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Mesenchymal stem cells (MSCs) that accumulate in the primary tumor due to their natural tropism for inflammatory tissues enhance the metastatic potential of tumor cells through direct interactions with tumor cells or paracrine signaling within the tumor microenvironment. MSCs also undergo senescence, which leads to increased production of pro-inflammatory cytokines and matrix-degrading enzymes. Senescence is a critical mechanism of limiting abnormal growth and cancer development through tumor suppression; however, senescent cells that accumulate in tissues eventually develop a senescence-associated secretory phenotype that alters the microenvironment to promote cancer. Increased understanding of the biophysical properties of senescent MSCs and how they mediate cell-cell interactions in the tumor may be useful in identifying novel biomarkers for senescent stromal cells in tissues or aggressive cancer cells that form in an aging stroma. A high-content single cell biophysical approach was used to define the mechanical properties of pre- and post- senescent MSCs. Our data shows post-senescent MSCs are larger and less motile, with more homogeneous mechanical properties than their pre-senescent counterparts. A robust molecular screening approach combining genome-wide microarray analysis with mass spec-based proteomics was used to establish the molecular differences in pre- and post- senescent MSCs. Our data show a consistent correlation of up and down regulated gene and peptide expression. A 3D co-culture model was used to assess the effects of pre- and post- senescent MSCs on breast cancer cell motility and invasion in 3D collagen gels. Post-senescent MSCs induced an invasive breast cancer cell phenotype, characterized by increased spreading of breast cancer cells in collagen, increased numbers of invading cells, and morphological elongation of breast cancer cells. Surprisingly, this invasive breast cancer cell behavior was further amplified when breast cancer cells were co-cultured with both pre- and post- senescent cells.
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Topological defects in the mesothelium suppress ovarian cancer cell clearance
We investigated an in vitro model for mesothelial clearance, wherein ovarian cancer cells invade into a layer of mesothelial cells, resulting in mesothelial retraction combined with cancer cell disaggregation and spreading. Prior to the addition of tumor cells, the mesothelial cells had an elongated morphology, causing them to align with their neighbors into well-ordered domains. Flaws in this alignment, which occur at topological defects, have been associated with altered cell density, motion, and forces. Here we identified topological defects in the mesothelial layer, and showed how they affected local cell density by producing a net flow of cells inward or outward, depending on defect type. At locations of net inward flow, mesothelial clearance was impeded. Hence, the collective behavior of the mesothelial cells, as governed by the topological defects, affected tumor cell clearance and spreading. Importantly, our findings were consistent across multiple ovarian cancer cell types, suggesting a new physical mechanism that could impact ovarian cancer metastasis.
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- Award ID(s):
- 1660703
- PAR ID:
- 10276098
- Date Published:
- Journal Name:
- APL bioengineering
- ISSN:
- 2473-2877
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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