M3L4 Epithelial-stromal crosstalk in cancer

  • Microenvironment promotes dissemination and colonisation\

  • Cancer associated fibroblast (CAF)

    • Mesenchymal (-ve for epithelial, endothelial, leukocyte markers)

    • No cancer mutations

    • Elongated shape

  • Different types of CAFs

    • May may depend of their origin

    • Differ in responsiveness to growth factors and drivers of CAF phenotype

    • Multiple functions

  • CAFs promote malignant transformation

  • Loss of TGFb2 receptor in CAFs can drive prostate cancer progression

  • CAFs ‘lead the way’ for tumour cells

    • Remodeling the ECM, making it easier for cancer cells to move through

  • Some CAFs are irreversibly altered, while others are reversible

  • At early stages of disease CAFs can activate the immune system and suppress cancer, though mostly afterwards they take on a pro-tumour role

  • Pre-metastatic niche - cancer cells can release factors to prime the pre-metastatic site to make it more favourable for establishing metastases

  • Drug resistance - site of the stromal cells affect drug resistance

    • Most studies show that stromal cells promote drug resistance

    • Stromal-induced EMT induces drug resistance

  • Cancer cells express bone specific markers (osteomimicry) to resist therapy, possibly to disguise as a body cell

  • BMP signalling enriched in stromal progenitors in transcriptomics of cell populations in MM bone microenvironment

    • MM bone disease reversed by BMP blockade

    • BMP-induced prevented by BMSCs, but not seen in cancer cells cultured with stromal cells

  • CAFs and BMSCs promote mitochondrial transfer to cancer cells to alter metabolism via formation of tunnelling nanotubules, EVs or connexin channels

    • Reverse Warburg effect??

  • Tumour promotes bone and bone promotes tumour (??)

    • Tumour cells release factors that activate osteoclasts and osteoclasts which then activate tumour cells, mediated by RANKL

  • Anti-RANKL - treatment of cencer induced bone disease

  • PCa cells compete with HSCs for endosteal HSC niche, increasing niche size promotes metastasis and HSC mobilisation protocols mobilise PCa cells ffrom niche to circulation (??) to target via chemo

  • Reactivation of dormant cells

  • Blocking dormant niche interactions

  • Senescence in TME

    • Aged stroma shows MDSC (myeloid derived suppressor cell) accumulation

    • Suppresses cytotoxic T cells and avoids immunosurveillance 

  • In vitro methods - difficult to study TME

    • Monoculture - understanding cancer cells

    • Transwell - can separate cell types, understand contact/migration

    • Conditioned media - understanding secreted factors

    • Coculture - multiple cell types, understanding interactions

    • Organoids - better 3D architecture, cell-cell interactions modeling

  • In vivo -

    • Neghbour labelling cells

      • Allows stroma to be labeled by cancer cells they come into contact with

      • Understanding cell interactions rather than bulk populations

    • Intravital imaging

      • Imaging different sites and track over time

  • Barcodes can be used to label cancer cells to see which metastasised, understand the differences, which ones are proliferating, how they interact with stroma…

  • Targeting tumour-stroma

    • ECM

    • Angiogenesis

    • CAF depletion

    • Engineered mesenchymal stromal cell (MSC)