P53 mutated and Cre to activate mutations in pancreas specifically)

  • Targetting primary tumour niche - to eradicate primary, shrink the primary for curative surgery, prevent metastasis, augment effects of other modalities, abscopal effects (targetting TME of primary tumour increases antigen presentation to immune system to promote targeting of metastases)

    • Primary tumour includes fibroblasts, vasculature, lymphatics, hypoxia. immune system, clonal interactions/evolution

  • Targeting vasculature - inhibiting VEGF to prevent neoangiogenesis (eg. bevacizumab/Avastin)

    • Provided reproducible survival benefit

    • Very tumour type specific

    • Switching off VEGF enables vessel co-option, tumour co-opts pre-existing blood vessels —> more aggressive phenotype

    • Increased hypoxia activates other transcriptional programs causing more aggressive phenotype

  • Targeting lymphatics - eg using albumin nanoparticle containing PI3Ky inhibitor and paclitaxel in combination with alpha-PD1

    • Induces breast cancer remission in mice

  • Targeting hypoxia - electron-affinic radiosensitisers, enhancing tumour oxygenation, hypoxia-activated pridrugs, acidosis, downstream targeting (most successful)

  • Targeting immune microenvironment - eg. checkpoint inhibitors, adoptive T cell therapy, cancer vaccines etc

    • Immune cells don’t behave in isolation

    • Interactions between CAFs and immune microenvironment governs largely the success of therapies

    • CAFs can secrete immune modulators, regulating the matrisome or metabolome, antigen presentation etc

  • Clonal interactions

    • Tumour has a dominant clone and less dominant sub-clones

    • Dominant clones can outcompete sub-clones