In cancer progression, tumor microenvironments progressively become denser and hypoxic, and cell migrate toward higher oxygen levels as they invade across the tumor-stromal boundary. While cell invasion dependence on optimal collagen density is well appreciated, it remains unclear whether past oxygen conditions alter future invasion phenotype of cells. Here, we show that normal human mammary epithelial cells (MCF10A) and leader-like human breast tumor cells (BT549) undergo higher rates of invasion and collagen deformation after past exposure to hypoxia, compared to normoxia controls. Upon increasing collagen density by ∼50%, cell invasion under normoxia reduced, as expected due to the increased matrix crowding. However, surprisingly, past hypoxia increased cell invasion in future normoxic dense collagen, with more pronounced invasion of cancer cells. This culmination of cancer-related conditions of hypoxia history, tumor cell, and denser collagen led to more aggressive invasion phenotypes. We found that hypoxia-primed cancer cells produce laminin332, a basement membrane protein required for cell-matrix adhesions, which could explain the additional adhesion feedback from the matrix that led to invasion after hypoxia priming. Depletion of Cdh3 disrupts the hypoxia-dependent laminin production and thus disables the rise in rates of cancer cell invasion and collagen deformation caused by hypoxia memory. These findings highlight the importance of considering past oxygen conditions in combination with current mechanical composition of tissues to better understand tumor invasion in physically evolving tumor microenvironments.

Cells exhibit a mysterious form of selective heritable short-term memory, influencing outcomes as diverse as cell fate decisions in embryos and environmental responses in cancer cells and bacteria. Here, we present a simple theoretical framework explaining how this selective memory can arise from the reactions regulating molecular levels in cells. Our key insight is that related cells retain more similar molecular concentrations relative to random cells when a greater variance of possible concentration states is created during a single cell generation than is created by cell division across a population. This persistence of molecular similarity down a lineage constitutes a form of heritable short-term memory. We identify the biochemical networks that produce, modify, and degrade molecules as an underexplored source of these additional molecular concentration states. Using experimentally informed simulations, we find that the strength and duration of molecular similarity down a lineage depend on tunable network properties, explaining why some cellular traits persist only briefly while others last generations. These contributions to molecular concentration variance from biochemical reaction networks act in concert with gene expression and other regulatory processes to shape the protein composition of cells. Our framework yields clear, testable predictions for determining how biochemical network architectures drive non-genetic cellular inheritance.