Tumour Cell Biology Laboratory, The Francis Crick Institute, London, United Kingdom.
Department of Pathology, Kitasato University, Sagamihara, Japan.
Elife. 2023 Mar 9;12:e76520. doi: 10.7554/eLife.76520.
Cancers, such as squamous cell carcinoma, frequently invade as multicellular units. However, these invading units can be organised in a variety of ways, ranging from thin discontinuous strands to thick 'pushing' collectives. Here we employ an integrated experimental and computational approach to identify the factors that determine the mode of collective cancer cell invasion. We find that matrix proteolysis is linked to the formation of wide strands but has little effect on the maximum extent of invasion. Cell-cell junctions also favour wide strands, but our analysis also reveals a requirement for cell-cell junctions for efficient invasion in response to uniform directional cues. Unexpectedly, the ability to generate wide invasive strands is coupled to the ability to grow effectively when surrounded by extracellular matrix in three-dimensional assays. Combinatorial perturbation of both matrix proteolysis and cell-cell adhesion demonstrates that the most aggressive cancer behaviour, both in terms of invasion and growth, is achieved at high levels of cell-cell adhesion and high levels of proteolysis. Contrary to expectation, cells with canonical mesenchymal traits - no cell-cell junctions and high proteolysis - exhibit reduced growth and lymph node metastasis. Thus, we conclude that the ability of squamous cell carcinoma cells to invade effectively is also linked to their ability to generate space for proliferation in confined contexts. These data provide an explanation for the apparent advantage of retaining cell-cell junctions in squamous cell carcinomas.
癌症，如鳞状细胞癌，通常以多细胞单位的形式侵袭。然而，这些侵袭单位可以以多种方式组织，从稀薄的不连续链到厚的“推进”集体。在这里，我们采用综合的实验和计算方法来确定决定细胞集体侵袭模式的因素。我们发现，基质蛋白水解与宽链的形成有关，但对侵袭的最大程度影响不大。细胞-细胞连接也有利于宽链，但我们的分析还揭示了细胞-细胞连接对于在均匀的定向信号下有效侵袭的要求。出乎意料的是，生成宽侵袭链的能力与在三维测定中被细胞外基质包围时有效生长的能力相关。对基质蛋白水解和细胞-细胞黏附的组合扰动表明，无论是在侵袭还是生长方面，最具侵袭性的癌症行为都是在高水平的细胞-细胞黏附和高水平的蛋白水解下实现的。与预期相反，具有经典间充质特征的细胞（没有细胞-细胞连接和高蛋白水解）表现出生长和淋巴结转移减少。因此，我们得出结论，鳞状细胞癌有效侵袭的能力也与其在有限的环境中产生增殖空间的能力有关。这些数据为保留鳞状细胞癌中的细胞-细胞连接的明显优势提供了一种解释。
