Abstract
Cancer cells at the invasive front directly interact with stromal tissue that provides a microenvironment with mechanical, nutrient, and oxygen supply characteristics distinct from those of intratumoral tissues. It has long been known that cancer cells at the invasive front and cancer cells inside the tumor body exhibit highly differentiated functions and behaviors. However, it is unknown whether cancer cells at different locations exhibit a variety of autophagic flux, an important catabolic process to maintain cellular homeostasis in response to environmental changes. Here, using transmission electron microscopy (TEM), we found that invading cancer cells at the invasive front, which show mesenchymal transcriptomic traits, exhibit higher autophagic flux than cancer cells inside the tumor body in human primary non-small cell lung cancer (NSCLC) tissues. This autophagic feature was further confirmed by a live cell autophagic flux monitoring system combined with a 3D organotypic invasion coculture system. Additionally, the increased autophagic flux endows cancer cells with invasive behavior and positively correlates with the advanced tumor stages and the reduced survival period of lung cancer patients. These findings expand the understanding of autophagic dynamics during cancer invasion.
Highlights
Metastasis is the leading cause of cancer-related deaths
We studied autophagic flux in cancer cells at different locations in human primary non-small cell lung cancers (NSCLCs) using ultrathin-section transmission electron microscopy (TEM)
To precisely locate the invasive front in lung cancer tissues, we prescreened resin-embedded semi-thick sections of primary human lung cancer tissues, including two squamous lung cancers (LUSC) and two lung adenocarcinomas (LUAD), by toluidine blue staining, and the invasive front region was subjected to further TEM analysis (Figure 1A)
Summary
Metastasis is the leading cause of cancer-related deaths. Metastasis begins with local invasion, whereby cancer cells at the primary site invade the surrounding tissues and migrate towards the vascular systems. Solid tumors are highly heterogeneous and can often be anatomically classified into areas of the leading edge and tumor body [1,2,3]. Cancer cells at different locations are exposed to microenvironments with distinct mechanical, nutrient, oxygen supply, and pH characteristics [4], which affect their transcriptomics, metabolism, and signaling cascades and resulting in dysregulated cellular behaviors [5,6,7]. Macroautophagy/autophagy (hereafter referred to as autophagy), a multistep lysosomal degradation pathway that supports nutrient recycling and metabolic adaptation, has been considered as a process that regulates cancer survival during stresses [11]. Autophagy induction may inhibit tumors initiation [12], evidence in mouse models demonstrates that autophagy inhibition can limit the growth of established tumors and improve the response to cancer therapeutics [13, www.aging-us.com
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